🛡️ Barriers & first-line defenses
Innate immunity is present from birth, acts within minutes to hours, and does not improve with repeated exposure. It relies on physical, chemical, and cellular barriers.
Physical barriers
- Skin: intact keratinized epithelium; slightly acidic pH (5.5) retards bacterial growth.
- Respiratory tract: mucus-coated ciliated epithelium traps and propels microbes outward; antimicrobial enzymes (lysozyme) in secretions.
- GI tract: gastric acid (pH 1.5–3.5) destroys most ingested pathogens; intestinal mucus and antimicrobial peptides (defensins) provide additional protection.
- Other: tears, saliva, breast milk contain lysozyme and lactoferrin.
Physiologic & chemical barriers
- Fever: pyrogenic cytokines (IL-1, IL-6, TNF) raise hypothalamic set point, inhibiting pathogen growth.
- Lysozyme: cleaves bacterial peptidoglycan.
- Defensins: pore-forming peptides in phagocytes and epithelial cells.
- Interferons α/β: induce an antiviral state by transiently blocking protein synthesis in neighboring cells.
💡 High‑yield: γδ T cells reside in epithelia and recognise shared microbial structures — they are considered part of the innate arm.
🧬 Innate cellular components
Neutrophils (polymorphonuclear leukocytes)
• most abundant circulating phagocyte
• short-lived, first responders (peak 6 h)
• multilobed nucleus, granules
• most abundant circulating phagocyte
• short-lived, first responders (peak 6 h)
• multilobed nucleus, granules
Monocytes / macrophages
• monocytes in blood → macrophages in tissues
• long-lived, potent phagocytes & cytokine producers
• M1 (classical, pro-inflammatory) vs M2 (anti-inflammatory, repair)
• monocytes in blood → macrophages in tissues
• long-lived, potent phagocytes & cytokine producers
• M1 (classical, pro-inflammatory) vs M2 (anti-inflammatory, repair)
Dendritic cells
• professional antigen-presenting cells
• bridge innate and adaptive immunity
• professional antigen-presenting cells
• bridge innate and adaptive immunity
Mast cells
• reside in skin & mucosa
• activated via TLR or IgE; release histamine and inflammatory mediators
• reside in skin & mucosa
• activated via TLR or IgE; release histamine and inflammatory mediators
Natural killer (NK) cells: large granular lymphocytes, CD16⁺ CD56⁺. Kill virus-infected or transformed cells via perforin/granzymes. Do not express antigen-specific receptors; rely on balance of activating (KAR) and inhibitory (KIR) signals.
🔍 Pattern recognition receptors (PRRs)
Germline-encoded receptors that recognise PAMPs (pathogen-associated molecular patterns) and DAMPs (damage-associated patterns).
| Receptor family | Examples | Ligands |
|---|---|---|
| Toll-like (TLR) extracellular | TLR-4, TLR-2, TLR-5 | LPS, peptidoglycan, flagellin |
| TLR endosomal | TLR-3, TLR-7/8, TLR-9 | dsRNA, ssRNA, CpG DNA |
| NOD-like (NLR) | NOD2, NLRP3 | bacterial peptidoglycan, uric acid, ATP, ROS |
| RIG-like (RLR) | RIG-1, MDA-5 | viral RNA |
Clinical correlate: NOD2 mutations are associated with inflammatory bowel disease (IBD); defects in TLR signalling lead to recurrent bacterial infections. Gain-of-function in NLRP3 inflammasome contributes to gout, atherosclerosis, and type 2 diabetes.
🔥 Inflammasome
Multiprotein complex in myeloid cells that acts as a sensor for microbes and cellular stress.
Activation of NLRP3 inflammasome → caspase-1 cleavage of pro-IL-1β and pro-IL-18 into active, pro-inflammatory cytokines.
- Triggers: microbial products, ATP, uric acid crystals, reactive oxygen species.
- Key role in sterile inflammation (e.g., gout).
🧪 Complement system
Liver-derived zymogens that amplify inflammation, opsonisation, and membrane attack. Three pathways: classical (Ab-dependent), lectin (MBL, Ab-independent), and alternative (spontaneous on microbial surfaces).
| Component | Function |
|---|---|
| C3a, C4a, C5a | anaphylatoxins (mast cell degranulation, smooth muscle contraction) |
| C5a | potent chemotactic factor for neutrophils |
| C3b | opsonin; enhances phagocytosis; clears immune complexes |
| C5b–C9 | membrane attack complex (MAC) – lysis of bacteria |
📌 USMLE: Mannose-binding lectin (MBL) pathway activates complement without antibody — part of innate immunity.
