Category Archive Anatomy A – Z

Clonal Selection and B-Cell Differentiation

B cells mature in the bone marrow, where they undergo VDJ recombination to produce unique receptors that do not react to self-antigens.

B cells are lymphocytes that play a large role in the humoral immune response (as opposed to the cell-mediated immune response, which is governed by T cells). B cells primarily function to make antibodies against antigens, act as antigen-presenting cells (APCs), and eventually develop into memory B cells to provide long-term immunity. B cells undergo clonal selection and develop similarly to T cells with some notable differences.

B Cell Development

Immature B cells are produced in the bone marrow of most mammals. Their development occurs through several stages, each representing a change in the genome content at the antibody loci. An antibody is composed of two identical light (L) and two identical heavy (H) chains and the genes specifying them are found in the V (variable) region and C (constant) region. The heavy-chain V region has three segments, V, D and J. These segments recombine randomly in a process called VDJ recombination to produce a unique variable domain in the immunoglobulin of each individual B cell.

Similar rearrangements occur for the light-chain V region but with only two segments involved: V and J. When the B cell fails in any step of the maturation process, it will die by apoptosis, here called a clonal deletion. This is a form of positive selection. B cells are also tested for autoreactivity through negative selection. If these B cells have a high affinity for binding to self-antigens, they will die by clonal deletion or another pathway such as energy.

B Cell Activation

B cell activation refers to the differentiation and clonal expansion of B cells. When the B cell receptor on the cell surface matches its cognate antigen in the body, the B cell proliferates and secretes a free form of those receptors (antibodies) in the body, with binding sites identical to those on the original cell surface. However, B cell recognition of antigens is not the only element necessary for B cell activation. B cells that have not been exposed to an antigen, also known as naïve B cells, can be activated in a T cell-dependent or independent manner.

• T cell-dependent activation is the activation of B cells by type 2 helper T cells in the lymph nodes.
• T cell-independent activation occurs when antigens directly bind to B cells themselves, usually through cross-linking the antigen to the B cell receptor or receiving the antigen with a toll-like receptor.

 

T-dependent B cell activation: T cell-dependent B cell activation, showing a TH2-cell (left), B cell (right), and several interaction molecules.

B Cell Differentiation and Clonal Expansion

After activation, the B cell undergoes differentiation and clonal expansion, which usually involves migration to germinal centers if the activation takes place in a lymph node. B cell differentiation is the process by which B cells change into different types, such as plasma cells and plasmablasts. Clonal expansion is the process by which daughter cells arise from a parent cell. During B cell clonal expansion, many copies of that B cell are produced that share affinity with and specificity of the same antigen.

Clonal Selection

Clonal selection is a theory stating that B cells express antigen-specific receptors before antigens are ever encountered in the body. After B cell activation, the B cells clone themselves through clonal expansion, but during each cellular division, random mutations occur that gradually increase the binding affinity for B cell-produced antibodies to antigens.

For example, memory B cells that differentiate after an adaptive immune response are thought to undergo clonal selection so that antibodies produced by newer memory B cells have considerably higher binding affinities to their antigens. This theory may explain why secondary immune responses from memory cells are so effective that repeated infections by the same pathogen are stopped before symptoms even develop. Following the initial infection, random mutations during clonal selection could produce memory B cells that can more easily bind to antigens than can the original B cells.

Structure and Function of Antibodies

An antibody is a Y-shaped protein produced by B cells to identify and neutralize antigens in the body.

An antibody (formally called immunoglobulin) is a large Y-shaped glycoprotein produced by B-cells and used by the immune system to identify and neutralize pathogens. Antibodies are produced by B cells, and are either secreted into circulation or remain expressed on the surface of the B cell.

Structure of Antibodies

The antibody recognizes a unique part of an antigen (foreign object). Each tip of the “Y” of an antibody contains a paratope (a structure analogous to a lock) that is specific for one particular epitope (similarly analogous to a key) on an antigen, allowing these two structures to bind together with precision. Using this binding mechanism, an antibody can neutralize its target directly or tag it for attack by other parts of the immune system.

 

Antibody: Each antibody binds to a specific antigen, an interaction similar to a lock and key.

Antibodies are glycoproteins belonging to the immunoglobulin superfamily, typically made of basic structural units each with two large heavy chains and two small light chains. Most antibodies exist as a monomer, in which they have a single “Y” shaped sub-unit, but some antibodies can exist as dimers (two subunits) or pentamers (five subunits). The paratope is considered a hypervariable region and has the same specificity and antigen-binding affinity as the B cell receptor of the B cell that created the antibody. In some isotypes, the tail end of the antibody is called the constant region and faces away from the “Y-shaped” paratope ends, functioning as an Fc tail to which phagocytes can bind.

Isotypes

Five different isotypes of antibodies each perform different functions and are generally found in different parts of the body.

• IgA: A dimer secreted into mucosal surfaces, such as the gut, respiratory tract, and urogenital tract, that prevents mucosal invasion into the body by pathogens. It is resistant to the proteolytic enzymes found in the gastrointestinal mucosae.
• IgD: Functions mainly as an antigen receptor on B cells that have not been exposed to antigens. It has been shown to activate basophils and mast cells to produce antimicrobial factors.
• IgE: Found in circulation and binds to allergens, triggering histamine release from mast cells and basophils. Also protects against parasitic worms.
• IgG: Has four different forms and provides the majority of antibody-based immunity against invading pathogens as the best opsonin of any type of antibody. This is because it expresses a tail for Fc receptors on phagocytes to bind to, which activates phagocytosis. It is the only antibody capable of crossing the placenta to give passive immunity to fetus and can activate the classical complement system.
• IgM: Expressed on the surface of B cells (monomer) and in a secreted pentamer with very high avidity. Eliminates pathogens in the early stages of B cell-mediated (humoral) immunity before there is sufficient IgG. Like IgG, it can also activate the classical complement system.

Function of Antibodies

Circulating antibodies are produced by clonal B cells that specifically respond to only one antigen. Antibodies contribute to immunity in three ways: preventing pathogens from entering or damaging cells by binding to them (neutralization); stimulating the removal of pathogens by macrophages and other cells by coating the pathogen (opsonization); and triggering the destruction of pathogens by stimulating other immune responses such as the complement pathway. The complement system starts a long cascade of protein productions that either opsonize a pathogen for phagocytosis or lyse it directly by forming a membrane attack complex. During opsonization, the antibody expresses the tail for an Fc receptor on a macrophage, neutrophil, or natural killer cell. The immune cell will then bind to the antibody’s Fc tail instead of the pathogen itself, which speeds up the process of finding pathogens to phagocytize. Additionally, because antibodies have two or more paratopes, they can sometimes link pathogens together, making phagocytosis more efficient.

Role of the Complement System in Immunity

The complement system is the ability of antibodies and phagocytic cells to remove pathogens from an organism.

The complement system or “complements” the ability of antibodies and phagocytic cells to clear pathogens from an organism. The complement system consists of a number of small proteins found in the blood, generally synthesized by the liver as a part of the acute phase reaction during systemic inflammation (from TNF-alpha release). When stimulated by one of several triggers, proteases in the system cleave specific proteins to release cytokines and initiate an amplifying cascade of further cleavages. The end result of this activation cascade is massive amplification of the response and activation of the cell-killing membrane attack complex (also called MAC). There are three different pathways by which the complement system may occur.

Classical Complement Pathway

The classical complement pathway is the main pathway by which the complement system occurs. It is comprised of a cascade of many steps with complement proteins cleaving one another in sequential order:

• The antibody binds to an antigen on the surface of a pathogen, activating the C1 complement protein.
• C1 acts as a protease and cleaves C2 and C4 to form C4b2b.
• C42b converts C3 into C3a and C3b, which forms a C5 convertase.
• C5 convertase cleaves C5 into C5a and C5b.
• C5b forms a complex with C6, C7, and then C8, and C9, which becomes the membrane attack complex that lyses the pathogen.

Note that C5a has a number of other functions in the immune system, such as causing vasodilation during inflammation and stimulating neutrophil chemotaxis. Additionally, the body’s cells express a glycoprotein called decay accelerating factor, which decays C3 and C5 convertase on the body’s cells. This factor prevents membrane attack complexes from forming on the body’s cells under normal conditions.

 

The Classical and Alternative Complement Pathways: The classical and alternative complement pathways start off differently, but end in the same cascade of complement proteins that combine to form a membrane attack complex.

The Alternative Complement Pathway

The alternative pathway may be a leftover evolutionary precursor to the classical pathway. Unlike the classical pathway, the alternative pathway is generally activated by microbial inflammatory mediators instead of antibodies. For example, lipopolysaccharide, the toxin of gram-negative bacteria, may activate this pathway. The steps for the alternative pathway are:

• The pathogenic antigen (such as LPS) activates C3 so it creates a C3B complex
• Factor D cleaves the C3B complex so that C3bBb is created.
• C3bBb is a C3 convertase, which converts more C3 into C3a and C3b.
• Similar to the classical pathway, C3b forms a C42b complex, and the rest of the steps are essentially the same as the classical pathway, ending with C5b forming a membrane attack complex with C6, C7, C8, and C9.

Lectin Pathway

The lectin pathway is not caused by antibody binding, but by a carbohydrate -binding-protein called mannan-binding-lectin (MBL). It is an acute-phase reactant produced in the liver and binds to the carbohydrates on the surfaces of many pathogens. The steps for the lectin pathway are:

• MBL binds to the carbohydrates on a pathogen.
• Proteases bound on the other side of the MBL cleaves C4 into C4a and C4b.
• C4b creates C3 convertase, and the rest of the steps happen identically to the classical pathway from the C3 convertase step.

Problems with the Complement System

The complement system might play a role in diseases with an immune component, such as Barraquer-Simons Syndrome, asthma, lupus erythematosus, glomerulonephritis, various forms of arthritis, autoimmune heart disease, multiple sclerosis, inflammatory bowel disease, ischemia-reperfusion injuries, and rejection of transplanted organs. The complement system is also becoming increasingly implicated in diseases of the central nervous system such as Alzheimer’s disease and other neurodegenerative conditions such as spinal cord injuries. Additionally, deficiencies in complement proteins produced in the liver can lead to a form of primary (congenital) immunodeficiency, in which the body is more susceptible to disease, particularly autoimmune diseases and severe bacterial infections.

Immunological Memory

Immunological memory refers to the ability of B and T cells to produce long-lived memory cells that defend against specific pathogens.

When B and T cells begin to replicate during an adaptive immune response, some offspring become long-lived memory cells. These memory cells remember all specific pathogens encountered during the animal’s lifetime and can thus call forth a stronger response, called the secondary immune response, if the pathogen ever invades the body again. The adaptive immune system is so-named because it is a result of an adaptation to an infection. Immunological memory can either exist in active long-term memory or passive short-term memory.

 

Immune response: When B and T cells begin to replicate, some of the offspring that they produce will end up becoming long-lived memory cells. These memory cells will remember all specific pathogens encountered during the animal’s lifetime and can thus call forth a strong response if the pathogen ever invades the body again.

Passive Memory

Newborn infants are particularly vulnerable to infections since they have no prior exposure to pathogens. Thus, the mother protects the infant through several layers of passive protection. During pregnancy, IgG, a certain isotype of antibody, is transported to the baby from the mother through the placenta, so even babies have high levels of antibodies with similar antigen specificities as the mother. Even breast milk contains antibodies that are transferred to the infant’s gastrointestinal tract and protect against bacterial infections until the baby is capable of making its own antibodies. Since the fetus isn’t making any memory cells or antibodies, this is called passive immunity. Passive immunity is short-lived, ranging from a couple days to a couple months.

As the infant matures, their thymus and bone marrow work to raise a stock of mature lymphocytes that form the foundation for the infant’s personal adaptive immune system. Because the passive memory comes from antibodies instead of B cells themselves, infants do not inherit long-term immunological memory from the mother. Even if the infant receives antibodies specific to certain diseases from its mother, the infant wouldn’t be able to bolster a long-term memory that would direct antigen exposure and presentation.

Active Memory and Immunization

Following an infection, long-term active memory is acquired by activation of B and T cells. Memory cells derive from their parent B and T cells, and undergo clonal selection following infection, which increases antigen-binding affinity. Following reinfection, the secondary immune response typically eliminates the pathogen before symptoms of an infection can occur. During the secondary immune response, memory T cells rapidly proliferate into active helper and cytotoxic T cells specific to that antigen, while memory B cells rapidly produce antibodies to neutralize the pathogen. Long-term active memory consists of rapid response and form permanent immunological memory so long as those memory cells survive.

Vaccinations take advantage of memory lymphocyte development by artificially-generating active immunity, a process called immunization. During a vaccination, the antigen of a pathogen is introduced into the body and stimulates the immune system to develop a specific immunity against that pathogen. It doesn’t cause the disease that the pathogen brings because the vaccine uses an attenuated form of the pathogen that contains the same antigen but doesn’t have the capacity for replication. This deliberate introduction of the pathogen is successful since it exploits the immune system’s natural specificity and inducibility. Vaccination is an extremely effective manipulation of the immune system that helps fight diseases. Over the course of vaccine development, they have saved countless lives, and diseases like rubella and polio are not the widespread causes of disability they once were.

Despite the effectiveness of vaccines, methods do not yet exist to develop vaccines for every pathogen. Many pathogens undergo mutations that change the expression of their antigens, making immunization attempts fruitless for diseases like the common cold or norovirus. Many parasitic pathogens, such as the plasmodium protist that causes malaria, haven’t successfully been vaccinated against because it is challenging to develop a vaccine that is strong enough to stimulate an immune response (sufficient immunogenicity) without causing a live infection.

Major Histocompatibility Complex Antigens (Self-Antigens)humoral immune response

The major histocompatibility complex (MHC) is a cell surface molecule that regulates interactions between white blood cells and other cells.

Major histocompatibility complex (MHC) is a cell-surface molecule encoded by a large gene family in all vertebrates. MHC molecules mediate the interactions of leukocytes with other leukocytes or body cells. MHC determines the compatibility of donors for organ transplant as well as one’s susceptibility to an autoimmune disease via cross-reacting immunization. In humans, MHC is also called human leukocyte antigen (HLA), because MHC can often act as an antigen for human leukocytes.

Types of MHC

MHC is a polymorphic protein attached to the surface of cells. Three different classes of MHC differ in structure and function in the immune system but are all encoded by the same set of gene sequences.

