Innate Immunity – Anatomy, Mechanism, Functions

Innate Immunity – Anatomy, Mechanism, Functions

Innate Immunity/ 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 response is the first mechanism for host defense found in all multicellular organisms. The innate immune system is more ancient than the acquired or adaptive immune response, and it has developed and evolved to protect the host from the surrounding environment in which a variety of toxins and infectious agents including bacteria, fungi, viruses and parasites are found ().

The system of defenses termed innate immunity involves immediate, nonspecific actions, including physical barriers such as the skin and mucous membranes of the gastrointestinal, respiratory, and urogenital tracts that prevent infections or penetration of the host body. Bacteria, fungi, and parasites that manage to penetrate these barriers are quickly removed by neutrophils

Summary of non-specific host-defense mechanisms for barriers of innate immunity []

Barrier Mechanism
Anatomic
 Skin • Mechanical barrier retards entry of microbes
• Acidic environment (pH 3–5) retards growth of microbes
 Mucous membrane • Normal flora compete with microbes for attachment sites
• Mucous entraps foreign microbes
• Cilia propel microbes out of body
Physiologic
 Temperature • Body temperature/fever response inhibits growth of some pathogens
 Low pH • Acidic pH of stomach kills most undigested microbes
 Chemical mediators • Lysozyme cleaves bacterial cell wall
• Interferon induces antiviral defenses in uninfected cells
• Complement lyses microbes or facilitates phagocytosis
Phagocytic/endocytic barriers
• Various cells internalize (endocytosis) and break down foreign macromolecules
• Specialized cells (blood monocytes, neutrophils, tissue macrophages) internalize (phagocytose), kill and digest whole organisms
Inflammatory barriers
• Tissue damage and infection induce leakage of vascular fluid containing serum protein with antibacterial activity, leading to influx of phagocytic cells into the affected area

Skin and Mucosae (Surface Barriers)

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

Key Points

The skin consists of the epidermis, dermis, and basement membrane.

The epidermis is the outermost layer of skin and forms a protective barrier over the body’s surface. Its layers continually grow outward as older layers shed away.

The dermis is below the epidermis and is made of connective tissue that cushions the body from stress and strain. It contains mechanoreceptors, blood vessels, and sweat glands.

The mucosae are linings covered in the epithelium and involved in absorption and secretion. They line cavities that are exposed to the external environment and internal organs.

The barrier immune system is part of the innate immune system and consists of anything that the skin, mucosae, and chemical secretions of the body do to prevent pathogens from invading.

The barrier system can fail when the skin breaks or when pathogens invade the mucosal epithelium, so other innate and adaptive immune system functions exist to destroy pathogens in these cases.

Key Terms

  • mucous membranes: Specialized epithelium for internal and semi-internal structures that usually secretes mucus and provides some barrier immune system function.
  • barrier immune system: A component of the innate immune system that refers to the physical and chemical barriers that prevent pathogens from entering and infecting the body.
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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.

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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.

image 

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.

Key Points

Many white blood cells and other cells in the body use phagocytosis to engulf and kill cells.

Phagocytosis occurs over several steps, which include binding to an opsonized pathogen with a receptor and killing it using an oxidative burst.

Monocytes are phagocytes that can differentiate into macrophages and dendritic cells based on conditions within the body.

Macrophages are the cleanup crew for the innate immune system. They remove debris, pathogens, and dead neutrophils after an inflammatory response.

Neutrophils are polymorphonuclear (PMN) granulocytes are the first responders to an inflammatory response. They kill pathogens through phagocytosis and degranulation but die as a result.

Mast cells are circulation PMN granulocytes that trigger an immune response by releasing an inflammatory mediator when they detect an antigen with their toll-like receptors.

Key Terms

  • oxidative burst: A chemical reaction that occurs in phagocytes in which an engulfed pathogen is destroyed by exposure to oxidative stress from reactive oxygen species.
  • PMN granulocyte: A type of phagocyte that contains PMN granules, most notably neutrophils and mast cells, but also basophils and eosinophils.

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.

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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.

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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.

This diagram of leukocyte differentiation indicates the self-renewing stem cell, B lymphocyte, T lymphocyte, NK cell, bi-potential cell, phagocytes, dendritic cell, macrophage, neutrophils, monocytes, and mast cells. 

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 []

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.

Key Points

NK cells differentiate from lymphocyte progenitor cells and are a critical part of the innate immune system.

NK cells recognize abnormal or infected cells with activating receptors and inhibitory receptors.

All normal cells in the body express MHC I to signal that those cells are part of the body.

Inhibitory receptors recognize MHC class I alleles, which inhibits the NK killing response and explains why NK cells will kill cells possessing few or no MHC class I molecules.

