Innate immune system

The innate immune system provides an immediate, nonspecific first line of defense against pathogens. It operates based on inherited cellular receptors that respond to broad pathogen-related patterns and common threat signals. The innate immune system develops in utero and, unlike the adaptive (acquired) immune system, does not require imprinting or adaptation to specific antigens nor does it provide permanent pathogen-specific immunity. For this reason, it is also referred to as “nonspecific immunity.” Response to pathogens is rapid, occurring within minutes to hours of exposure. The innate immune system comprises physical, chemical, and biological barriers (e.g., the skin, gastric acid, commensal organisms) and both cellular (e.g., granulocytes, natural killer cells, mast cells) and humoral (complement system) defense mechanisms.

General

• The innate immune system comprises the following host defense mechanisms:
  • Immune cells (granulocytes, natural killer cells, mast cells)
  • Physical and biochemical barriers
  • Humoral defenses (e.g., complement)
• Develops in utero: does not require imprinting or adaptation to specific antigens
• Response to pathogens is rapid but nonspecific

Immune cells

• Granulocytes
  • Neutrophils
  • Eosinophils
  • Basophils
• Natural killer cells
• Mast cells
• Antigen-presenting cells (APCs)
  • Mononuclear phagocyte system
    • Monocytes
    • Macrophages
  • Dendritic cells

Host barriers to infection

Physical barriers

• Coughing and sneezing (reflex)
  • Irritation of receptors in nose, sinuses, and lower and upper airways triggers coughing and/or sneezing.
  • Protective mechanisms that serve to remove irritants (e.g., dust) and pathogens through expulsion of air and mucus from the lungs and nasal cavity
• Intact skin and mucous membranes (e.g., respiratory tract, genitourinary system, digestive tract)
  • Tight junctions between epithelial cells
  • Ciliary function of ciliated epithelium in the respiratory tract
  • Symbiosis with microorganisms: imbalances can lead to various diseases (e.g., oral thrush, bacterial vaginosis, pseudomembranous colitis)

Biochemical barriers

• Production of mucus and body secretions: Mucus and body secretions contain nonspecific and specific protective substances against infections.
  • Enzymes
    • Lysozyme: enzyme formed from neutrophils, granulocytes, and macrophages that can lyse bonds in peptidoglycans (e.g., cell walls of certain, especially gram‑positive, bacteria)
    • Lactoferrin
      • Has enzyme activity (e.g., protease, ATPase, phosphatase) ^[1]
      • Contained in neutrophils and secretory fluids
      • Iron chelation → suppression of microbial growth
    • Acid hydrolases
    • RNases
  • Peptides: defensins
  • Acids: gastric acid and vaginal flora with acidic pH
• Exocytosis of cytotoxic molecules and proteins
  • Major basic protein: a protein secreted by eosinophils that is involved in host defense (especially against parasites)
    • Produced by eosinophils in response to antibody-dependent processes (e.g., IgE, antibody-dependent cell-mediated cytotoxicity)
    • Recognition of IgE-coated pathogens by Fc receptor-bearing granulocytes (eosinophils) → release of major basic protein → destruction of pathogen (e.g., helminths)
  • Toxic products of respiratory burst
    • Superoxide (O₂^‑)
    • Hypochlorite (HOCl)
    • Hydrogen peroxide
    • Hydroxyl radicals
    • Nitric oxide (NO)
    • See also “Respiratory burst” below.

Humoral defenses

• Acute phase proteins
• Complement system
• See “Humoral mechanisms” below.

HLA system

• The human leukocyte antigen (HLA) is a gene complex that encodes the major histocompatibility complex (MHC) proteins.
• MHC proteins play a vital role in initiating immune responses as they present antigen fragments to T cells and bind T-cell receptors.
• During their maturation process in the thymus gland, T cells (T lymphocytes) that recognize self-derived peptides (including peptides derived from self-MHC molecules) are selected and undergo apoptosis to prevent autoimmunity.

MHC I-associated loci (HLA-A/-B/-C) only have 1 letter after the hyphen, while MHC II-associated loci (HLA‑DR/‑DP/‑DQ) have 2 letters.
HLA A3: Fe³⁺ is increased in HE3mochromatosis.
HLA B8: If you go fishing for HLA, use MAGgots (Myasthenia gravis, Addison disease, Graves disease) for b8 (bait).
HLA B27: They are Both 27 and a PAIR (Psoriatic arthritis, Ankylosing spondylitis, IBD-associated arthritis, Reactive arthritis).
HLA C: Psoriasis is a Cutaneous Condition.

HLA DQ2/DQ8: I 8 2 (ate too) much gluten at Dairy Queen.
HLA DR2: At DooR 2, they sell multiple good hay products (SLE, Multiple sclerosis, Goodpasture syndrome, hay fever).
HLA DR2/DR3: 2, 3, S-L-E.
HLA DR3/DR4: 3,4 – sugar no more (DM type 1).
HLA DR4: 4 walls make 1 “rheum” (room).
HLA DR3/DR5: DR. Hashimoto is odd (odd numbers: 3, 5).