• MHC I is presented on all cells of the body. It contains an epitope that forms the structural binding site for an antigen. MHC I interacts with natural killer (NK) cells and cytotoxic T cells to signal whether a cell is a self or non-self and whether it contains an antigen-specific to that T cell.
• MHC II is presented mainly on macrophages, dendritic cells, and helper T cells, which are all involved in antigen presentation. It has a longer helical region than MHC I, which allows it to bind to CD4 (helper T cells) during antigen presentation.
• MHC III is a secreted enzyme that is neither membrane-bound nor involved in antigen presentation like MHC I and II. It is merely included as an MHC protein because it is encoded by the same set of genes. It is involved in the production of complement proteins and inflammatory cytokines.

During antigen processing prior to presentation, protein peptides from pathogens and MHC (I or II) travel through the cytoplasm and then to the cell membrane surface. A complex series of vesicles enables MHC transport from the cell, and the endoplasmic reticulum and Golgi bodies facilitate this transport during antigen processing. After processing, the MHC can present the peptide antigen bound to it to naive T cells.

 

MHC Class I processing: MHC class I pathway: proteins in the cytosol are degraded by the proteasome, liberating peptides internalized by the TAP channel in the endoplasmic reticulum, there associating with MHC-I molecules freshly synthesized. MHC-I/peptide complexes enter the Golgi apparatus, are glycosylated, enter secretory vesicles, fuse with the cell membrane, and externalize on the cell membrane interacting with T lymphocytes.

 

MHC Class I: MHC class I protein molecule.

 

MHC Class II: MHC class II protein molecule.

HLA and Organ Rejection

Organ transplantation is a complex procedure that can potentially cure many chronic diseases and acute injuries. However, surgically replaced organs are often rejected by the body’s immune system. MHC is also called human leukocyte antigen (HLA) and varies considerably among different members of the same species. If the T and B cells of the body recognize the HLA of the graft as foreign, they will attack the organ graft. The damage in organ rejection can be acute or chronic, cell-mediated or antibody-mediated, and often involves diffuse damage of the graft that causes necrosis and infarction ( tissue death from lack of oxygen) to the graft tissue by attacking its vascular components.

In nearly all cases, immunosuppressive chemotherapy is a requirement for successful organ transplantation. These drugs can stop acute organ rejection after the procedure, but will not stop chronic organ rejection, in which gradual vascular lesions and endothelial thickening slowly kill the graft. If an organ donor has HLA similar to that of the recipient, the risk of organ rejection is reduced. However, this isn’t feasible for heart, liver, or lung transplants because there generally isn’t enough time in these cases to find a matching organ donor.

Antigens and Antigen Receptors

Antigens are molecules that initiate the immune response and can be bound by antibodies.

In immunology, an antigen is a substance that evokes an immune response. Formally they are defined as a substance that causes the production of antibodies specific to that antigen, however they also cause T cell-mediated immune responses, and may lead to an inflammatory response. The substance may be from the external environment or formed within the body. The immune system will try to destroy or neutralize any antigen that is recognized as a foreign and potentially harmful invader.” Self” antigens are usually tolerated by the immune system; whereas “non-self” antigens can be identified as invaders and can be attacked by the immune system.

Molecular Structure of Antigens

At the molecular level, an antigen is characterized by its ability to be “bound” at the antigen-binding site of an antibody. Antibodies tend to discriminate between the specific molecular structures presented on the surface of the antigen. Antigens are usually either proteins, peptides, or polysaccharides. This includes parts (coats, capsules, cell walls, flagella, fimbriae, and toxins) of bacteria, viruses, and other microorganisms. Lipids and nucleic acids are antigenic only when combined with proteins and polysaccharides. For example, the combination of lipids and polysaccharides are lipopolysaccharides (LPS), which are the primary component of gram-negative bacterial endotoxin. LPS forms the cell wall of gram-negative bacteria and causes a powerful immune response when bound. Cells present their immunogenic-antigens to the immune system via a major histocompatibility (MHC) molecule. Depending on the antigen presented and the type of the histocompatibility molecule, several types of immune cells can become activated due to an antigen.

Antigens have several structural components of interaction that may be bound by different classes of antibodies. Each of these distinct structural components is considered to be an epitope, also called an antigenic determinant. Therefore, most antigens have the potential to be bound by several distinct antibodies, each of which is specific to a particular epitope. The antigen binding receptor on an antibody is called a paratope and is specific to the epitope of the antigen. Using the “lock and key” metaphor, the antigen itself can be seen as a string of keys – any epitope being a “key” – each of which can match a different lock.

Types of Antigens

Antigens are categorized into broad classes of antigens based on their origin. So many different molecules can function as an antigen in the body, and there is considerable diversity even within these categories.

These are the main classes of antigens that are involved in immune system activation. Their diversity is analogous to the immense diversity of the diseases that the immune system works to overcome.

Exogenous Antigens

Exogenous antigens are antigens that have entered the body from the outside, for example by inhalation, ingestion, or injection. Exogenous antigens are the most common kinds of antigens and include pollen or foods that may cause allergies, as well as the molecular components of bacteria and other pathogens that could cause an infection.

Endogenous Antigens

Endogenous antigens are that have been generated within previously normal cells as a result of normal cell metabolism or because of viral or intracellular bacterial infection (which both change cells from the inside in order to reproduce). The fragments are then presented on the surface of the infected cells in the complex with MHC class I molecules.

 Autoantigens

Autoantigens are normal “self” proteins or complex of proteins or nucleic acid that is attacked by the host’s immune system, causing an autoimmune disease. These antigens should, under normal conditions, not be the target of the immune system, but due to mainly genetic and environmental factors, the normal immunological tolerance for such an antigen has been lost.

Tumor Antigens (Neoantigens)

These antigens are presented by MHC I or MHC II molecules on the surface of tumor cells. These antigens result from a tumor-specific mutation during the malignant transformation of normal cells into cancer cells. Despite expressing this antigen, many tumors have developed ways to evade antigen recognition and immune system killing.

Native Antigens

A native antigen is an antigen that is not yet processed by an APC to smaller parts. T cells cannot bind native antigens, but require that they be digested and processed by APCs, whereas B cells can be activated by native ones without prior processing.

Neoantigens

Neoantigens are those that are entirely absent from the normal human genome. As compared with nonmutated self-proteins, neoantigens are of relevance to tumor control, as the quality of the T cell pool that is available for these antigens is not affected by central T cell tolerance. Technology to systematically analyze T cell reactivity against neoantigens became available only recently.^[rx] Neoantigens can be directly detected and quantified through a method called MANA-SRM developed by a molecular diagnostics company, Complete Omics Inc., through collaborating with a team in Johns Hopkins University School of Medicine.^[rx]

Viral antigens

For virus-associated tumors, such as cervical cancer and a subset of head and neck cancers, epitopes derived from viral open reading frames contribute to the pool of neoantigens.^[rx]

Complete Antigens and Haptens

Haptens are molecules that create an immune response when attached to proteins.

Antigens are basic molecules that induce an immune response when detected by immune system cells. Antigens may be either complete or incomplete based on the nuances of their molecule structure.

Haptens

A hapten is essentially an incomplete antigen. These small molecules can elicit an immune response only when attached to a large carrier such as a protein; the carrier typically does not elicit an immune response by itself. Many hapten carriers are normal molecules that circulate through the body. When haptens and carriers combine, the resulting molecule is called an adduct, the combination of two or more molecules. Haptens cannot independently bind to MHC complexes, so they cannot be presented to T cells.

The first haptens used were aniline and its carboxyl derivatives (o-, m-, and p-aminobenzoic acid). One well-known hapten is urushiol, the toxin found in poison ivy and a common cause of cell-mediated contact dermatitis. When absorbed through the skin from a poison ivy plant, urushiol undergoes oxidation in the skin cells to generate the actual hapten, a reactive molecule called a quinone, which then reacts with skin proteins to form hapten adducts. Usually, the first exposure causes only sensitization, in which there is a proliferation of helper and cytotoxic T cells. After a second exposure, the proliferated T cells can become activated, generating an immune reaction and producing the characteristic blisters of poison ivy exposure.

Fluorescein Molecule: Fluorescein is an example of a hapten used in molecular biology.

Antigenic Determinants and Processing Pathways of Antigens

Antigen epitopes make it possible for the immune system to recognize pathogens.

An epitope, also known as an antigenic determinant, is the part of an antigen that is recognized by the immune system, specifically by antibodies, B cells, and T cells. The latter can use epitopes to distinguish between different antigens, and only binds to their specific antigen. In antibodies, the binding site for an epitope is called a paratope. Although epitopes are usually derived from non-self proteins, sequences derived from the host that can be recognized are also classified as epitopes. Epitopes determine how antigen binding and antigen presentation occur.

Types of Antigenic Determinants

The epitopes of protein antigens are divided into two categories based on their structures and interaction with the paratope.

• A conformational epitope is composed of discontinuous sections of the antigen’s amino acid sequence. These epitopes interact with the paratope based on the 3-D surface features and tertiary structure (overall shape) of the antigen. Most epitopes are conformational.
• Linear epitopes interact with the paratope based on their primary structure (shape of the protein’s components). A linear epitope is formed by a continuous sequence of amino acids from the antigen, which creates a “line” of sorts that builds the protein structure.

Antigenic determinants recognized by B cells and the antibodies secreted by B cells can be either conformational or linear epitopes. Antigenic determinants recognized by T cells are typically linear epitopes. T cells do not recognize polysaccharides or nucleic acid antigens. This is why polysaccharides are generally T-independent antigens and proteins are generally T-dependent antigens. The determinants need not be located on the exposed surface of the antigen in its original form, since recognition of the determinant by T cells requires that the antigen be first processed by antigen-presenting cells. Free peptides flowing through the body are not recognized by T cells, but the peptides associate with molecules coded for by the major histocompatibility complex (MHC). This combination of MHC molecules and peptides is recognized by T cells.

Antigen-Processing Pathways

Antigen-Binding Site of an Antibody: Antigen-binding sites can recognize different epitopes on an antigen.

Overview of Adaptive Immunity

The adaptive immune system is composed of highly specialized systemic cells and processes that eliminate or prevent pathogenic growth.

The adaptive immune system, also known as the specific immune system, is composed of highly specialized systemic cells and processes that eliminate or prevent pathogenic growth. The adaptive immune system works to protect and heal the body when the innate immune system fails. It provides the body with the ability to recognize and remember specific pathogens through their antigens. This mechanism allows the immune system to mount stronger attacks each time the pathogen is encountered, thus preparing itself for future challenges and preventing reinfection by the same pathogen.

Functions of the Adaptive Immune System

The adaptive immune system starts to work after the innate immune system is activated. If the infection progresses despite the inflammation, fever, natural killer (NK) cell, and phagocyte activity of the innate immune system, a more coordinated response is required in order to destroy the pathogen. The adaptive immune response occurs a few days after the innate immune response is initiated. The major functions of the adaptive immune system include:

• The recognition of specific “non-self” antigens in the presence of “self” during the process of antigen presentation
• The generation of responses that are tailored to maximally eliminate specific pathogens or pathogen-infected cells
• The development of immunological memory in which each pathogen is “remembered” by a signature antibody, which can then be called upon to quickly eliminate a pathogen should subsequent infections occur.

Formation of Adaptive Immunity

Adaptive immunity is triggered when a pathogen evades the innate immune system for long enough to generate a threshold level of an antigen. An antigen is any molecule that induces an immune response, such as a toxin or molecular component of a pathogen cell membrane, and is unique to each species of pathogen. A typical adaptive immune response includes several steps:

• The antigen for the pathogen is taken up by an antigen-presenting cell (APC), such as a dendritic cell or macrophage, through phagocytosis.
• The APC travels to a part of the body that contains immature T and B cells, such as a lymph node.
• The antigen is processed by the APC and bound to MHC class II receptors and MHC class I receptors on the cell membrane of the APC.
• The antigen is presented to immature helper T cells and cytotoxic T cells through binding the MHC II (helper T) or MHC I (cytotoxic T) to T-cell receptors.
• These T lymphocytes mature and proliferate. Helper T cells activate B cells, which proliferate and produce antibodies specific to the antigen, while cytotoxic T cells destroy pathogens that bear the antigen that was presented to them by the APCs.
• Memory B and T cells are formed after the infection ends.

Immunological Memory

When B cells and T cells are activated, some become memory cells. Throughout the lifetime of an animal, these memory cells form a database of effective B and T lymphocytes. Upon interaction with a previously encountered antigen, the appropriate memory cells are selected and activated. In this manner, the second and subsequent exposures to an antigen produce a stronger and faster immune response. This is “adaptive” because the body’s immune system prepares itself for future challenges, which can stop an infection by the same pathogen before it can even cause symptoms.

Antibody: An antibody is made up of two heavy chains and two light chains. The unique variable region allows an antibody to recognize its matching antigen

Immunological memory can either be in the form of passive short-term memory or active long-term memory. Passive memory is usually short-term, lasting between a few days and several months, and is particularly important for newborn infants, who are given passive memory from maternal antibodies and immune cells before birth. Active immunity is generally long-term and can be acquired by infection followed by B cells and T cells activation, or artificially acquired by vaccines in a process called immunization.

The memory system does have a few flaws. Pathogens that undergo mutation often have different antigens than those known by memory B and T cells, meaning that different strains of the same pathogen can avoid the memory-enhanced immune response. Additionally, the memory cell function enables the development of hypersensitivity disorders, such as allergies and many chronic diseases (like multiple sclerosis or myasthenia gravis). In these cases, memory cells form for an antigen that elicits an immune response without actually being caused by a pathogen, which leads to immune system-mediated damage to the body from mast cell, antibody, or T-cell mediated activities and inflammation.

Types of Adaptive Immunity

The adaptive immune response is mediated by B and T cells and creates immunity memory.

The adaptive immune system mounts a stronger, antigen-specific immune response after the innate immune response fails to prevent a pathogen from causing an infection. There are two subdivisions of the adaptive immune system: cell-mediated immunity and humoral immunity.

Cell-Mediated Immunity

Cell-mediated immunity is controlled by type 1 helper T cells (T_h1) and cytotoxic T cells. These cells are activated by antigen-presenting cells, which causes them to rapidly mature into forms specific to that antigen. T cells then circulate through the body to destroy pathogens in several ways. Helper T cells facilitate the immune response by guiding cytotoxic T cells to pathogens or pathogen-infected cells, which they will then destroy.

Cytotoxic T cells kill pathogens in several ways, including the release of granules that contain the cytotoxins perforin and granzyme, which lyse small pores in the membrane of a pathogen. Then T-cell produced proteases enter the pathogen and induce an apoptosis response within the cell. Helper T cells secrete cytokines such as interferon-gamma, which can activate cytotoxic T cells and macrophages.

