Innate immune system

The innate immune system provides a non-specific first line of defense against pathogens. It comprises physical barriers (e.g. the skin) and both cellular (granulocytes, natural killer cells) and humoral (complement system) defense mechanisms. The reaction of the innate immune system is immediate, but unlike the adaptive immune system, it does not provide permanent immunity against pathogens.

Definition

The innate immune response is composed of physical, chemical, cellular, and humoral defense mechanisms against pathogens. It is present at birth and does not require imprinting or adaptation to specific antigens. For this reason, it is also referred to as nonspecific immunity. Response to pathogens is rapid, occurring within minutes to hours of exposure. The components of the innate immune system include neutrophils, macrophages, monocytes, dendritic cells, natural killer cells, and the complement system.

Physical, chemical, and biological mechanisms

• Intact outer skin and mucous membranes (physical barrier)
  • Tight junctions between epithelial cells
  • Ciliary function of the respiratory tract (ciliated epithelium of the trachea and bronchi)
  • Gastric acid and vaginal flora with acidic pH
  • Normal flora (commensal microorganisms): harmless microorganisms that protect against pathogens
    • Imbalances in natural flora can lead to various diseases: e.g., oral thrush, bacterial vaginosis, pseudomembranous colitis
• Mucus (chemical barrier) contains nonspecific and specific protective substances against infection.
  • Lysozyme: enzyme formed from neutrophils, granulocytes, and macrophages that can lyse linkages in peptidoglycans (e.g., the cell wall of gram‑positive bacteria).
  • Lactoferrin: exhibits enzyme‑like properties and binds iron.
  • Immunoglobulins: (particularly IgA) bridge the innate and adaptive immune responses.
• Coughing and sneezing (reflex) protect airways
• Exocytosis of cytotoxic molecules and proteins
  • Major basic protein: produced by eosinophils in response to antibody-dependent processes (IgE, antibody-dependent cell-mediated cytotoxicity) and important in the defense against helminthic infections.
    • IgE coat pathogens; → recognized by Fc receptor-bearing granulocytes (eosinophils) → release of major basic protein → destruction of the pathogen
  • Defensins
  • Acid hydrolases
  • RNases
  • Toxic products of respiratory burst: superoxide (O₂^‑), hypochlorite (HOCl), hydrogen peroxide, hydroxyl radicals, and nitric oxide (NO)

Cells

The cells involved in innate immunity are listed below. For the specific function of the individual populations see basics of hematology.

• Granulocytes
  • Neutrophils
  • Eosinophils
  • Basophils
• Mast cells
• Antigen-presenting cells
  • Mononuclear phagocyte system
    • Monocytes
    • Macrophages
  • Dendritic cells
  • B cells (link to adaptive immunity)

Respiratory burst (oxidative burst)

• Definition: generation of reactive oxygen species (free radicals) in phagocytes (e.g., neutrophils, monocytes) for the destruction of ingested pathogens in phagosomes
• Mechanism
  • Generation of oxygen radicals (O₂^•–) from O₂ via the NADPH oxidase complex
  • Generation of hydrogen peroxide (H₂O₂) from O₂^•– via superoxide dismutase
  • Generation of hydroxyl-halide radicals (HClO^•) from H₂O₂ and Cl^- via myeloperoxidase
  • Oxidative burst also leads to K⁺ influx, which releases lysosomal enzymes into the phagosome.

Defects in the NADPH oxidase cause chronic granulomatous disease.

Myeloperoxidase contains a blue-green heme-containing pigment that gives sputum and pus a green-yellow color.

Catalase positive organisms can degrade H₂O₂ into H₂O and O₂ and prevent the formation of hydroxyl-halide radicals.

HLA system and pattern recognition receptors

• Human leukocyte antigen (HLA)
  • Major histocompatibility complex class I (MHC class I)
    • Located on the surface of all nucleated body cells and platelets
    • Encoded in HLA‑A, HLA‑B, and HLA‑C
    • Comprised of two polypeptide chains; of different length; : The long chain contains the alpha domains; (α1, α2, α3; ), the short chain is the peptide β₂-microglobulin and carries the β₂ domain.
    • Continuously presents endogenous fragments of proteins located in the cell, which allows for rapid detection and destruction of cells in infections with intracellular pathogens; (e.g., viruses) and cells that produce atypical proteins (neoplastic or malignant cells) → cytotoxic T‑cell reaction
    • The exception is the cross-presentation of extracellular antigens by dendritic cells → primes CD8⁺ T cells, which can only interact with MHC I
    • Antigens are peptides, lipids, or polysaccharides which are transported to the RER via transporter associated with antigen processing (TAP).
    • MHC I-antigen complexes are assembled in the RER.
    • The polymorphic zone presents antigens derived from within the cell. The nonpolymorphic zone binds to CD8 T lymphocytes.
    • Several viruses prevent the expression of MHC class I on the cell surface. The absence of MHC class I receptors on infected or malignant cells is recognized by natural killer cells (NK cells).
  • Major histocompatibility complex class II (MHC class II)
    • Located on the surface of antigen‑presenting cells (APCs; dendritic cells, monocytes/macrophages, B lymphocytes): encoded in HLA‑DR, HLA‑DP, and HLA‑DQ
    • Comprised of two polypeptide chains of equal length (alpha and beta) that each contain two domains (α1, α2 and β1, β2)
    • Antigen-presenting cells can ingest exogenous material (extracellular pathogens) into fragments via phagocytosis and present them on the cell surface via MHC class II receptors.
    • MHC II-antigen complexes are assembled in acidified endosomes after the release of the invariant chain.
    • Antigen presentation leads to the activation of CD4⁺ T lymphocytes, which then activate B lymphocytes and, thus, provides a connection between innate and adaptive immunity.
• Toll-like receptors (TLRs)
  • Pattern recognition receptors that bind to pathogen-associated molecular patterns (PAMPs)
  • Activate the NF-κB pathway

References:^[1]

Humoral mechanisms

The humoral mechanisms of innate immunity is mediated by proteins that are secreted into bodily fluids or the blood stream. These proteins often initiate additional immune responses via:

• Vasodilation and increasing vascular permeability → increased blood flow
• Activation, proliferation, and attraction (chemotaxis) of immune cells
• Killing the pathogen

Acute phase proteins

• see acute phase reaction

Complement system

• Group of proteins that circulate in the blood as inactive precursors. After stimulation by antibody complexes or by pathogens, complement proteases can activate other complement precursors, leading to a cascade of reactions that is referred to as “complement activation.” The complement system can enhance the function of antibodies and phagocytes as detailed below.
• Activation
  • Classical pathway: activated by IgM or IgG complexes binding to the pathogen (via C1)
  • Alternative pathway: activated directly by pathogen rather than by antigen-antibody complexes (via C3)
  • Lectin pathway (via C1-like complex)
• Effect
  • Opsonization: the process of altering bacteria to increase their susceptibility to phagocytosis. C3b and IgG are the two main opsonins for bacteria (via C3b).
  • Lysis of bacteria (particularly gram‑negative bacteria).
    • C5–C9 form the membrane attack complex (MAC) → perforation of the cell wall → cell lysis
  • Activation of mast cells and granulocytes (C3/C4/C5) → anaphylaxis
  • Chemotaxis of neutrophils → C5a
  • Clearance of immune-complexes → C3b
• Inhibition
  • DAF decay accelerating factor (CD55)
  • C1 esterase inhibitor → e.g. on red blood cells