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, ) and both cellular (e.g., granulocytes, natural killer cells, mast cells) and humoral (complement system) defense mechanisms.
- The innate immune system comprises the following host defense mechanisms:
- Develops in utero: does not require imprinting or adaptation to specific antigens
- Response to pathogens is rapid but nonspecific
- Natural killer cells
- Mast cells
- Antigen-presenting cells (APCs)
- Physical barriers (e.g., skin and mucous membranes)
- Biochemical barriers (e.g., body secretions, exocytosis of cytotoxic molecules and proteins)
Innate vs. adaptive immunity
|Key features of innate and adaptive immune systems|
|Innate immune system||Adaptive immune system|
|Genetics|| || |
|Inheritance|| || |
|Response time|| || |
|Specificity|| || |
|Memory response|| |
- Coughing and sneezing (reflex)
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)
Mucosa-associated lymphoid tissue (MALT)
- Found in various submucosal membrane sites of the body (e.g., gastrointestinal tract, nasopharynx, lung, skin, and conjunctiva)
- Populated by lymphocytes, plasma cells, and macrophages protecting the body from invasion
Production of mucus and body secretions: Mucus and body secretions contain nonspecific and specific protective substances against infections.
- Lysozyme: enzyme formed from neutrophils, granulocytes, and macrophages that can lyse bonds in peptidoglycans (e.g., cell walls of certain, especially gram‑positive, bacteria)
- Acid hydrolases
- 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)
- Toxic products of respiratory burst
- 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.
|Overview of MHC molecules|
|MHC class I (MHC I)||MHC class II (MHC II)|
|Loci|| || |
|Antigen presentation|| |
|HLA and disease association|| |
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
- Pathogen-associated molecular patterns: a group of molecules expressed by pathogens that are recognized by PRRs as foreign to the host
- 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)
- NADPH oxidase complex
- Superoxide dismutase: generates hydrogen peroxide (H2O2) from •O2–
- Myeloperoxidase: an enzyme in neutrophil granulocytes
- Release of oxidative burst causes K+ influx, which triggers secretion of lysosomal enzymes into the phagosome.
- Respiratory burst is a vital component of innate immune response
- Impaired respiratory burst leads to an elevated risk of infection with catalase-positive pathogens (e.g., Aspergillus, S. aureus).
- P. aeruginosa uses pyocyanin; to form ROS and eliminate competing organisms.
can degrade H2O2 into H2O and O2 and prevent the formation of hydroxyl-halide radicals.
- Vasodilation and increasing vascular permeability → ↑ blood flow
- Activation, proliferation, and attraction (chemotaxis) of immune cells
- 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 “.”
- 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.
- Both decay-accelerating factor (DAF, aka CD55) and C1 esterase inhibitor prevent complement activation.
- 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
- Lectin pathway
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.
- 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)
- 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.
Complement receptors 
- Membrane-bound receptors that bind complement protein fragments produced in the plasma during an acute inflammatory response
- Activation contributes to inflammation regulation, leukocyte extravasation, and phagocytosis
|Overview of complement receptors|
|Receptor||Major ligands||CD number||Cell types||Function|
|Complement receptor type 1 (CR1)|| || |
|Complement receptor type 2 (CR2)|
|Complement receptor type 3 (CR3)|| |
|Complement receptor type 4 (CR4)|| |
|C3a receptor|| |
|C5a receptor|| |
Defects of innate immunity
|Overview of innate immune defects |
|Defective element/complement||Associated conditions|| |
Increased susceptibility to