Humoral Immunity

Humoral immunity refers to the component of the adaptive immune response that is caused by B cells, antibodies, and type 2 helper T cells (T_h2), as well as circulating mast cells and eosinophils to a lesser extent. Its name comes from the idea that blood is one of the humors of the body since antibodies provide passive or active immunity through circulation in the bloodstream.

Type 2 helper T cells are included in the humoral immune system because they present antigens to immature B-cells, which undergo proliferation to become specific to the presented antigen. The B cells then rapidly produce a large number of antibodies that circulate through the body’s plasma.

Antibodies provide a number of functions in humoral immunity. Six different classes of antibodies provide distinct functions and interact with different cells in the immune system. All antibodies bind to pathogens to opsonize them, which makes it easier for phagocytic cells to bind to and destroy the pathogen. They also neutralize the toxins produced by certain pathogens and provide complement pathway activation, in which circulating proteins are combined in a complex cascade that forms a membrane attack complex on a pathogen cell membrane, which lyses the cell.

Mast cells and eosinophils are considered part of the humoral immune system because they can be sensitized towards certain antigens through circulating immunoglobin E (IgE), a specific type of antibody produced by B cells. IgE binds to the mast cells and eosinophils when an antigen is detected, using a type of Fc receptor on the mast cell or eosinophil that has a high binding affinity with IgE. This binding will cause degranulation and release of inflammatory mediators that start an immune response against the antigen. This process is the reason why memory B cells can cause hypersensitivity (allergy) formation, as circulating IgE from those memory cells will activate a rapid inflammatory and immune response.

Maturation of T Cells

T cells originate from hematopoietic stem cells in the bone marrow and undergo positive and negative selection in the thymus to mature.

T cells belong to a group of white blood cells known as lymphocytes and play a central role in the cell-mediated branch of the adaptive immune system. They are distinguished from other lymphocytes, such as B cells and natural killer cells (NK cells), by the presence of a T cell receptor (TCR) on the cell surface. T cells are produced in the bone marrow but travel to the thymus to mature. T cells can be either helper T cells or cytotoxic T cells based on whether they express CD4 (helper) or CD8 ( cytotoxic ) glycoprotein.

Maturation of T Cells

All T cells originate from hematopoietic stem cells in the bone marrow, which are capable of differentiating into any type of white blood cell. Immature T cells that migrate to the thymus are called thymocytes. The earliest thymocytes express neither CD4 nor CD8 and are therefore classed as double-negative (CD4-CD8-) cells. As they progress through their development they become double-positive thymocytes (CD4+CD8+) and finally mature to single-positive (CD4+CD8- or CD4-CD8+) thymocytes that are released from the thymus to peripheral tissues. Typically, these mature thymocytes are still referred to as either “immature” or “naive” because they have not been presented with an antigen. They travel to sites that contain secondary lymphoid tissue, such as the lymph nodes and tonsils, where antigen presentation. This facilitates the development of antigen-specific adaptive immunity.

The thymus contributes fewer cells as a person ages. As its functional mass shrinks by about 3% a year throughout middle age, there is a corresponding fall in the thymic production of naive T cells, leaving clonal expansion of immature T cells to play a greater role in protecting older subjects. The thymus is thus thought to be important in building a large stock of naive T cells soon after birth that can later function without thymus support.

Positive Selection of T Cells

During thymocyte maturation, 98% of T cells are discarded by the selection, which is a mechanism designed to ensure that T cells function without major problems. Positive selection designates T cells capable of interacting with MHC. Double-positive thymocytes (CD4+/CD8+) move deep into the thymic cortex tissue where they are presented with self-antigens. These are expressed by thymic cortical epithelial cells that express both MHC I and MHC II molecules on the surface of cortical cells. Only those thymocytes that interact with MHC I or MHC II will receive a vital “survival signal.” Those that can’t interact will undergo apoptosis (cell death). This ensures T cell functionality since T cells with non-functional receptors cannot receive antigens and are thus useless to the immune system. If non-functional T cells were allowed into circulation, they would crowd out functional T cells and slow down the rate at which adaptive immune responses are formed. The vast majority of thymocytes die during this process.

A thymocyte’s differentiation into either a helper or cytotoxic version is also determined during positive selection. Double-positive cells (CD4+/CD8+) that are positively selected on MHC class II molecules will eventually become CD4+ helper T cells, while cells positively selected on MHC class I molecules mature into CD8+ cytotoxic T cells. A T cell is then signaled by the thymus to become a CD4+ cell by reducing the expression of its CD8 cell surface receptors. If the cell does not lose its signal, it will continue reducing CD8 and become a CD4+, single positive cell. But if there is a signal interruption, it will instead reduce CD4 molecules, eventually becoming a CD8+, single positive cell. This process does not remove thymocytes that may become sensitized against self-antigens, which causes autoimmunity. The potentially autoimmune cells are removed by the process of negative selection.

Negative Selection of T Cells

Negative selection removes thymocytes that are capable of strongly binding with self-antigens presented by MHC. Thymocytes that survive positive selection migrate towards the boundary of the thymic cortex and thymic medulla (the part of the thymus where T cells enter circulation). While in the medulla, they are again presented with self-antigen in complex with MHC molecules on thymic epithelial cells. Thymocytes that interact too strongly with the antigen receive an apoptotic signal that leads to cell death.

Blood cells: Scanning electron micrograph of T lymphocyte (right), a platelet (center), and a red blood cell (left).

However, some cells are selected to become T-reg cells, which retain their ability to bind to self-antigens in order to suppress overactive immune responses. These cells may be protective against autoimmunity. The remaining cells exit the thymus as mature naive T cells. This process is an important component of central tolerance, a process that prevents the formation of self-reactive T cells that are capable of inducing autoimmune diseases in the host. Autoimmune diseases reflect a loss of central tolerance in which the body’s own B and T cells become sensitized towards self-antigens. Many autoimmune disorders are primarily antibody-mediated, but some are T cell-mediated. One example of the latter is Crohn’s disease, in which T cells attack the colon. These autoimmune disorders may be caused by problems in negative selection and tend to have genetic components.

Lymphocytes

A lymphocyte is a type of white blood cell in the vertebrate immune system.

A lymphocyte is a type of white blood cell in the immune system, including both the B and T cells of the adaptive immune system and natural killer (NK) cells of the innate immune system.

B and T cells and their various subdivisions perform many adaptive immune functions.

T Cells

T cells mature in the thymus and contain T cell receptors (TCRs) that allow them to bind to antigens on MHC complexes. T cells are a major component in cell-mediated adaptive immunity because they provide a pathway for the direct killing of pathogens. There are two main types of T cells that express either CD4 or CD8 depending on signals that occur during T cell maturation, as well as less common types:

• Helper T cells (CD4s) facilitate the organization of immune responses and can bind to MHC class II. Subtype 2 helper T cells present antigens to B cells. Subtype 1 helper T cells produce cytokines that guide cytotoxic T cells to pathogens and activate macrophages.
• Cytotoxic T cells (CD8s) destroy pathogens associated with an
  antigen. They function similarly to NK cells by binding to
  MHC class I and releasing perforin, granzymes, and proteases to induce apoptosis in a pathogen. They are different from NK cells because they only bind to
  cells that express their specific antigen, and are not large or granular like NK cells.
• Suppressor T cells (T-reg cells) retain some of their ability to bind to self-cells. They have an immunosuppressive effect that inhibits cell-mediated immunity at the end of the response and destroys autoimmune T cells that aren’t filtered out by negative selection in the thymus.
• Memory T cells are created after an adaptive immune response subsides, retaining the presented antigen. They rapidly proliferate and differentiate into helper and cytotoxic T cells that are specific to that antigen should it be detected in the body again.

While these are the main categories of T lymphocytes, there are other subtypes within these categories as well as additional categories that are not fully understood.

B Cells

Lymphocyte: A scanning electron microscope (SEM) image of a single human lymphocyte.

B cells are involved in humoral adaptive immunity, producing the antibodies that circulate through the plasma. They are produced and mature in bone marrow tissues and contain B cell receptors (BCRs) that bind to antigens. While in the bone marrow, B cells are sorted through positive and negative selection in a manner somewhat similar to T cell maturation in the thymus, with the same process of killing B cells that are nonreactive to antigens or reactive to self-antigens. Instead of apoptosis, though, defective B cells are killed through other mechanisms such as clonal deletion. Mature B cells leave the thymus and travel to secondary lymphoid tissue such as the lymph nodes.

During antigen presentation, antigen-presenting cells first present antigens to T cells. Then mature helper T cells bind their antigen to naive B cells through BCRs. After antigen presentation, the naive B cells migrate together to germinal centers within the lymphoid tissue, where they undergo extensive proliferation and differentiation into different types of mature B cells. Some of the major categories of B cells that arise include:

• Plasma cell and long-lived B cells that are the main source of antibodies. They do not have the ability to proliferate and are considered terminally differentiated.
• Plasmablasts are short-lived B cells produced early in an infection. Their antibodies have a weaker binding affinity than those of plasma cells.
• Regulatory B cells (B reg cells) are immunosuppressive B cells that secrete anti-inflammatory cytokines (such as IL-10) to inhibit autoimmune lymphocytes.
• Memory B cells are dormant B cells with the same BCR as the B cell from which they differentiated. They are specific to the antigen presented to that BCR and rapidly secrete large amounts of antigen-specific antibodies to prevent reinfection if that antigen is detected again.

Besides antibody production, B cells may also function in antigen presentation, though not to the degree of macrophages or dendritic cells. B cells are important to adaptive immune function but can cause problems as well. Autoreactive B cells may cause autoimmune disease that involves antibody-induced damage and inflammation. Certain B cells may undergo malignant transformation into cancer cells such as lymphoma, in which they continually divide and form solid tumors.

Antigen-Presenting Cells

Antigen presentation is a process by which immune cells capture antigens and then enable their recognition by T cells.

Antigen presentation is a process in the body’s immune system by which macrophages, dendritic cells and other cell types capture antigens, then present them to naive T-cells. The basis of adaptive immunity lies in the capacity of immune cells to distinguish between the body’s own cells and infectious pathogens. The host’s cells express “self” antigens that identify them as belonging to the self. These antigens are different from those in bacteria (“non-self” antigens) or in virally infected host cells (“missing-self”). Antigen presentation broadly consists of pathogen recognition, phagocytosis of the pathogen or its molecular components, processing of the antigen, and then the presentation of the antigen to naive (mature but not yet activated) T cells. The ability of the adaptive immune system to fight off pathogens and end an infection depends on antigen presentation.

Antigen-Presenting Cells

Antigen Presenting Cells (APCs) are cells that capture antigens from within the body and present them to naive T-cells. Many immune system cells can present antigens, but the most common types are macrophages and dendritic cells, which are two types of terminally differentiated leukocytes that arise from monocytes. Both of these APCs perform many immune functions that are important for both innate and adaptive immunity, such as removing leftover pathogens and dead neutrophils after an inflammatory response. Dendritic cells (DCs) are generally found in tissues that have contact with the external environment (such as the skin or respiratory epithelium) while macrophages are found in almost all tissues. Some types of B cells may also present antigens as well, though it is not their primary function.

APCs phagocytize exogenous pathogens such as bacteria, parasites, and toxins in the tissues and then migrate, via chemokine signals, to lymph nodes that contain naive T cells. During migration, APCs undergo a process of maturation in which they digest phagocytized pathogens and begin to express the antigen in the form of a peptide on their MHC complexes, which enables them to present the antigen to naive T cells. The antigen digestion phase is also called “antigen processing,” because it prepares the antigens for presentation. This MHC antigen complex is then recognized by T cells passing through the lymph node. Exogenous antigens are usually displayed on MHC Class II molecules, which interact with CD4+ helper T cells.

This maturation process is dependent on signaling from another pathogen-associated molecular pattern (PAMP) molecules (such as a toxin or component of a cell membrane from a pathogen) through pattern recognition receptors (PRRs), which are received by Toll-like receptors on the DC’s body. They may also recognize damage-associated molecular pattern (DAMP) molecules, which include degraded proteins or nucleic acids released from cells that undergo necrosis. PAMPs and DAMPS are not technically considered antigens themselves, but instead are signs of pathogen presence that alert APCs through Toll-like receptor binding. However, if a DC phagocytes a PAMP or DAMP, it could be used as an antigen during antigen presentation. APCs are unable to distinguish between different types of antigens themselves, but B and T cells can due to their specificity.

Antigen Presentation

T cells must be presented with antigens in order to perform immune system functions. The T cell receptor is restricted to recognizing antigenic peptides only when bound to appropriate molecules of the MHC complexes on APCs, also known in humans as Human leukocyte antigen (HLA).

Several different types of T cells can be activated by APCs, and each type of T cell is specially equipped to deal with different pathogens, whether the pathogen is bacterial, viral, or a toxin. The type of T cell activated, and therefore the type of response generated, depends on which MHC complex the processed antigen-peptide binds to.

MHC Class I molecules present antigen to CD8+ cytotoxic T cells, while MHC class II molecules present antigen to CD4+ helper T cells. With the exception of some cell types (such as erythrocytes), Class I MHC is expressed by almost all host cells. Cytotoxic T cells (also known as TC, killer T cell, or cytotoxic T-lymphocyte (CTL)) are a population of T cells that are specialized for inducing the death of other cells. Recognition of antigenic peptides through Class I by CTLs leads to the killing of the target cell, which is infected by a virus, intracytoplasmic bacterium, or are otherwise damaged or dysfunctional. Additionally, some helper T cells will present their antigen to B cells, which will activate their proliferation response.

Skin and Mucosae (Surface Barriers)

In mammals, the skin and mucosae constitute complex protective barriers that guard against infection and injury.

The skin is one of the most important body parts because it interfaces with the environment and is the first line of defense from external factors. While it performs a wide range of functions, including sensation, heat regulation, control of evaporation, storage, synthesis, absorption, and water resistance, but its innate immune system functions as the barrier immune system are the most critical.

In humans, the outer covering of the body consists of the skin and mucosae, which together make up the barrier immune system.

Components of the Skin

The skin is made up of several layers that together protect the body, regulate temperature, keep water inside the body, and have a sensory function. The skin is the largest organ in the body, and consists of three components that differ greatly in structure and function:

• The epidermis comprises the outermost layers of the skin. It forms a protective barrier over the body’s surface, responsible for keeping water in the body and preventing pathogens from entering. It is made of stratified squamous epithelium tissues, composed of proliferating basal and differentiated suprabasal keratinocytes that form an extracellular matrix that continually divides as the older outer layers of the epidermis shed. The epidermis also helps the skin regulate body temperature through sweat pores that connect to underlying sweat glands in the dermis.
• The basement membrane is  a thin sheet of fibers called the basement membrane that separates the dermis and epidermis. It controls the traffic of cells and molecules between the dermis and epidermis and the release of cytokines and growth factors during wound healing.
• The dermis is the layer of skin beneath the epidermis that consists of connective tissue and cushions the body from stress and strain. The dermis provides strength and elasticity to the skin through an extracellular matrix composed of collagen fibrils, microfibrils, and elastic fibers, embedded in proteoglycans. It harbors many mechanoreceptors (sensory nerve endings) that provide the sensations of touch and heat. It also contains the hair follicles, sweat glands, sebaceous glands, apocrine glands, lymphatic vessels, and blood vessels. The blood vessels in the dermis provide nourishment and waste removal for their own cells and for the epidermis.