🚨 Acute inflammation & leukocyte extravasation
Triggered by tissue injury or microbial products. Four sequential steps:
- Rolling: selectins on endothelium bind mucin-like molecules on leukocytes (weak, transient).
- Activation: chemokines (IL-8), C5a, f-Met peptides bind leukocyte receptors → integrin conformational change.
- Arrest / adhesion: integrins (e.g., LFA-1) bind Ig-superfamily CAMs (ICAM-1) on endothelium – firm adhesion.
- Transmigration: leukocytes squeeze between endothelial cells into tissue.
Leukocyte adhesion deficiency (LAD): autosomal recessive defect in CD18 (β₂ integrin chain). Patients have recurrent bacterial infections, no pus formation, marked neutrophilia. Diagnosis by flow cytometry for CD18.
🧫 Phagocytosis & intracellular killing
Opsonisation by IgG or C3b increases phagocytic efficiency up to 4000‑fold.
Respiratory burst
• NADPH oxidase → superoxide (O₂⁻)
• superoxide dismutase → H₂O₂
• myeloperoxidase (MPO) → HOCl (bleach)
• NADPH oxidase → superoxide (O₂⁻)
• superoxide dismutase → H₂O₂
• myeloperoxidase (MPO) → HOCl (bleach)
Oxygen‑independent
• lysozyme, defensins, lactoferrin, hydrolytic enzymes
• lysozyme, defensins, lactoferrin, hydrolytic enzymes
Nitric oxide (NO): iNOS converts arginine to NO, potent antimicrobial.
Chronic granulomatous disease (CGD): defect in NADPH oxidase subunit → no superoxide / H₂O₂.
• Catalase‑positive organisms (S. aureus, Aspergillus, Klebsiella) survive because they destroy H₂O₂.
• Catalase‑negative bacteria supply H₂O₂ for MPO → killing occurs.
• Diagnosis: NBT test (negative in CGD) or dihydrorhodamine flow cytometry.
• Catalase‑positive organisms (S. aureus, Aspergillus, Klebsiella) survive because they destroy H₂O₂.
• Catalase‑negative bacteria supply H₂O₂ for MPO → killing occurs.
• Diagnosis: NBT test (negative in CGD) or dihydrorhodamine flow cytometry.
⚠️ Phagocyte defects – high yield
| Disorder | Defect | Consequence |
|---|---|---|
| LAD (type I) | CD18 (β₂ integrin) | no adhesion / extravasation; recurrent bacterial infections, omphalitis |
| CGD | NADPH oxidase (any subunit) | no respiratory burst; recurrent catalase‑positive infections; NBT negative |
| MPO deficiency | myeloperoxidase | mild, often asymptomatic; Candida susceptibility |
💊 Treatment: CGD patients benefit from IFN‑γ (boosts macrophage activity) and prophylactic antibiotics. Bone marrow transplantation is curative for LAD.
🧪 Cytokines in innate immunity
| Cytokine | Main source | Innate actions |
|---|---|---|
| IL‑1, IL‑6, TNF‑α | macrophages | fever, acute‑phase proteins, endothelial activation, cachexia |
| IL‑8 (CXCL8) | macrophages | neutrophil chemotaxis and adhesion |
| IL‑12 | macrophages, DCs | NK cell IFN‑γ production |
| IL‑10 | macrophages, DCs | anti‑inflammatory; inhibits IL‑12, MHC class II |
| IFN‑α / β | virally infected cells | antiviral state, increased MHC I, NK activation |
| TGF‑β | macrophages, lymphocytes | anti‑inflammatory, tissue repair |
Systemic effects: IL‑1, IL‑6, TNF‑α induce fever, leukocytosis, and hepatic acute‑phase protein synthesis (CRP, serum amyloid A).
📋 Innate immunity at a glance
- Barriers: skin, mucosa, pH, lysozyme
- PRRs: TLR, NLR, RLR
- Inflammasome → IL‑1β, IL‑18
- Complement: opsonins, anaphylatoxins, MAC
- Extravasation: selectins → integrins → diapedesis
- Phagocytosis: respiratory burst, MPO, NO
- CGD: NADPH oxidase defect, catalase‑positive infections
- LAD: CD18 deficiency, no pus
- NK cells: KAR/KIR balance, HLA‑E
- Interferons: antiviral, immunomodulatory
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