Immunity and Neutrophils- Types and Function

Immunity/The immune system is a host defense system comprising many biological structures and processes within an organism that protects against disease. To function properly, an immune system must detect a wide variety of agents, known as pathogens, from viruses to parasitic worms, and distinguish them from the organism’s own healthy tissue. In many species, there are two major subsystems of the immune system: the innate immune system and the adaptive immune system. Both subsystems use humoral immunity and cell-mediated immunity to perform their functions. In humans, the blood–brain barrier, blood-cerebrospinal fluid barrier, and similar fluid–brain barriers separate the peripheral immune system from the neuroimmune system, which protects the brain.

Types of Immunity

Innate immunity – evolutionarily conserved rapid defense without immunologic memory

• • predominant cell types
    • phagocytes
      • neutrophils (polymorphonuclear leukocytes) are most abundant cells of innate immune system and earliest responders to infection
      • monocytes and macrophages are predominant immune cells at site of inflammation several days after infection
    • natural killer (NK) cells kill infected, malignant, and stressed cells
    • mast cells are commonly found in mucosal tissues and are first responders to environmental antigens
    • dendritic cells are efficient in uptake and presentation of antigens for initiation of adaptive response
  • functions of innate immunity include
    • recognizing microbial components via pattern recognition receptors and initiating inflammatory response
    • removing and destroying pathogen-associated antigens through phagocytosis and complement activation
    • killing infected or stressed cells by NK cell-mediated cytotoxicity
    • transporting antigens to lymphoid tissues for adaptive response
  • Reference – Rich RR, Fleisher TA, Shearer WT, Schroeder H, Frew AJ, Weyand CM. Clinical Immunology. 5th ed. Elsevier; 2019
• acquired or adaptive immunity – antigen-specific lymphocyte response that generates long-lasting immunological memory composed of 2 arms
  • humoral immunity – antibody (immunoglobulin)-producing B-cell response
  • cell-mediated (or cellular) immunity – major histocompatibility complex (MHC)-restricted T-cell response
  • Reference – Rich RR, Fleisher TA, Shearer WT, Schroeder H, Frew AJ, Weyand CM. Clinical Immunology. 5th ed. Elsevier; 2019
• immunodeficiency
  • primary (congenital) immunodeficiency – genetic disorders leading to defects in development or function of the immune system
  • secondary (acquired) immunodeficiency – exposure to factors resulting in suppression of normal immune system, such as
    • malnutrition
    • HIV infection
    • immunosuppressive medications
    • malignancy

Neutrophils are a type of phagocyte and a major contributor to innate immune defense against bacteria and fungi¹

• Development

• • • neutrophils arise from hematopoietic stem cells in bone marrow and cytoplasmic granules within neutrophils evolve throughout neutrophil development
    • band (or stab) cells are immature neutrophils released into circulation
    • mature neutrophils are terminally differentiated cells incapable of further cell division
• Neutrophils may be found in bone marrow, peripheral blood, adherent to endothelium, and in tissues

• • • unique morphology with multilobed nucleus (polymorphonuclear) and numerous granules allows easy identification by light microscopy
    • express CD13, CD15, CD16 (Fc gamma receptor III), and CD89 (Fc alpha receptor) detectable via flow cytometry
    • about 3-6 × 10⁹ cells/L may be found in peripheral blood, representing 30%-50% of circulating leukocytes
    • short half-life in circulation (about 7 hours), but can survive up to 2 days in tissues
• Neutrophil granules
• Characteristics of Neutrophil Granules

• • neutrophil response
    • recruitment to tissues
      • proinflammatory cytokines such as tumor necrosis factor (TNF) and interleukin 1 (IL-1) beta as well as chemokines recruit neutrophils to sites of infection
      • activation by cytokines and chemokines results in translocation of adhesion molecules to cell surface and allows rolling of neutrophils along endothelium
      • integrins on neutrophils bind intracellular adhesion molecules (ICAMs) on endothelium to adhere
      • after adhesion, neutrophils transmigrate between endothelial cells into extracellular matrix of tissue
    • microbial killing facilitated by
      • release of proteases, acid hydrolases, and inflammatory mediators within granules (degranulation) into extracellular fluid
      • phagocytosis of microbes and fusion of phagosomes with granules to form phagolysosomes that digest phagosome contents
      • production of reactive oxygen species with antimicrobial activity by phagocyte-derived nicotinamide adenine dinucleotide phosphate (NADPH) oxidase
      • release of neutrophil extracellular traps (NETs) to capture microbes and digest them via autophagy
• evaluation of neutrophil counts by complete blood count (CBC) and blood smear
  • absolute neutrophil count (ANC) includes segmented neutrophils (also called polymorphonuclear cells) and band forms
    • neutropenia defined as ANC ≤ 1.5 × 10⁹/L
    • neutrophilia defined as ANC > 7-7.7 × 10⁹/L
  • band neutrophils
    • immature neutrophils
    • morphologically characterized by absence of complete separation of nuclear lobes with a visible distinction between chromatin and parachromatin in the narrowest segment of the nucleus
    • often flagged on 5-part automated differential and confirmed by manual inspection of peripheral blood smear
  • immature/total granulocyte (I/T-G) ratio
    • defined as immature neutrophil count (myelocytes + metamyelocytes + bands +/- promyelocytes)/total neutrophil count
    • used as an indicator of a granulocyte left shift
  • granulocyte left shift indicates an abnormally high proportion of immature neutrophils in the blood, defined as either
    • increased band neutrophils in the peripheral blood (typically > 10% of WBC) by manual differential cell count
    • elevated I/T-G ratio by manual differential cell count
    • elevated number or percent of immature granulocytes detected by automated cell analyzer, which typically represents promyelocytes, myelocytes, and metamyelocytes (but not blasts)

• combined B- and T-cell immunodeficiencies
• well-defined syndromes with immunodeficiency
• predominantly antibody deficiencies
• diseases of immune dysregulation
• congenital defects of phagocyte number, function, or both
• defects of innate immunity
• autoinflammatory disorders
• complement deficiencies

Classification of primary immunodeficiency disorders as stated by the Primary Immunodeficiency Expert Committee (PID EC) of the International Union of Immunological Societies (IUIS)

• immunodeficiencies affecting cellular and humoral immunity
• combined immunodeficiencies with associated or syndromic features
• predominantly antibody deficiencies
• diseases of immune dysregulation
• congenital defects of phagocyte number or function
• defects in intrinsic and innate immunity
• autoinflammatory disorders
• complement deficiencies