Mucous Membranes

The mucous membranes (or mucosae; singular mucosa) are linings of mostly endodermal origin, covered in various types of epithelium, that are involved in absorption and secretion. They line cavities that are exposed to the external environment and internal organs. They attached to skin at the nostrils, mouth, lips, eyelids, and genital area, but are also located within the body cavities, such as in the stomach, anus, trachea, and ears.

Most mucous membranes secrete a sticky, thick fluid called mucus, which facilitates several barrier immune system functions and provides a moist environment for internal and semi-internal structures. The mucosae are highly specialized in each organ to deal with different conditions. The most variation is seen in the epithelium. In the esophagus and oropharynx, the epithelium is stratified, squamous and non-keratinizing, to protect these areas from harsh or acidic foods. In the stomach, it is columnar and organized into gastric pits and glands to secrete acids and pepsin. The small intestine epithelium is specialized for absorption, organized into simple columnar epithelium on protruding villi with narrow crypts that have a high surface area. The mucosal epithelium in the nasopharynx is pseudostratified and ciliated, which helps accumulate and remove mucus.

The Barrier Immune System

Together, the skin and mucosae from the barrier immune system technically considered a component of the innate immune system. These structures form physical barriers to infection that prevent pathogens from entering the body through a variety of methods. While the skin simply prevents pathogen entry, more specialized structures like the mucociliary escalator in the trachea trap pathogens in mucus secretions and use cilia to push them out of the trachea to prevent entry into the lungs.

The barrier system also includes chemical barriers that prevent pathogen entry. Notable examples include stomach acidity which kills most microbes, antimicrobial peptides on mucosal epithelial tissue, and even the flow of urine that flushes pathogens out of the urethra.

The barrier system is the first line of defense against pathogen invasion, though it is not perfect. The skin can be broken through cuts or abrasions that expose the bloodstream to the environment. Not every pathogen is caught nor inhibited in mucus, and some may infect the mucosal epithelium directly. Smoking and alcohol abuse damages the mucociliary escalator and make it easier for pathogens to invade the lungs. Fortunately, other mechanisms of the innate and adaptive immune systems defend the body when the barrier system fails.

 

Dermis: A diagrammatic view of a skin section.

Phagocytes

Phagocytes are the white blood cells that protect the body by ingesting harmful foreign particles and help initiate an immune response.

Any cell that undergoes phagocytosis, a process in which pathogens and other foreign particles and debris are engulfed by a cell to be destroyed, is considered a phagocyte. Most phagocytes are types of white blood cells that use phagocytosis to perform basic innate immune system function within the body.

The Mechanism of Phagocytosis

Phagocytosis is the process by which a phagocyte engulfs a pathogen or debris. It can occur in almost any tissue, most often in the bloodstream and interstitial space but also the alveoli of the lungs and the parenchyma of most other major organs in the body. Typical phagocytosis occurs over the course of a few steps:

• A receptor on the phagocyte’s cell membrane binds to a foreign particle, such as a pathogenic microbe or a toxin. The Fc receptor is typically the receptor of use, which binds to antibodies that have opsonized (marked) a pathogen or toxin.
• The cytoplasm surrounds and engulfs the bound pathogen through endocytosis.
• The engulfed pathogen is kept in a vacuole called a phagosome, which then binds to the lysosomes inside the cell.
• A series of chemical reactions called an oxidative burst occurs, which uses reactive oxygen species and NADPH oxidase to damage and kill the pathogen through oxidative stress. Oxidative stress can kill a cell through DNA, cell membrane, or mitochondrial damage.
• The remains of the pathogen are expelled by exocytosis.

These are the general mechanisms used by phagocytosis to engulf and kill pathogens, but some variations can occur. For instance, other receptors may be used to engulf pathogens, and other non-oxidative methods (such as lysozyme) exist to kill the phagocytized pathogen.

Types of Phagocytes

There are many classes of phagocytes within the body, each with different specialized functions involving phagocytosis. Most phagocytes are derived from stem cells in the bone marrow. The main types of phagocytes are monocytes, macrophages, neutrophils, tissue dendritic cells, and mast cells. Other cells, such as epithelial cells and fibroblasts, may also engage in phagocytosis, but lack receptors to detect opsonized pathogens and are not primarily immune system cells.

Monocytes

Monocytes develop in the bone marrow and reach maturity in the blood. Mature monocytes have large, smooth, lobed nuclei and an abundant cytoplasm that contains granules, but are not technically considered granulocytes. Monocytes ingest foreign or dangerous substances and present antigens to other cells of the immune system. Monocytes form two groups: a circulating group and a marginal group that remains in other tissues (approximately 70% are in the marginal group). Most monocytes leave the bloodstream after 20–40 hours to travel to tissues and organs; during this process, they differentiate into macrophages or dendritic cells depending on the signals they receive.

Macrophages

Mature macrophages are derived from monocytes, granulocyte stem cells, or the cell division of pre-existing macrophages. Macrophages do not have granules but contain many lysosomes. They are found throughout the body in almost all tissues and organs but are rarely found in the bloodstream. Macrophages cause inflammation through the production of interleukin-1, interleukin-6, and TNF-alpha. Macrophages are activated in a number of ways, including by T cells, cytokines such as IFN-gamma, or pathogen-derived compounds such as LPS toxins from bacteria. During inflammation, they enter about 72 hours after the initial response to clean up debris and dead neutrophils.

Dendritic Cells

Dendritic cells are specialized antigen-presenting cells that have long outgrowths called dendrites, which help to engulf microbes and other invaders. They express MHC class II molecules, which makes them the ideal antigen-presenting cell. Dendritic cells are present in the tissues that are in contact with the external environment, mainly the skin, the inner lining of the nose, the lungs, the stomach, and the intestines.

Once activated, they mature and migrate to the lymphoid tissues, where they present antigens to T and B cells to initiate the adaptive immune response. This involves deriving T and B cells that are specific towards a single antigen from naive lymphocytes.

Neutrophils

Neutrophils are a type of PMN granulocyte normally found in the bloodstream. They are the most abundant type of phagocyte and the first responder during inflammation. Once they have received the appropriate chemokine signals, neutrophils leave the bloodstream and reach the site of an infection through adhering to the vascular endothelium to squeeze into the tissues. There, they rapidly engulf invaders coated with antibodies, damaged cells, or cellular debris. They also degranulate to release perforin, granzyme, proteases, and other chemicals to cause cytotoxic damage to pathogens (and occasionally normal bodily tissues as well). Neutrophils die after phagocytosis, becoming pus that is later cleaned up by macrophages.

 

Extraversion of Neutrophils: Neutrophils move through the blood to the site of infection by rolling onto the vascular endothelium and adhering to it to slip through small gaps into the tissues during an inflammatory response.

Mast Cells

Mast cells are PMN granulocytes with toll-like receptors that tend to trigger inflammatory responses. Mast cells express MHC class II molecules and can participate in antigen presentation; however, the mast cell’s role in antigen presentation is not well-understood. Mast cells can consume, kill, and process their antigens. In addition to these functions, mast cells produce cytokines kept in their granules, such as histamine,  that induce an inflammatory response when a pathogen is detected. Because of this function, allergic inflammatory responses occur when a mast cell is sensitized to an antigen that it normally wouldn’t react to.

 

Leukocyte Differentiation: Phagocytes derive from stem cells in the bone marrow. Monocytes differentiate into dendritic cells and macrophages, while mast cells and neutrophils are in a separate group of PMN granulocytes as well.

Overview of the defining features of innate and adaptive immunity [rx]

	Innate immune system	Adaptive immune system
Cells	Hematopoietic cells: • Macrophages • Dendritic cells • Mast cells • Neutrophils • Basophils • Eosinophils • NK cells • T cells Non-hematopoietic cells • Epithelial cells (skin, airways, gastrointestinal tract)	Hematopoietic cells: • T cells • B cells
Molecules	• Cytokines • Complement • Proteins and glycoprotein	• Antibodies (Ig) • Cytokines
Response time	• Immediate	• Delayed by hours to days
Immunologic memory	• None: responses are the same with each exposure	• Responsiveness enhanced by repeated antigen exposure

Self vs. Non-self: How does the body know?

In order to be effective, the immune system needs to be able to identify which particles are foreign, and which are a part of your body. Let’s define some terms before we jump in to how this works:

• Self refers to particles, such as proteins and other molecules, that are a part of, or made by, your body. They can be found circulating in your blood or attached to different tissues. Something that is self should not be targeted and destroyed by the immune system. The non-reactivity of the immune system to self particles is called tolerance.
• Non-self refers to particles that are not made by your body, and are recognized as potentially harmful. These are sometimes called foreign bodies. Non-self particles or bodies can be bacteria, viruses, parasites, pollen, dust, and toxic chemicals. The non-self particles and foreign bodies that are infectious or pathogenic, like bacteria, viruses, and parasites, make proteins called antigens that allow the human body to know that they intend to cause damage.
• Antigens are anything that causes an immune response. Antigens can be entire pathogens, like bacteria, viruses, fungi, and parasites, or smaller proteins that pathogens express. Antigens are like a name tag for each pathogen that announce the pathogens’ presence to your immune system. Some pathogens are general, whereas others are very specific. A general antigen would announce “I’m dangerous”, whereas a specific antigen would announce “I’m a bacteria that will cause an infection in your gastrointestinal tract” or “I’m the influenza virus”.
• Cytokines are molecules that are used for cell signaling, or cell-to-cell communication. Cytokines are similar to chemokines, wherein they can be used to communicate with neighboring or distant cells about initiating an immune response. Cytokines are also used to trigger cell trafficking, or movement, to a specific area of the body.
• Chemokines are a type of cytokines that are released by infected cells. Infected host cells release chemokines in order to initiate an immune response, and to warn neighboring cells of the threat.

Innate Immune System

The innate immune system is made of defenses against infection that can be activated immediately once a pathogen attacks. The innate immune system is essentially made up of barriers that aim to keep viruses, bacteria, parasites, and other foreign particles out of your body or limit their ability to spread and move throughout the body. The innate immune system includes:

• Physical Barriers

  • such as skin, the gastrointestinal tract, the respiratory tract, the nasopharynx, cilia, eyelashes and other body hair.
• Defense Mechanisms

  • such as secretions, mucous, bile, gastric acid, saliva, tears, and sweat.
• General Immune Responses

  • such as inflammation, complement, and non-specific cellular responses. The inflammatory response actively brings immune cells to the site of an infection by increasing blood flow to the area. Complement is an immune response that marks pathogens for destruction and makes holes in the cell membrane of the pathogen.

The innate immune system is always general, or nonspecific, meaning anything that is identified as foreign or non-self is a target for the innate immune response. The innate immune system is activated by the presence of antigens and their chemical properties.

Cells of the Innate Immune System

There are many types of white blood cells, or leukocytes, that work to defend and protect the human body. In order to patrol the entire body, leukocytes travel by way of the circulatory system.

The following cells are leukocytes of the innate immune system:

• Phagocytes, or Phagocytic cells: Phagocyte means “eating cell”, which describes what role phagocytes play in the immune response. Phagocytes circulate throughout the body, looking for potential threats, like bacteria and viruses, to engulf and destroy. You can think of phagocytes as security guards on patrol.

Phagocytosis diagram

• Macrophages: Macrophages, commonly abbreviated as “Mφ”, are efficient phagocytic cells that can leave the circulatory system by moving across the walls of capillary vessels. The ability to roam outside of the circulatory system is important, because it allows macrophages to hunt pathogens with less limits. Macrophages can also release cytokines in order to signal and recruit other cells to an area with pathogens.

Macrophage and cytokines diagram

• Mast cells: Mast cells are found in mucous membranes and connective tissues, and are important for wound healing and defense against pathogens via the inflammatory response. When mast cells are activated, they release cytokines and granules that contain chemical molecules to create an inflammatory cascade. Mediators, such as histamine, cause blood vessels to dilate, increasing blood flow and cell trafficking to the area of infection. The cytokines released during this process act as a messenger service, alerting other immune cells, like neutrophils and macrophages, to make their way to the area of infection, or to be on alert for circulating threats.

Mast cell and histamine diagram

• Neutrophils: Neutrophils are phagocytic cells that are also classified as granulocytes because they contain granules in their cytoplasm. These granules are very toxic to bacteria and fungi, and cause them to stop proliferating or die on contact.

Neutrophil and granules diagram

The bone marrow of an average healthy adult makes approximately 100 billion new neutrophils per day. Neutrophils are typically the first cells to arrive at the site of an infection because there are so many of them in circulation at any given time.

• Eosinophils: Eosinophils are granulocytes target multicellular parasites. Eosinophils secrete a range of highly toxic proteins and free radicals that kill bacteria and parasites. The use of toxic proteins and free radicals also causes tissue damage during allergic reactions, so activation and toxin release by eosinophils is highly regulated to prevent any unnecessary tissue damage.
  While eosinophils only make up 1-6% of the white blood cells, they are found in many locations, including the thymus, lower gastrointestinal tract, ovaries, uterus, spleen, and lymph nodes.

Eosinophil and granules diagram

• Basophils: Basophils are also granulocytes that attack multicellular parasites. Basophils release histamine, much like mast cells. The use of histamine makes basophils and mast cells key players in mounting an allergic response.
• Natural Killer cells: Natural Killer cells (NK cells), do not attack pathogens directly. Instead, natural killer cells destroy infected host cells in order to stop the spread of an infection. Infected or compromised host cells can signal natural kill cells for destruction through the expression of specific receptors and antigen presentation.
• Dendritic cells: Dendritic cells are antigen-presenting cells that are located in tissues, and can contact external environments through the skin, the inner mucosal lining of the nose, lungs, stomach, and intestines. Since dendritic cells are located in tissues that are common points for initial infection, they can identify threats and act as messengers for the rest of the immune system by antigen presentation. Dendritic cells also act as bridge between the innate immune system and the adaptive immune system.

Dendritic cell diagram

The Complement System

The complement system (also called the complement cascade) is a mechanism that complements other aspects of the immune response. Typically, the complement system acts as a part of the innate immune system, but it can work with the adaptive immune system if necessary.