Activating receptors recognize antigens, antibodies, or other opsonins on a cell’s surface and activate a killing response.

NK cells are cytotoxic; small granules in their cytoplasm contain proteins such as perforin and proteases known as granzymes that trigger either apoptosis or cell lysis in an abnormal cell.

NK cells may release two potent immune system cytokines, IFN-gamma and TNF-alpha when certain receptors are activated.

Key Terms

  • Major Histocompatibility Complex I: A molecule expressed on cells to signal to immune system cells that they are normal cells of that organism’s body. Abbreviated as MHC I.
  • apoptosis: A response in which a cell undergoes programmed cell death and its DNA and other components are destroyed completely. It is a mechanism to stop viral infections and cancer development and is a result of cellular stress.

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.

This schematic indicates the induction of apoptosis, cytolytic T cell, MHC I inhabitor receptor, natural killer cell, normal MHC class I expression, pathogenic antogen, MHC class I molecule, intracellular pathogen, and MHC Class I downregulation by pathogen: "Missing Self". 

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.

Key Points

Acute inflammation occurs due to infection, injury, or irritation, and is an essential part of the healing process to remove pathogens and start the wound-healing process.

During inflammation, vasodilation occurs, the endothelium becomes more permeable as exudate leaks into the tissues, and neutrophils migrate to the site of inflammation.

Acute inflammation is initiated by cells already present in all tissues, such as mast cells that recognize pathogen-associated molecular patterns (PAMPs) with toll-like receptors, but other cells like natural killer (NK) cells can trigger inflammation as well.

Acute inflammation is characterized by pain, redness, immobility (loss of function), swelling, and heat.

Neutrophils migrate to inflamed tissues by rolling onto the endothelium with selectins, adhering to it with integrins, and sliding through its gaps with PECAM-1. Then they follow chemokines to the tissues to find pathogens to destroy.

Repeated bouts of acute inflammation lead to chronic inflammation, a process of constant healing and inflammation-induced damage as the initial problem is never truly healed.

Allergic reactions are the result of an inappropriate immune response that triggers inflammation.

Key Terms

  • extravasation:
  • exudate: Protein-rich edema caused by proteins flowing into the tissues during inflammation due to increased vascular permeability and oncotic pressure.
  • inflammatory mediator: Any chemical released from cells that stimulate the vasodilation and increased permeability that occurs during acute inflammation.

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

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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.

Key Points

Antimicrobial peptides include a net positive charge and hydrophilic and hydrophobic ends, which allow them to adhere to the lipid membranes of bacterial cell membranes.

The positive charge makes antimicrobial peptides selective, so they only adhere to negatively charged bacterial cell membranes instead of host cell membranes.

The modes of action by which antimicrobial peptides kill bacteria are varied and include disrupting membranes, interfering with metabolism, and targeting cytoplasmic components.

Many bacteria have developed antimicrobial resistance, in which a component of their cell membranes or enzyme secretions is altered to prevent the peptides from binding to the bacteria, or by inhibiting the peptides directly.

Key Terms

  • antimicrobial resistance: Any mechanism that enables bacteria to evade or inhibit antimicrobial action.
  • peptide: A class of organic compounds consisting of various numbers of amino acids in which the amine of one is reacted with the carboxylic acid of the next to form an amide bond.
  • amphipathic: A molecule with both hydrophobic and hydrophilic groups that allow it to adhere to lipid structures more easily.

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.

This diagram indicates antimicrobial peptides, hydrophobic and electrostatic interaction, plant and mammal membranes, bacterial membranes, cholesterol, and zwitterionic phospholipids. 

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.

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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.

Key Points

Temperature is ultimately regulated in the hypothalamus. A trigger of the fever, called a pyrogen, causes a release of prostaglandin E2 (PGE2). PGE2 then acts on the hypothalamus, which raises the temperature setpoint so that the body temperature increases through heat generation and vasoconstriction.

Fever may be useful as an innate immune response to fight off infections by killing bacteria and viruses.

Aspirin is a potent anti-fever drug because it inhibits COX-2 production, which inhibits PGE2 release.

A pyrogen is a substance that induces fever and can be either internal (endogenous) or external (exogenous) to the body.

During severe infections, fever can be more harmful than helpful as the body’s cells are injured in addition to the bacterial cells, which can cause more problems for the innate immune system to handle.

Key Terms

  • pyrogen: Any substance that produces fever or a rise in body temperature through the arachidonic acid pathway.
  • arachidonic acid pathway: The pathway by which the fever regulator prostaglandin E-2 and several inflammatory mediators are produced by pyrogen activity with phospholipids and COX-2, usually in the brain or liver.

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.

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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.

References

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