Pattern recognition receptors (PRRs)

• Definition: receptors on the surface of cells of the innate immune system that recognize pathogen-related molecules and activate an immune response
• Recognized molecules
  • Pathogen-associated molecular patterns: a group of molecules expressed by pathogens that are recognized by PRRs as foreign to the host
    • Viral nucleic acids
    • LPS of gram-negative bacteria
    • Bacterial flagellin
  • Damage-associated molecular patterns (DAMPs): endogenous molecules that are released from damaged host cells and trigger a noninfectious inflammatory response
• Types of PRRs
  • Toll-like receptors (TLRs): pattern recognition receptors that bind to pathogen-associated molecular patterns (PAMPs) and activate the NF-κB pathway
  • Nucleotide-binding oligomerization domain-like receptors (NLRs): a family of intracellular PRR that can recognize both pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs)
    • Play a crucial role in innate immune signaling: activation of NOD-like receptors → upregulation of NF-κB → ↑ transcription of proinflammatory cytokines (e.g., IL-1β, IL-18).
    • Defects in NOD2 receptor activity alter NF-κB activity, leading to a dysfunctional innate immune response and have been linked to Crohn disease, sarcoidosis, and graft-versus-host disease.

Respiratory burst (oxidative burst)

• Description
  • Phagocytes (e.g., neutrophils, monocytes) ingest pathogens
  • Activation of the NADPH oxidase complex generates and releases ; reactive oxygen species (ROS; free radicals) that destroy the pathogens in phagosomes
• Mechanism
  • NADPH oxidase complex
    • Can generate oxygen radicals (^•O₂^–) from O₂, but also to neutralize them
    • Defective NAPDH oxidase leads to chronic granulomatous disease.
  • Superoxide dismutase: generates hydrogen peroxide (H₂O₂) from ^•O₂^–
  • Myeloperoxidase: an enzyme in neutrophil granulocytes
    • Generates hydroxyl-halide radicals (HCl^•O) from H₂O₂ and Cl^-
    • Contains heme pigment responsible for the occasionally blue-green color of pus and sputum
  • Release of oxidative burst causes K⁺ influx, which triggers secretion of lysosomal enzymes into the phagosome.
• Clinical significance
  • Respiratory burst is a vital component of intact immune response
  • Impaired respiratory burst leads to an elevated risk of infection with catalase-positive pathogens (e.g., Aspergillus, S. aureus).
    • Normally, phagocytes can transform H₂O₂ generated by invading pathogens into ROS.
    • Catalase-positive organisms can degrade their own H₂O₂, leaving phagocytes without substrate to convert.
  • P. aeruginosa uses pyocyanin to form ROS and eliminate competing organisms.

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

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

• Vasodilation and increasing vascular permeability → ↑ blood flow
• Activation, proliferation, and attraction (chemotaxis) of immune cells

Acute phase proteins

• Set of biomarkers whose plasma concentration increases (positive markers, e.g., CRP) or decreases (negative markers, e.g., transferrin) in response to an ongoing inflammatory process.
• See “Acute phase reaction.”

Complement system

• Group of plasma proteins (e.g., C1, C2, C3)
• Synthesized in the liver as inactive precursors
• Activation (e.g., via immunoglobulins, enzymes) triggers an amplifying cascade of reactions that leads to inflammation, activation of membrane attack complex (MAC), and enhanced phagocytosis of pathogens and foreign material.

Activation pathways

• Classical pathway
  • Activated by IgM or IgG complexes binding to the pathogen
  • C1q, C1r, and C1s activation → C1 complex → split of C4 into C4a and C4b and C2 into C2a and C2b → formation of C3 convertase (C4b2b) from C4b and C2b
  • Activation of this pathway can be assessed via the total complement activity test (also called CH₅₀ test).
• Alternative pathway
  • Activated directly by pathogen surface molecules rather than by antigen-antibody complexes
  • C3 is split into C3a and C3b → binding of factor B → formation of C3 convertase (C3bBb).
• Lectin pathway
  • Activated by mannose or other sugars on pathogen surface
  • Mannose-binding lectin (MBL) binds to mannose → formation of the C1-like complex, which cleaves C4 into C4a and C4b → C4b binding C2 and splitting of C2 into C2a and C2b → formation of C3 convertase (C4b2b).
• Common end phase
  • C3-convertase (C4b2b or C3bBb) cleaves complement component 3 (C3) to factor C3a (chemotaxin) → creation of C5-convertase (C4b2b3b or C3b2Bb), which can cleave factor C5.
  • C5a acts as anaphylatoxin, while C5b binds factors C6–9 to form the membrane attack complex (MAC), which induces the lysis of the target cell.
  • Anaphylatoxins are fragments of complement proteins (e.g., C3a, C4a, C5A) that cause proinflammatory responses; (e.g., cytokine release, neutrophil and macrophage activation, platelet activation).

IgG and IgM activate the classic pathway: General Motors (GM) makes classic cars.

Effect

• Opsonization
  • Increases the susceptibility of target particles (e.g., bacteria) to phagocytosis
  • Attachment of opsonins (e.g., immunoglobulins) causes structural changes that facilitate interaction with immune cells.
  • C3b and IgG are the two main opsonins for bacteria
  • C3b is also involved in eliminating immune complexes.
• Membrane attack complex (MAC)
  • Formed by C5b–C9
  • Lysis of bacteria (especially gram‑negative bacteria) by perforation of the cell wall
• Anaphylaxis: activation of mast cells and granulocytes via C3a/C4a/C5a
• Chemotaxis: attraction of neutrophils via C5a

C3b binds to bacteria.

C3a, C4a, C5a lead to mast-cell activation and anaphylaxis.

Inhibition

• Both decay accelerating factor (DAF, aka CD55) and C1 esterase inhibitor prevent complement activation on body cells (e.g., red blood cells).

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