The complement system is made of a variety of proteins that, when inactive, circulate in the blood. When activated, these proteins come together to initiate the complement cascade, which starts the following steps:

1. Opsonization: Opsonization is a process in which foreign particles are marked for phagocytosis. All of the pathways require an antigen to signal that there is a threat present. Opsonization tags infected cells and identifies circulating pathogens expressing the same antigens.
2. Chemotaxis: Chemotaxis is the attraction and movement of macrophages to a chemical signal. Chemotaxis uses cytokines and chemokines to attract macrophages and neutrophils to the site of infection, ensuring that pathogens in the area will be destroyed. By bringing immune cells to an area with identified pathogens, it improves the likelihood that the threats will be destroyed and the infection will be treated.
3. Cell Lysis: Lysis is the breaking down or destruction of the membrane of a cell. The proteins of the complement system puncture the membranes of foreign cells, destroying the integrity of the pathogen. Destroying the membrane of foreign cells or pathogens weakens their ability to proliferate, and helps to stop the spread of infection.
4. Agglutination: Agglutination uses antibodies to cluster and bind pathogens together, much like a cowboy rounds up his cattle. By bringing as many pathogens together in the same area, the cells of the immune system can mount an attack and weaken the infection. Other innate immune system cells continue to circulate throughout the body in order to track down any other pathogens that have not been clustered and bound for destruction.

Complement cascade diagram

The steps of the complement cascade facilitate the search for and removal of antigens by placing them in large clumps, making it easier for other aspects of the immune system to do their jobs. Remember that the complement system is a supplemental cascade of proteins that assists, or “complements” the other aspects of the innate immune system.

The innate immune system works to fight off pathogens before they can start an active infection. For some cases, the innate immune response is not enough, or the pathogen is able to exploit the innate immune response for a way into the host cells. In such situations, the innate immune system works with the adaptive immune system to reduce the severity of infection, and to fight off any additional invaders while the adaptive immune system is busy destroying the initial infection.

Natural Killer Cells

Natural killer (NK) cells are cytotoxic lymphocytes critical for the innate immune system.

Natural killer (NK) cells are cytotoxic lymphocytes critical to the innate immune system. The role of NK cells is similar to that of cytotoxic T cells in the adaptive immune response. NK cells provide rapid responses to virus-infected cells and respond to tumor formation by destroying abnormal and infected cells. NK cells use wo cytolytic granule-mediated apoptosis to destroy abnormal and infected cells.

Natural Killer Overview

Typically, immune cells detect major histocompatibility complex (MHC) presented on cell surfaces, triggering cytokine release and lysis or apoptosis in cells that do not express MHC I or express much less of it than normal cells. Unlike phagocytes, NK cells do not need their targets to be opsonized (marked) by antibodies before they can act, allowing for a much faster immune reaction. However, opsonins do speed up the process.

These cells named “natural killers” because they were thought to work without cytokine or chemokine activation. However, later research proved that cytokines play a role in guiding NK cells to stressed cells that may need to be destroyed.

NK cells are large granular lymphocytes derived from the common lymphoid progenitor cells (lymphoblasts), which also generate B and T lymphocytes. NK cells differentiate and mature in the bone marrow, lymph nodes, spleen, tonsils and thymus, where they then enter into the bloodstream.

MHC I Recognition

In order for NK cells to defend the body against viruses and pathogens, they require mechanisms to determine whether a cell is infected. The exact mechanisms remain the subject of the current investigation, but recognition of an “altered self” state is thought to be involved. To control their cytotoxic activity, NK cells possess two types of surface receptors: activating receptors and inhibitory receptors. Most of these receptors are also present in certain T cells. These receptors recognize major histocompatibility complex I (MHC I), a molecule expressed on every cell to signal that the cell belongs to the body.

When the NK cell recognizes MHC I on a cell using an inhibitory receptor, its killing response is inhibited. When the NK cell does not recognize MHC I on the cell with an inhibitory receptor or detects an antigen with an activating receptor, the killing response is activated. Virus-infected cells and foreign pathogens such as bacteria and fungi will not express the MHC I specific to the host organism, which will fail to inhibit the NK cell’s killing responses. If both types of receptors are being stimulated, the receptor that experiences a higher degree of relative stimulation will determine the NK cell behavior. Some tumor cells may still express MHC I in low amounts, so they may evade NK cell destruction based on the balance of activating and inhibiting stimuli.

 

Complimentary Activities of Cytotoxic T-cells and NK cells: Schematic diagram indicating the complementary activities of cytotoxic T-cells and NK cells. T-cells are activated by recognizing antigens, while NK cells are activated by not recognizing MHC I.

Mechanisms of Cytotoxicity

The granules of NK cells contain proteins such as perforin and proteases known as granzymes. Upon binding to a cell slated for killing, perforin forms pores in the cell membrane of the target cell, creating an aqueous channel through which the granzymes and associated molecules can enter, inducing either apoptosis or osmotic cell lysis (a form of cell necrosis ). Defensins, an antimicrobial secreted by NK cells, directly kills bacteria by disrupting its cell walls.

Apoptosis is a form of “programmed cell death” in which the cell is stimulated by the cytotoxic mechanisms to destroy itself. Unlike lysis, apoptosis does not degrade DNA, and cells are destroyed cleanly and completely on their own. Cellular lysis causes necrosis of that cell, in which the DNA and cell components degrade into debris that must be phagocytized by macrophages. This distinction has many important implications. Virus-infected cells destroyed by cell lysis release their replicated virus particles into the body, which infects other cells. In apoptosis, these virus particles are destroyed. However, cancer cells often develop genetic mechanisms to prevent apoptosis signals from occurring, so cell lysis is generally more effective.

Cells that are opsonized with antibodies are easier for NK cells to detect and destroy. Antibodies that bind to antigens can be recognized by FcϒRIII (CD16) receptors (a type of activating receptor), resulting in NK activation, the release of cytolytic granules, and consequent cell apoptosis.

Cytokines in NK Cell Activity

Cytokines play a role in NK cell activation. Many cells release cytokines as a result of cellular stress when infected with a virus. Cytokines involved in NK activation include IL-12, IL-15, IL-18, IL-2, and CCL5. NK cells are activated in response to interferons or macrophage-derived cytokines. They serve to contain viral infections while the adaptive immune response generates antigen-specific cytotoxic T cells that can clear the infection.

NK cells also secrete their own cytokines of their own to help facilitate immune responses, generally upon NK cell activation. NK cells work to control viral infections by secreting IFNγ (interferon-gamma) and TNFα (tumor necrosis factor-alpha). IFNγ activates macrophages for phagocytosis and lysis while TNFα acts to promote direct NK tumor cell killing. It is also a potent inflammatory mediator that causes long-lasting inflammatory responses and fever in response to more severe infections. Patients deficient in NK cells prove to be more susceptible to most infections than people with normal levels of NK cells, due to a loss of innate immune system function and efficiency.

Inflammation

Inflammation is part of the biological response of vascular tissues to harmful stimuli.

Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, injury or trauma, and irritants. Inflammation is a protective attempt by the organism to remove injurious stimuli and initiate the healing process. Inflammation is not a synonym for infection, even in cases where inflammation is caused by infection. Rather, it refers to the response of the body to try and fight the infection. While inflammation is an important mechanism of innate immunity, it can harm the body in cases of allergy, autoimmunity, and infections in tissues with poor regenerative capacity such as the heart.

Functions and Components of Inflammatory Response

The main function of inflammation is to trigger an immune response in an area of the body that needs it to fight off pathogens that may cause an infection or to help heal an injury. The main symptoms of acute inflammation are swelling, redness, pain, loss of function, and heat. Three components to the basic acute inflammatory response occur every time: vasodilation increased vascular permeability, and migration of leukocytes to the affected tissues.

Vasodilation

An inflammatory response can be caused by any of the numerous inflammatory mediators released from innate immune system cells. The most common short-term mediators are histamine and serotonin from mast cells, but bradykinin, complement proteins, some interleukins, prostaglandins, and TNF-alpha may also trigger inflammation from other types of cells. Circulating mast cells contain toll-like receptors, which can detect pathogen-associated molecular patterns (PAMPS) on the surface of pathogens and release an inflammatory mediator such as histamine in response. Alternatively, mast cells may release inflammatory mediators due to signals from damaged cells (which will release clotting factors) during trauma or injury.

After an inflammatory mediator is released in the bloodstream, a period of transient vasoconstriction, lasting only a few seconds, occurs. Then blood vessels expand to undergo vasodilation from the stimulus of the vasoactive inflammatory mediator, which increases blood flow to the area. This causes slowing and stasis of red blood cells, which can be involved in the clotting response needed to stop bleeding in the case of injury. Vasodilation is the reason for the redness, heat, and pain associated with inflammation.

Increased Vascular Permeability

The next step of acute inflammation is an increase in vascular permeability due to inflammatory mediator activity, which causes the blood vessels to become more permeable. Normally only water and small compounds can exit the bloodstream into the tissues, but during inflammation, large proteins in the bloodstream, such as serum albumins, can leak out and into the tissues. Water follows these proteins due to the force of oncotic pressure that the proteins exert. This is called exudate, a form of edema. As exudate accumulates within the tissues, they become swollen. The exudate may carry antimicrobial proteins and antibodies into the tissues and stimulates lymphatic drainage.

Leukocyte Migration to the Tissues

The next step of the acute inflammatory response is chemotaxis migration of neutrophils to the affected area. Neutrophils are recruited to the site of inflammation by various cytokines. Other inflammatory mediators, such as TNF-alpha and IL-1, increase the expression of adhesion molecules on vascular endothelial cells. The neutrophils loosely attach to the endothelial cells through the use of selectins, a process called rolling. Then integrins firmly attach to the adhesion molecules on the endothelial cells, which is called adhesion. Together, rolling and adhesion are referred to as margination, the accumulation of leukocytes on the endothelium.

The next step is for neutrophils to squeeze through the gaps in the endothelium into the tissues through binding with PECAM-1 expressed on the endothelium, a process called extravasation. Then the neutrophils follow a chemotactic gradient to the site of infection or injury in the tissues, where they will degranulate and phagocytize pathogens. Later, macrophages enter the tissues through a similar process to clean up dead neutrophils and cellular debris.

Outcomes of Acute Inflammation

 

Inflammation: Toes inflamed by chilblains

When acute inflammation ends (typically by release of anti-inflammatory mediators such as IL-10 or an end to the release of inflammatory mediators) resolution will occur if the problem is alleviated. Resolution involves physiological responses that are part of the healing process, such as wound healing. If the problem is not resolved, acute inflammation could occur again. Repeated bouts of acute inflammation, known as chronic inflammation, lead to a progressive shift in the type of cells present at the site of inflammation and are characterized by simultaneous destruction and healing of the tissue from the inflammatory process. In particular, fibrosis (scarring) and tissue necrosis are common outcomes of chronic inflammation.

Antimicrobial Proteins

Antimicrobial peptides are an evolutionarily conserved component of the innate immune response found among all classes of life.

Antimicrobial peptides (also called host defense peptides) are an evolutionarily conserved component of the innate immune response found among all known species. These peptides are found in many of the mucus membranes across the human body and are therefore considered to be part of the barrier immune system. The function of these peptides is to kill microbial pathogens and prevent them from entering the body.

Structure

Antimicrobial peptides are a unique and diverse group of molecules. As peptides, they consist of chains of amino acids that determine their composition and structure. These peptides have a stronger positive than negative charge, which is an important component of their selectivity. They also include hydrophobic and hydrophilic groups that enable them to latch onto other molecules (often lipids) through intermolecular forces, such as the lipid bilayer that forms cell membranes.

The secondary structures of these molecules follow four themes, including i) α-helical, ii) β-stranded due to the presence of two or more disulfide bonds, iii) β-hairpin or loop due to the presence of a single disulfide bond and/or cyclization of the peptide chain, and iv) extended. Many of these peptides are unstructured and inactive in free solution and fold into their final configuration upon reaching mucus membranes. The amphipathicity (hydrophilic and hydrophobic ends) and positive charge of peptides are their defining structural features.

Antimicrobial Action

The modes of action by which antimicrobial peptides kill bacteria are varied and include disrupting cell membranes, interfering with metabolism, and damaging organelles. The initial contact between the peptide and target organism is electrostatic due to the force of negative and positive ionic charges. The amino acid composition, amphipathicity, cationic charge, and size allow them to attach to and insert into membrane bilayers to form pores by barrel-stave, carpet, or toroidal-pore mechanisms.

The peptides are selective and thus more likely to adhere to bacterial cell membranes than to cell membranes of the host cells. The peptides have a greater positive charge than negative charge, while bacterial cell membranes have a greater negative charge than host cell membranes. This causes the peptide to bind to bacterial membranes instead of host cell membranes.

 

Mechanism of Selectivity of Antimicrobial Peptides: Cell membranes of bacteria are different from the cell membranes of plants and animals and are preferentially targeted by antimicrobial proteins.

 

Modes of Action by Antimicrobial Peptides: Antimicrobial peptides multiple various modes of action.

Other antimicrobial mechanisms include intracellular binding models. These involve inhibition of cell wall synthesis, alteration of the cytoplasmic membrane, activation of autolysin, inhibition of DNA, RNA, and protein synthesis, and inhibition of certain bacterial enzymes. However, in many cases, the exact killing mechanism is unknown. In general, the antimicrobial activity of these peptides is determined by measuring the minimal inhibitory concentration (MIC), the lowest concentration of drug that inhibits bacterial growth, and an indicator of the antimicrobial strength of that peptide.

Antimicrobial Resistance

Despite the efficiency of antimicrobial peptides to inhibit and kill bacteria, they are still able to get inside the body and cause infections. Bacteria can develop resistance to antimicrobial peptides (as well as separate resistances to antibiotics and other antimicrobials). Bacteria like staphylococcus aureas, which form the highly resistant MRSA strain, can reduce the negativity of the charge of its cell membrane by bringing amino acids from the cytoplasm into its cell membrane so antimicrobial peptides won’t bind to it. Other forms of antimicrobial resistance include producing enzymes that inhibit the antimicrobial peptides, altering the hydrophobic forces on the cell membrane, and capturing antimicrobial peptides in vesicles on the cell membrane to remove them from the bacterium.

Additionally, commensal bacteria have developed antimicrobial resistance to peptides, but they are normal flora of the body. Most never act as pathogens, though some may be opportunistic pathogens or only act as pathogens in people with certain genetic characteristics.

Fever

Fever is an elevation of body temperature above the regulatory setpoint, mediated through the release of prostaglandin E2.

Fever (also known as pyrexia) is a physiological process of the innate immune response against many infections and diseases, characterized by an elevation of temperature above the normal range of 36.5–37.5 °C (98–100 °F) due to an increase in the body temperature regulatory set-point. Although the person’s temperature increases, there is often a feeling of cold. Once the new temperature is reached, there is a feeling of warmth. A fever can be caused by many conditions ranging from benign to potentially serious. Fevers are helpful in fighting infections, but can also cause damage in the body.

 

Performance of the Various Types of Fever: Performance of the various types of fever: a) Fever continues b) Fever continues to abrupt onset and remission c) Fever remittent d) Intermittent fever e) Undulant fever f) Relapsing fever

Fever Pathways

Temperature is ultimately regulated in the hypothalamus. The primary fever mediator in the human body is prostaglandin E2 (PGE2), which acts on the hypothalamus to raise the temperature set point. PGE2 release comes from the arachidonic acid pathway, which also produces inflammatory mediators such as thromboxane and leukotriene.

This pathway is mediated by the enzymes phospholipase A2 (PLA2), cyclooxygenase-2 (COX-2), and prostaglandin E2 synthase. These enzymes ultimately mediate the synthesis and release of PGE2. Therefore, COX-2 inhibitors such as aspirin are commonly used to reduce fever, although treatments designed to inhibit pyrogens are also effective.

The hypothalamus is the thermostat of the body, in that it alters the temperature set point during temperature feedback and fevers. During a fever, the set point is raised, which causes the body to increase its temperature through both actively generating and retaining heat (vasoconstriction). If these measures are insufficient to make the blood temperature in the brain match the new setting in the hypothalamus, then shivering begins so those muscle movements produce more heat. When the fever stops (when PGE2 release ends), the temperature set point is lowered to normal, and the reverse of these processes (vasodilation, end of shivering, and nonshivering heat production) as well as sweating are used to cool the body to the new, lower setting.

Pyrogens

A pyrogen is a substance that induces fever and can be either internal (endogenous) or external (exogenous) to the body. Pyrogenicity can vary: in extreme examples, bacterial pyrogens known as superantigens can cause rapid and dangerous fevers. Depyrogenation may be achieved through filtration, distillation, chromatography, or inactivation.

Exogenous factors s lipopolysaccharide toxin (from gram-negative bacteria) which can activate a number of innate immune activation pathways. These pathways induce the expression of endogenous pyrogens, including a variety of cytokines such as IL1α, IL1β, IL6, TNFα, TNFβ, IFNα, INFβ, and INFγ. For example, if an NK cell detects lipopolysaccharide from a pathogen, it will release TNFα, which will travel through the bloodstream to induce a number of long-lasting inflammatory changes including fever. When TNFα or any of these cytokine factors bind to cells in phospholipids in the brain, the arachidonic acid pathway is activated and PGE2 released to act on the hypothalamus and cause the fever response.

Problems with Fever

Fever is normally a beneficial immune process since increased body temperature can kill off bacteria and viruses and denature bacterial enzymes. But when the body temperature climbs too high, fever is often more harmful than helpful. High fevers also denature the body’s own proteins, which can alter normal cell metabolism, leading to cell injury and death. Persistent high body temperature can also trigger apoptosis. Treatments for severe fevers include antipyrogens and aspirin, which also help to stop blood clots that may coincide with a severe fever.

High fevers (more than 104 degrees Fahrenheit) are a symptom of severe infections. While fevers typically aren’t the direct cause of death in these cases, they do tend to worsen the prognosis. For example, septic shock is a severe bacterial infection in which bacterial toxins stimulate pyrogen and inflammatory mediator activity causes high fever. The fever makes it harder for the body to stop the systemic organ failure that occurs from the compensatory mechanisms in septic shock. Organs fail as blood is pulled away from them to fight the infection (compensatory mechanisms), the damage caused by the fever results in even more compensatory mechanism activity. While septic shock is one of the worst possible examples of fever, it illustrates an important concept in pathophysiology: that normal immune functions are as easily able to hurt us as help us.

Thymus

The thymus is a specialized organ that “educates” T cells or T lymphocytes, which are part of the adaptive immune system.

The thymus is a specialized organ of the immune system. It consists of primary lymphoid tissue, which provides a site for the generation and maturation of T lymphocytes, critical cells of the adaptive immune system.

Structure of the Thymus

The thymus is of a pinkish-gray color, soft, and lobulated on its surfaces. The organ enlarges during childhood into adolescence and begins to atrophy at puberty due to hormonal changes. After puberty, the thymus shrinks rapidly with age, eventually becoming almost indistinguishable from the surrounding fatty tissue.

The thymus consists of two lateral lobes placed in close contact along the middle line situated partly in the thorax, resting in the chest beneath the neck. The two lobes differ slightly in size, maybe united or separated, and maybe broken down into smaller lobules. It is covered with a capsule of connective tissue that provides structural support.

Histologically, the thymus contains mature lymphocytes, immature lymphocytes, and stroma, while lobule tissues consist of an inner medulla and an outer cortex. The cortex and medulla play different roles in the development of T cells. The cortex is the site of T cell generation and proliferation, while the medulla connects to the venous bloodstream and allows for transport of mature inactive T cells to the lymph nodes and transport of immature T cells from bone marrow tissue into the thymus cortex for proliferation and maturation.

The function of the Thymus

Thymus: The thymus is the site of T-cell generation and maturation.

The thymus provides an environment for T cells to mature and proliferate, a process called lymphopoiesis. First, immature T cells generated in bone marrow travel to the cortex tissues of the thymus through the bloodstream. Then the immature T cells undergo proliferative expansion, in which they are exposed to growth factors and antigen receptors are formed. Then the T cells are sorted by the thymus so that only T cells that express T-cell receptors (TcRs) and can bind to foreign MHC molecules will survive. The surviving cells will not mistake self-molecules for antigens. Only 2-4% of T cells survive this sorting process. The thymus is most active early in life for building a large reservoir of T cells. Though the removal of the thymus in childhood causes severe immunodeficiency, later in life this is not an issue because of the proliferation of thymus activity early in life.

Central tolerance is another function of the thymus. Autoimmune diseases occur when central tolerance is lost, which causes lymphocytes to recognize host molecules as antigens and attack them, even if those tissues otherwise function normally. The thymus sorts T cells so that they will be inactive towards host molecules, though sometimes a few T cells evade this sorting process and may initiate an autoimmune disease. Though the thymus is most effective at preventing this occurrence, those with certain genetic characteristics (such as altered MHC complexes) may be more likely to develop autoimmune diseases with the few T-cells that aren’t properly selected by the thymus.

Spleen

The spleen, similar to a large lymph node, acts primarily as a blood filter in the mononuclear phagocyte system of the immune system.

The spleen is the largest distinct organ of the lymphatic system. Similar in structure to a large lymph node, it acts primarily as a blood filter. Despite this important function, healthy life is possible after removal. The spleen plays important role in regards to red blood cells and the immune system.

Structure of the Spleen

The spleen is located in the left upper quadrant of the abdomen. It is similar to an enlarged lymph node but is a bit more complex. The spleen is made up of two distinct tissue types:

• The red pulp is the site of blood filtration in the spleen. It is made of connective tissue called the cord of Billroth that can fill with blood and contains many macrophages.
• White pulp is secondary lymphoid tissue that is similar to that in the adenoid tonsils. They contain large amounts of lymphocytes and antigen-presenting cells.

Unlike lymph nodes, the spleen possesses only efferent lymphatic vessels, because it only filters blood instead of lymph fluid. The splenic artery forms its primary blood supply. The spleen is unique in respect to its development within the gut because it is derived from mesenchymal tissue rather than endoderm tissue during embryonic development. However, it still shares the same blood supply as the foregut organs in the abdominal cavity.

The function of the Spleen

Spleen: This diagram of the spleen indicates the vein, artery, white pulp, red pulp, and capsule.

The primary function of the spleen is blood filtration. Blood cells have a lifespan of roughly 120 days. When blood passes through the red pulp of the spleen, healthy blood cells easily pass, while older red blood cells are caught phagocytized by the macrophages within. The macrophages also remove pathogens, denatured hemoglobin, and other cellular debris. Iron from old or damaged hemoglobin content in the blood is filtered out and sent to the liver so that new red blood cells can be created. Antigens are also filtered by the red pulp, which may be presented to naive lymphocytes in the white pulp of the spleen. This stimulates the same type of adaptive immune response that occurs in the lymph nodes.

The spleen is also important for generating new red blood cells early in embryonic development, but this function stops after birth. The spleen may also function as a reservoir of blood and platelets during hypovolemic shock, which occurs when overall tissue perfusion falls due to severe dehydration or severe bleeding or hemorrhage. During hypovolemic shock, the spleen can release up to a cup of extra blood to help mitigate the complications of fluid loss.

The spleen is often removed surgically if it becomes damaged or infected. This causes modest increases in circulating white blood cells and platelets, diminished responsiveness to some vaccines, and increased susceptibility to infection by bacteria and protozoa. In particular, there is an increased risk to infection from gram negative bacteria that cause pneumonia. Besides these increased risks, the loss of the spleen does not cause major immune system impairment, and most people will still live normal and healthy lives because the lymph nodes and liver perform the same functions as the spleen. In particular, those with splenomegaly (an enlarged spleen that could rupture) or splenic cancers are typically better off living without their spleen than living with the risk of severe bleeding from a ruptured spleen or the plethora of symptoms caused by splenic cancer and its metastases.

Tonsils

The tonsils are one of the immune system’s first lines of defense against ingested or inhaled foreign pathogens.

The tonsils are small masses of secondary lymphoid tissue located in the pharynx. They function similarly to other types of secondary lymphoid organs and also capture antigens from respiratory tract pathogens.

Location and Structure of the Tonsils

There are four pairs of tonsils located within the pharynx. They function similarly but have a few structural differences.

• The adenoids are located in the wall of the nasopharynx.
• The palatine tonsils are located in the sides of the oropharynx.
• The tubal tonsils are located in the wall of the nasopharynx near the entrance to each Eustachian tube.
• The lingual tonsils are located behind the tongue.

The tonsils are made of secondary lymphoid tissue and covered with an epithelium characteristic of the part of the body where they are located. For example, the adenoids and tubal tonsils are covered with the ciliated pseudostratified columnar epithelium of the nasopharynx, while the palatine and lingual tonsils are made up of the non-keratinized stratified squamous epithelium of the oropharynx. The tonsils also contain very deep and narrow folds in their tissues called crypts. Like the thymus, the tonsils reach their largest size near puberty and gradually atrophy thereafter.

The function of the Tonsils

Tonsils: Palatine tonsils can be seen on the left and right sides at the back of the throat.

The tonsils primarily facilitate adaptive immune responses in the upper respiratory tract, one of the most common pathways for pathogen entry in the body. In a way, the tonsils are the “first line of defense” against potential respiratory pathogens. They contain specialized M cells that collect antigens produced by respiratory tract pathogens. The secondary lymphoid tissue within the tonsils functions like the same type of the tissue in lymph nodes. Captured antigens are presented to B and T cells within the tonsil, then the B cells migrate to germinal centers within the tonsil as an adaptive immune response is initiated. Additionally, evidence exists that suggests that tonsils may play a role in  T cell maturation and development like the thymus does, but more research is needed.

Tonsil removal (tonsillectomy) is a common procedure to treat swollen and infected lymph nodes (tonsillitis). It does not appear to cause weakened immune function. Chronic infection of the adenoids can cause adenoid hypertrophy, increases in cell size from repeated damage. Enlarged tonsils can make it more difficult to breath and disrupt normal mucus drainage in the pharynx, so removal is generally recommended in those cases. Squamous cell carcinomas (epithelial tumor) and lymphomas (lymphocyte tumor) can also develop in the tonsillar tissue, and removal is a key treatment. Epidemiological studies show no significant change in immune system function in those that have a tonsillectomy, but minor increases in helper T cell levels and minor decreases in IgA levels (an antibody produced by B cells) were observed.

Cytokine network

Lymphoid Cells

A lymphocyte is a type of white blood cell in the vertebrate immune system.

A lymphocyte is a type of white blood cell in the immune system. Lymphocytes develop from lymphoblasts (differentiated blood stem cells) within lymphoid tissue in organs such as the thymus. Lymphocytes are vital for normal immune system function. The three major types of lymphocytes are T cells, B cells, and natural killer cells.

Natural Killer Cells

Lymphocyte: A stained lymphocyte surrounded by red blood cells viewed using a light microscope.

Lymphoid Tissue

Lymphoid tissue consists of many organs that play a role in the production and maturation of lymphocytes in the immune response.

The tissues of lymphoid organs are different than the tissues in most other organ systems in that they vary considerably based on cell cycle proliferation of lymphocytes. The lymphoid tissue may be primary or secondary depending upon its stage of lymphocyte development and maturation. Specialized lymphoid tissue supports proliferation and differentiation of lymphocytes.

Primary Lymphoid Organs

Central or primary lymphoid organs generate lymphocytes from immature progenitor cells such as lymphoblasts. The thymus gland and bone marrow contain primary lymphoid tissue where B and T cells are generated.

Besides generation, primary lymphoid tissue is the site where lymphocytes undergo the early stages of maturation. T cells mature in the thymus, while B cells mature in the bone marrow. T cells born in bone marrow travel to the thymus gland to mature.

Secondary Lymphoid Organs

Secondary or peripheral lymphoid organs maintain mature naive lymphocytes until an adaptive immune response is initiated. During antigen presentation, such as from the dendritic cells, lymphocytes migrate to germinal centers of the secondary lymphoid tissues, where they undergo clonal expansion and affinity maturation. Mature lymphocytes ill then recirculate between the blood and peripheral lymphoid organs until they encounter the specific antigens where they perform their immune response functions.

Secondary lymphoid tissue provides the environment for the antigens to interact with the lymphocytes. It is found mainly in the lymph nodes, but also in the lymphoid follicles in tonsils, Peyer’s patches, spleen, adenoids, skin, and other areas associated with the mucosa-associated lymphoid tissue (MALT). In addition to supporting B and T lymphocyte activation, other secondary lymphoid organs perform other unique functions, such as the spleen’s ability to filter blood and the tonsil’s ability to capture antigens in the upper respiratory tract.

Development of Lymphatic Tissue

Lymphatic tissue begins to develop by the end of the fifth week of embryonic development. Lymphatic vessels develop from lymph sacs that arise from developing veins, which are derived from mesoderm, the inner tissue layer of the embryo. Development of lymphatic tissue starts when venous endothelial tissues differentiate into lymphatic endothelial tissues. The lymphatic endothelial cells proliferate into sacs that eventually become lymph nodes, with afferent and efferent vessels that flow out from the lymph nodes. This process begins with he lymph nodes closest to the thoracic and right lymph ducts, which arises from immature subclavian-jugular vein junction. The lymph nodes organized around other lymph trunks, such as those in the abdomen and intestine, develop afterwards from nearby veins. Smaller lymph vessels and lymphatic capillaries develop after that until the lymphatic system is completed at the closed end of each lymphatic capillary.

More specialized primary lymph tissue, such as the thymus, develops from pharyngeal pouches (embryonic structures that differentiate into organs near the pharynx and throat) by the eighth week of gestation.

Lymph Nodes

Lymph nodes are small oval-shaped balls of lymphatic tissue distributed widely throughout the body and linked by lymphatic vessels.

Lymph nodes are small oval-shaped balls of lymphatic tissue, distributed widely throughout the body and linked by a vast network of lymphatic vessels. Lymph nodes are repositories of B cells, T cells, and other immune system cells, such as dendritic cells and macrophages. They act as filters for foreign particles in the body and are one of the sites where adaptive immune responses are triggered.

Structure of Lymph Nodes

Lymph node structure: This diagram of a lymph node shows the outer capsule, cortex, medulla, hilum, sinus, valve to prevent backflow, nodule, and afferent and efferent vessels.

The lymphatic system: This diagram shows the network of lymph nodes and connecting lymphatic vessels in the human body.

Lymph fluid flows into and out of the lymph nodes via the lymphatic vessels, a network of valved vessels that are similar in structure to cardiovascular veins. Each lymph node has an afferent lymph vessel that directs lymph into the node, and an efferent lymph vessel called the hilum that directs lymph out of the node at the concave side of the node. The hilum also contains the blood supply of the lymph node.

Function of Lymph Nodes

Lymph nodes are the primary site for antigen presentation and activation in adaptive immune response in B and T lymphocytes. These lymphocytes are continuously recirculated through the lymph nodes and the bloodstream. Molecules called antigens are found on bacteria cell walls, the cell walls of virus-infected cells, or even chemical substances and toxins secreted from bacteria. These antigens may be taken by cells into the lymph nodes. There, antigen-presenting cells called dendritic cells present the antigen molecule to naive B and T lymphocytes. These undergo cell cycle proliferation into lymphocytes that are able to specifically detect and eliminate pathogens associated with that antigen, through various methods such as cytotoxic action (T cells) and antibody production (B cells).

The lymph nodes also filter the lymph fluid. Macrophages in the sinus spaces phagocytize (engulf) foreign particles such as pathogen, so that lymph fluid that returns to the bloodstream is cleaned of problematic abnormalities. The lymph node is also arranged in such a way that the chance of B and T lymphocytes encountering dendritic cells is quite high, to facilitate antigen presentation.

Lymphadenopathy

Lymphadenopathy describes the clinical condition of swollen lymph nodes. This is usually caused by increased lymph flow into the nodes. This fluid may carry a higher amount of debris, so inflammation occurs as more neutrophils and later macrophages enter the node to remove debris from the lymph.

Lymphadenopathy is a symptom in conditions from trivial, such as a common cold or a minndor infection, to life-threatening, such as cancer or severe infection. Cancers that are severe and widespread from frequent metastases tend to have lymphadenopathy, so cancer staging criteria includes lymph node involvement. Additionally, cancers like lymphomas that have tumors made out of aberrant lymphocytes nearly always show lymphadenopathy, often an early warning sign for this type of cancer.

Lymphatic Vessel Structure

The lymphatic structure is based on that of blood vessels.

The general structure of lymphatic vessels is similar to that of blood vessels since these are the only two types of vessels in the body. While blood and lymph fluid are two separate substances, both are composed of the same water (plasma or fluid) found elsewhere in the body.

Layers of Lymph Vessels

The endothelium, a general term for the inner layer of a vessel, is composed of an inner lining of single, flattened epithelial cells (simple squamous epithelium). This layer mechanically transports fluid. It sits on a highly permeable basement membrane made out of an extracellular matrix that separates the endothelium from the other layers. The endothelium is designed with junctions between cells that allow interstitial fluid to flow into the lumen when the pressure becomes high enough (such as from blood capillary hydrostatic pressure) but does not normally allow lymph fluid to leak back out into the interstitial space.

The next layer is smooth muscles arranged in a circular fashion around the endothelium that alter the pressure inside the lumen (space) inside the vessel by contracting and relaxing. The activity of smooth muscles allows lymph vessels to slowly pump lymph fluid through the body without a central pump or heart. By contrast, the smooth muscles in blood vessels are involved in vasoconstriction and vasodilation instead of fluid pumping.

The outermost layer is the adventitia, consisting of fibrous tissue. It is made primarily out of collagen and serves to anchor the lymph vessels to structures within the body for stability. Larger lymph vessels have many more layers of adventitia than do smaller lymph vessels. The smallest vessels, such as the lymphatic capillaries, may have no outer adventitia. As they proceed forward and integrate into the larger lymph vessels, they develop adventitia and smooth muscle. Blood vessels also have adventitia, sometimes referred to as tunica.

Lymphatic Valves

One of the main structural features of lymph vessels is their valves, which are semilunar structures attached to opposite sides of the lymphatic endothelium. Valves are found in larger lymph vessels and collecting vessels and are absent in the lymphatic capillaries. The valves is to prevent the backflow of fluid, so that lymph eventually flows forward instead of falling backward. When the pressure of lymph fluid increases to a certain point due to filling with more lymph fluid or from smooth muscle contraction, the fluid will be pushed through the valve (opening it) into the next chamber of the vessel (called a lymphangion). As the pressure falls, the open valve then closes so that the lymph fluid cannot flow backward.

A lymphangion is the term for the space between two semilunar valves in a lymphatic vessel, the functional unit of the lymphatic system. Lymph fluid can only flow forward through lymphangitis due to the closing of valves after fluid is pushed through by fluid accumulation, smooth muscle contraction, or skeletal muscle contraction.

Without valves, the lymphatic system would be unable to function without a central pump. Smooth muscle contractions only cause small changes in pressure and volume within the lumen of the lymph vessels, so the fluid would just move backward when the pressure dropped. Blood vessels also have valves, but only in the low-pressure venous circulation. They function similarly to lymphatic valves, though are comparatively more dependent on skeletal muscle contractions.

Distribution of Lymphatic Vessels

The lymphatic system comprises a network of conduits called lymphatic vessels that carry lymph unidirectionally towards the heart.

The lymphatic system is a circulatory system for lymphatic fluid, comprising a network of conduits called lymphatic vessels that carry the fluid in one direction toward the heart. Its functions include providing sites for certain immune system functions and facilitating plasma circulation in the cardiovascular system. The lymphatic system is composed of many different types of lymph vessels over a wide distribution throughout the body.

Lymph Node Distribution

Lymphatic System: The lymph nodes and lymph vessels in human beings.

Lymphatic vessels are most densely distributed near lymph nodes: bundles of lymphoid tissue that filter the lymph fluid of pathogens and abnormal molecules. Adaptive immune responses usually develop within lymphatic vessels. Large lymphatic vessels can be broadly characterized into two categories based on lymph node distribution.

• Afferent lymphatic vessels flow into a lymph node and carry unfiltered lymph fluid.
• Efferent lymphatic vessels flow out of a lymph node and carry filtered lymph fluid. Lymph vessels that leave the thymus or spleen (which lack afferent vessels) also fall into this category.

Lymph nodes are most densely distributed around the pharynx and neck, chest, armpits, groin, and intestines. Afferent and efferent lymph vessels are also most concentrated in these areas so they can filter lymph fluid close to the end of the lymphatic system, where fluid is returned into the cardiovascular system. Conversely, lymph nodes are not found in the areas of the upper central nervous system, where tissue drains into cerebrospinal fluid instead of lymph, though there are some lymph vessels in the meninges. There are few lymph nodes at the ends of the limbs. The efferent lymph vessels in the left and lower side of the body drain into the left subclavian vein through the thoracic duct, while the efferent lymph vessels of the right side of the body drain into the right subclavian vein through the right lymphatic duct.

Flow-Through Lymph Vessels

The lymphatic vessels start with the collection of lymph fluid from the interstitial fluid. This fluid is mainly water from plasma that leaks into the interstitial space in the tissues due to pressure forces exerted by capillaries (hydrostatic pressure) or through osmotic forces from proteins (osmotic pressure). When the pressure for interstitial fluid in the interstitial space becomes large enough it leaks into lymph capillaries, which are the site for lymph fluid collection.

Like cardiovascular capillaries, lymph capillaries are well distributed throughout most of the body’s tissues, though they are mostly absent in bone or nervous system tissue. In comparison to cardiovascular capillaries, lymphatic capillaries are larger, distributed throughout connective tissues, and have a dead-end that completely prevents backflow of lymph. That means the lymphatic system is an open system with a linear flow, while the cardiovascular system is a closed system with the true circular flow.

Lymph flows in one direction toward the heart. Lymph vessels become larger, with better developed smooth muscle and valves to keep lymph moving forward despite the low pressure and adventitia to support the lymph vessels. As the lymph vessels become larger, their function changes from collecting fluid from the tissues to propelling fluid forward. Lymph nodes found closer to the heart filter lymph fluid before it is returned to venous circulation through one of the two lymph ducts.

Lymph Transport

Lymph circulates to the lymph node via afferent lymphatic vessels and drains into the lymph node in the subcapsular sinus.

Lymph transport refers to the transport of lymph fluid from the interstitial space inside the tissues of the body, through the lymph nodes, and into lymph ducts that return the fluid to the venous circulation.

Transport in the Lymph Capillaries and Vessels

Lymphatic capillaries are the site of lymph fluid collection from the tissues. The fluid accumulates in the interstitial space inside tissues after leaking out through the cardiovascular capillaries. The fluid enters the lymphatic capillaries by leaking through the mini valves located in the junctions of the endothelium. Under ordinary conditions, these mini valves prevent the lymph from flowing back into the tissues. In addition to interstitial fluid, pathogens, proteins, and tumor cells may also leak into the lymph capillaries and be transported through the lymph.

The lymph capillaries feed into larger lymph vessels. The lymph vessels that receive lymph fluid from many capillaries are called collecting vessels. Semilunar valves work together with smooth muscle contractions and skeletal muscle pressure to slowly push the lymph fluid forward while the valves prevent backflow. The collecting vessels typically transport lymph fluid either into lymph nodes or lymph trunks.

Transport Within Lymph Nodes

Lymph circulates to the lymph node via afferent lymphatic vessels. The lymph fluid drains into the node just beneath the capsule of the node into its various sinus spaces. These spaces are loosely separated by walls, so lymph fluid flows around them throughout the lymph node.

The sinus space is filled with macrophages that engulf foreign particles and pathogens and filter the lymph. The sinuses converge at the hilum of the node, where the lymph then leaves the node via an efferent lymphatic vessel toward either a more central lymph node or a lymph duct for drainage into one of the subclavian veins.

The lymph nodes contain a large number of B and T lymphocytes, which are transported throughout the node during many components of the adaptive immune response. When a lymphocyte is presented with an antigen (such as by an activated helper T cell), B cells become activated and migrate to the germinal centers of the node, where they proliferate and differentiate to be specific to that antigen. When antibody-producing B cells are formed, they migrate to the medullary (central) cords of the node. Stimulation of the lymphocytes by antigens can accelerate the migration process to about ten times normal, resulting in the characteristic swelling of the lymph nodes that is a common symptom of many infections. The lymphocytes are transported through lymph fluid and leave the node through the efferent vessels to travel to other parts of the body to perform adaptive immune response functions.

The End of Lymphatic Transport

After leaving the lymph node through efferent vessels, lymph travels either to another node further into the body or to a lymph trunk, the larger vessel where many efferent vessels converge. Four pairs of lymph trunks are distributed laterally around the center of the body, along with an unpaired intestinal trunk.

The lymph trunks then converge into the two lymph ducts, the right lymph duct and the thoracic duct. These ducts take the lymph into the right and left subclavian veins, which flow into the vena cava. This is where lymph fluid reaches the end of its journey from the interstitial space of tissues back into blood circulation.

Lymphatic Capillaries

Lymph capillaries are tiny, thin-walled vessels, closed at one end and located in the spaces between cells throughout the body.

Lymphatic circulation begins in the smallest type of lymph vessels, the lymph capillaries. These regulate the pressure of the interstitial fluid by draining lymph from the tissues.

Structure of Lymphatic Capillaries

Lymph or lymphatic capillaries are tiny thin-walled vessels, closed at one end and located in the spaces between cells throughout the body. These are particularly dense within connective tissue. Lymphatic capillaries are slightly larger in diameter than blood capillaries and contain flap-like “mini valves” that permit interstitial fluid to flow into them but not out, under normal conditions.

Lymphatic capillaries are primarily made out of an endothelium layer that sits on a permeable basement membrane. The flap-like mini valves, located at gap-like junctions in the endothelium, are formed from the overlap of endothelial cells and are normally closed. Attached to the outer opening of the mini valves are anchoring filaments containing elastic fibers. They extend out from the lymphatic capillary, attaching the endothelium to fibroblast cells in the connective tissue. Unlike larger lymphatic vessels, lymphatic capillaries do not contain smooth muscle nor do they have a well-developed adventitia, only small elastic filaments that perform a similar function.

The function of Lymphatic Capillaries

The lymph capillaries serve a variety of important functions.

Fluid Pressure Regulation

Lymphatic capillaries collect lymph fluid from the tissues, which allows them to regulate the pressure of the interstitial fluid. This fluid is essentially plasma that leaks out of cardiovascular capillaries into the tissues due to the forces of hydrostatic or oncotic pressure. When pressure is greater in the interstitial fluid than in lymph due to the accumulation of interstitial fluid, the mini valves separate slightly like the opening of a one-way swinging door so that fluid can enter the lymphatic capillary. When pressure is greater inside the lymphatic capillary, the cells adhere more closely to each other to prevent lymph backflow. The anchoring filaments are also pulled when the tissues are swollen. This opens the lymph capillaries more, increasing their volume and reducing their pressure to further facilitate fluid flow into the capillaries.

Lymph capillaries have a greater oncotic pressure (a pulling pressure exerted by proteins in solution) than blood plasma due to the greater concentration of plasma proteins in lymph. Additionally, the greater size of lymphatic capillaries compared to cardiovascular capillaries allows them to take more fluid proteins into lymph compared to plasma, which is the other reason for their greater levels of oncotic pressure. This also explains why lymph flows into the lymph capillaries easily, since fluid follows proteins that exert oncotic pressure.

Edema Prevention

Under normal conditions, lymph capillaries prevent the accumulation of edema (abnormal swelling) in the tissues. However, edema will still occur during acute inflammation or diseases in which lymph vessels are obstructed. During inflammation, fluid leaks into the tissues at a rate faster than it can be removed by the lymph capillaries due to the increased permeability of cardiovascular capillaries. During lymph vessel obstruction (such as through elephantiasis infection), lymph will be unable to progress normally through the lymphatic system, and pressure within the blocked-off lymph capillaries increases to the point where backflow into tissues may occur, while the pressure of interstitial fluid gradually rises.

Drive Lymph Through Lymphatic Vessels

Lymph Capillary: Diagram showing the formation of lymph from interstitial fluid (labeled here as “Tissue fluid”). Note: how the tissue fluid is entering the blind ends of lymph capillaries (indicated by deep green arrows).

The lymphatic capillaries bring lymph further into the lymphatic vessels. The capillaries have external valves but no internal valves or smooth muscle, so the pressure of lymph accumulation itself must propel the fluid forward into the larger vessels. Because lymphatic capillaries have closed-end and mini valves normally prevent backflow into tissues, the pressure of lymph becomes higher as more lymph is collected from the tissues, which sends the lymph fluid forward. Multiple capillaries converge in collecting vessels, where the internal valves and smooth muscle start to appear. This moves lymph further along the system despite the fall in pressure that occurs when moving from the higher-pressure capillaries to the lower-pressure collecting vessels.

Lymph Trunks and Ducts

The lymph trunks drain into the lymph ducts, which in turn return lymph to the blood by emptying into the respective subclavian veins.

After filtration by the lymph nodes, efferent lymphatic vessels take lymph to the end of the lymphatic system. The final goal of the lymphatic system is to recirculate lymph back into the plasma of the bloodstream. There are two specialized lymphatic structures at the end of the lymphatic system, called the lymph trunks and ducts.

Lymphatic Trunks

Lymphatic Ducts: The thoracic duct and right lymphatic duct.

Structure of the Lymphatic System

The lymphatic system consists of lymphatic vessels and associated lymphoid organs.

The lymphatic system is a collection of structures and vessels that drains lymph from blood and has several other functions. It is a circulatory system for lymph fluid and the site of many key immune system functions.

Lymphatic Vessels

The lymphatic vessels are the lymphatic system equivalent to the blood vessels of the circulatory system and drain fluid from the circulatory system. The network of lymph vessels consists of the initial collectors of lymph fluid, which are small, valveless vessels, and goes on to form the collector vessels, which have rudimentary valves that are not fully functional. These structures then form increasingly larger lymphatic vessels which form collaterals and have lymph regions (lymph hearts).  The larger lymph vessels contain valves that prevent the backflow of lymph.

The lymphatic system is an active pumping system driven by segments that have a function similar to peristalsis. They lack a central pump (like the heart in the cardiovascular system), so smooth muscle tissue contracts to move lymph along through the vessels. Skeletal muscle contractions also move lymph through the vessels. The lymphatic vessels make their way to the lymph nodes, and from there the vessels form into trunks. In general, the lymph vessels bring lymph fluid toward the heart and above it to the subclavian veins, which enable lymph fluid to re-enter the circulatory system through the vena cava.

Lymphatic Tissues and Organs

Lymphoid tissue is found in many organs including the lymph nodes, as well as in the lymphoid follicles in the pharynx such as the tonsils. Lymph nodes are found primarily in the armpits, groin, chest, neck, and abdomen. Lymphoid tissues contain lymphocytes (a type of highly differentiated white blood cell), but they also contain other types of cells for structural and functional support, such as the dendritic cells, which play a key role in the immune system. The system also includes all the structures dedicated to the circulation and production of lymphocytes, including the spleen, thymus, and bone marrow.

Functions of the Lymphatic System

The lymphatic system plays a prominent role in immune function, fatty acid absorption, and removal of interstitial fluid from tissues.

Your lymphatic system has many functions. Its key functions include:

• Maintains fluid levels in your body: As just described, the lymphatic system collects excess fluid that drains from cells and tissue throughout your body and returns it to your bloodstream, which is then recirculated through your body.
• Absorbs fats from the digestive tract: Lymph includes fluids from your intestines that contain fats and proteins and transports it back to your bloodstream.
• Protects your body against foreign invaders: The lymphatic system is part of the immune system. It produces and releases lymphocytes (white blood cells) and other immune cells that monitor and then destroy the foreign invaders — such as bacteria, viruses, parasites and fungi — that may enter your body.
• Transports and removes waste products and abnormal cells from the lymph.

The lymphatic system is the site of many key immune system functions. It is important to distinguish that immune system functions can happen almost anywhere in the body, while the lymphatic system is its own system where many immune system functions take place. Besides immune system function, the lymphatic system has many functions of its own. It is responsible for the removal and filtration of interstitial fluid from tissues, absorbs and transports fatty acids and fats as chyle from the digestive system, and transports many of the cells involved in immune system function via lymph.

Removal of Fluid

Interstitial fluid accumulates in the tissues, generally as a result of the pressure exerted from capillaries (hydrostatic and osmotic pressure) or from protein leakage into the tissues (which occurs during inflammation). These conditions force fluid from the capillaries into the tissues. One of the main functions of the lymphatic system is to drain the excess interstitial fluid that accumulates.

The lymphatic system is a blunt-ended linear flow system, in which tissue fluids, cells, and large extracellular molecules, collectively called lymph, are drained into the initial lymphatic capillary vessels that begin at the interstitial spaces of tissues and organs. They are then transported to thicker collecting lymphatics, which are embedded with multiple lymph nodes, and are eventually returned to the blood circulation through the left and right subclavian veins and into the vena cava. They drain into venous circulation because there is lower blood pressure in veins, which minimizes the impact of lymph cycling on blood pressure. Lymph nodes located at junctions between the lymph vessels also filter the lymph fluid to remove pathogens and other abnormalities.

Fluid removal from tissues prevents the development of edema. Edema is any type of tissue swelling from increased flow of interstitial fluid into tissues relative to fluid drainage. While edema is a normal component of the inflammation process, in some cases it can be very harmful. Cerebral and pulmonary edema are especially problematic, which is why lymph drainage is so important. Abnormal edema can still occur if the drainage components of the lymph vessels are obstructed.

 

The lymphatic system: A diagram of fluid movement in the lymphatic system.

Fatty Acid Transport

The lymphatic system also facilitates fatty acid absorption from the digestive system. During fat digestion, fatty acids are digested, emulsified, and converted within intestinal cells into a lipoprotein called chylomicrons. Lymph drainage vessels that line the intestine, called lacteals, absorb the chylomicrons into lymph fluid. The lymph vessels then take the chylomicrons into blood circulation, where they react with HDL cholesterols and are then broken down in the liver.

Immune Cell Transport

In addition to tissue fluid homeostasis, the lymphatic system serves as a conduit for transport of cells involved in immune system function. Most notably, highly-specialized white blood cells called lymphocytes and antigen -presenting cells are transported to regional lymph nodes, where the immune system encounters pathogens, microbes, and other immune elicitors that are filtered from the lymph fluid. Much of the adaptive immune system response, which is mediated by dendritic cells, takes place in the lymph nodes. Lymphatic vessels, which uptake various antigens from peripheral tissues, are positively regulated by chemokines/cytokines secreted by various immune cells during inflammation. This allows antigens to enter lymph nodes, where dendritic cells can present them to lymphocytes to trigger an adaptive immune response.

While the lymphatic system is important for transporting immune cells, its transport capabilities can also provide a pathway for the spread of cancer. Lymph circulation is one of the main ways that tumors can spread to distant parts of the body, which is difficult to prevent.

Blood Supply and Lymphatics

Lymph Nodes of the Head and Neck

The lymph nodes in the head and neck are paired and broadly split into superficial and deep nodes.

Superficial

• Occipital nodes – At the lateral border of the trapezius muscles

  • These drain the skin overlying the occiput.

• Mastoid (post-auricular) nodes – At the insertion of the sternocleidomastoid muscle on the mastoid process of the temporal bone

  • These drain the posterior neck, the superior portion of the external ear, and the ear canal until the tympanic membrane.

• Pre-auricular nodes – Anterior to the tragus of the ear

  • These drain the superficial face and temporal region.

• Superficial parotid nodes – Overlying the parotid gland.

  • This drain the nose, the nasal cavity, part of the external ear canal, and the lateral orbit

• Submental nodes – Overlying the mylohyoid muscle.

  • These drain the middle-lower lip, the floor of the mouth, and the tip of the tongue.

• Submandibular nodes – Found in the submandibular triangle, bounded by the inferior edge of the mandible and the anterior and posterior bellies of the digastric muscle, overlying the mylohyoid and hyoglossus muscles

  • These drain the submental and facial nodes, the cheeks, the upper lip, and the marginal areas of the lower lip.

• Facial nodes – Comprised of maxillary, buccinator, and submandibular lymph nodes

  • These drain the mucus membranes of the inside of the cheek, the nasal mucosa, the eyelids, and the conjunctiva.

• Superficial cervical

  • Anterior superficial cervical – Along the anterior jugular vein.

    • These drain the superficial portions of the anterior neck.
  • Posterior superficial cervical – Along the external jugular vein

    • These also drain the superficial tissues of the neck.

Deep

• Deep parotid – Found deep to the parotid gland.

  • These drain the nasal cavity and the nasopharynx.

• Deep cervical – Found along the internal jugular vein. These are named prelaryngeal, pretracheal, retropharyngeal, infrahyoid, jugulodigastric, jugulo-omohyoid, and supraclavicular nodes, depending on their anatomical positional.

  • These drain the superficial nodes and all of the head and neck.

In terms of anatomical dissection, these more easily split into levels of the neck.[rx]

Level I

• Level Ia (submental nodes) – anteriorly, in the midline between the anterior bellies of the paired digastric muscles
• Level Ib (submandibular nodes) – in the submandibular triangle, as described above.

Level II

These nodes, also called the upper internal jugular nodes, are found in an anatomical area bounded by the base of the skull superiorly, the hyoid bone inferiorly, the submandibular gland anteriorly, the posterior border of the sternocleidomastoid muscle laterally, and the internal carotid artery medially. The spinal accessory nerve separates the level IIa and IIb nodes.

• Level IIa (jugulo-digastric nodes) – superficial or anterior to internal jugular vein
• Level IIb – deep or posterior to the internal jugular vein

Level III

These nodes are also names the middle internal jugular nodes and are bound superiorly by the hyoid bone, the cricoid cartilage inferiorly, the anterior edge of the sternocleidomastoid muscle anteriorly,  the posterior margin of the sternocleidomastoid muscle, and the common carotid artery medially.

Level IV

These nodes are also named the lower internal jugular nodes and include Virchow’s node. The anatomical area in which they are found is bound superiorly by the cricoid cartilage, the clavicle inferiorly, the sternocleidomastoid muscle anteriorly, and the common carotid artery medially.

Level V

These are also named the posterior triangle nodes and are bounded by the convergence of the sternocleidomastoid and trapezius muscles superiorly, the clavicle inferiorly, the sternocleidomastoid muscle anteriorly and medially, and the trapezius muscle posteriorly.

• Level Va – superior to the cricoid cartilage and include the spinal accessory nodes
• Level Vb – inferior to the cricoid cartilage and include the transverse cervical nodes and  the supraclavicular nodes

Level VI

This level is also named the anterior compartment and contains the anterior jugular, pre-tracheal, para-tracheal, pre-cricoid, pre-laryngeal, and thyroid nodes. It is bound superiorly by the hyoid bone, inferiorly by the suprasternal notch, by the platysma muscle anteriorly, and the common carotid artery laterally.

Lymph Nodes of the Upper Limb

The deep and superficial lymphatics in the upper limb eventually drain into the axillary nodes. However, there are supratrochlear and cubital lymph nodes at the level of the elbow, brachial lymph nodes, and deltopectoral lymph nodes. The drainage of the upper limbs is particular due to the presence of sentry or sentinel lymph nodes. These are usually larger than the rest of the lymph nodes and are the first to filter the incoming lymph. However, it is not uncommon for multiple smaller sentry lymph nodes to also be present.[rx][rx]

Axillary Nodes

• Anterior nodes (pectoral) – They drain the breast and the anterior thoracic wall.

• Posterior nodes (subscapular) – They drain the posterior thoracic wall and the scapular area.

• Lateral nodes (humeral) – These are found posterior to the axillary vein and are the primary draining nodes for the upper limb.

• Central nodes – These are found close to the 2nd part of the axillary artery and receive lymph from the anterior, posterior, and lateral nodes.

• Apical nodes – These are located near the 1st part of the axillary artery and vein and filter the lymph received from the central axillary nodes and the cephalic vein.

The apical nodes further form the subclavian lymphatic trunk, which then drains into the right lymphatic duct.

Lymph Nodes of the Lower Limb

The superficial and deep lymphatic vessels of the lower limb drain into the inguinal lymph nodes in the femoral triangle. This anatomical region, also named Scarpa’s triangle, is bounded by the inguinal ligament above, the medial border of the sartorius muscle laterally, and the medial border of the adductor longus muscle medially.[rx][rx]

Inguinal Nodes

The inguinal lymph nodes split at the level (where the great saphenous vein becomes the deep femoral vein) into sub-inguinal lymph nodes below and superficial inguinal nodes above.[rx]

• Sub-inguinal nodes

  • Superficial sub-inguinal nodes – These are found alongside the proximal saphenous vein and drain the superficial lymphatic vessels.
  • Deep sub-inguinal nodes – These nodes are commonly found alongside the medial femoral vein and collect lymph from the deep lymphatic channels of the lower limb.

• Superficial inguinal nodes – These nodes are traditionally found immediately inferior to the inguinal ligament and drain the perineal area (penis, scrotum, perineum), the gluteal region, and part of the abdominal wall.

Iliac Nodes:[rx]

• External iliac nodes

  • Lateral external iliac lymph nodes – These are found lateral to the external iliac artery.
  • Intermediate external iliac lymph nodes – These are found medial to the external iliac artery and anterior to the external iliac vein.
  • Medial external iliac lymph nodes – These are found medial to the external iliac vein.

• Common iliac nodes – They commonly arise at the level of the aortic bifurcation (4th lumbar vertebra) and extend until the level of the common iliac bifurcation (2nd sacral vertebra)

  • Lateral common iliac lymph nodes – These are found lateral to the common iliac artery.
  • Intermediate common iliac lymph nodes – These appear alongside the posteromedial common iliac artery.
  • Medial common iliac lymph nodes – These are alongside the medial common iliac artery.

Terms and Definitions