Innate Immunity

The body's first line of defence — germline-encoded, non-specific, immediate, and without memory. Innate immunity recognises broad molecular patterns shared by microbes, acts within minutes to hours, and instructs the slower adaptive response. This topic anchors your understanding of complement deficiencies, sepsis, TLR signalling, and acute-phase reactants — all repeat NEET PG favourites.

Innate vs Adaptive Immunity — the core contrast

Examiners love the head-to-head comparison. Anchor every fact to this table.

Feature	Innate immunity	Adaptive immunity
Specificity	Broad — molecular patterns (PAMPs)	Highly specific — individual epitopes
Receptors	Germline-encoded (TLRs, NLRs)	Somatically rearranged (BCR, TCR)
Diversity	Limited, fixed	Vast (gene rearrangement)
Memory	Absent (classically); "trained immunity" is an exception	Present (memory B/T cells)
Onset	Immediate (minutes–hours)	Delayed (days)
Cells	Neutrophils, macrophages, NK cells, dendritic cells, mast cells	T lymphocytes, B lymphocytes
Soluble factors	Complement, lysozyme, defensins, cytokines, acute-phase proteins	Antibodies, cytokines
Self/non-self	Recognises absence of self markers (NK), conserved microbial motifs	Discriminates via clonal selection + tolerance

High-yield: The defining feature distinguishing innate from adaptive immunity is the absence of immunological memory and the use of germline-encoded (non-rearranged) receptors. The exception worth knowing is "trained immunity" — epigenetic reprogramming of monocytes/NK cells (e.g. after BCG vaccination) giving a non-specific memory-like enhancement.

Components — the four arms

Innate immunity is built on four functional pillars:

1. Anatomical/physical & chemical barriers
2. Cellular components (phagocytes, NK cells, etc.)
3. Humoral/soluble components (complement, acute-phase proteins, antimicrobial peptides)
4. Cytokines orchestrating the response

1. Physical, chemical and microbiological barriers

• Skin — keratinised stratified squamous epithelium; physical barrier plus low pH (~5.5, "acid mantle") and fatty acids from sebum.
• Mucous membranes & mucociliary escalator — trap and sweep pathogens (respiratory tract).
• Lysozyme (muramidase) — in tears, saliva, mucus; cleaves the β-1,4 glycosidic bond between NAM and NAG in peptidoglycan → lyses gram-positive cell walls.
• Gastric acid (pH ~2), bile salts, proteolytic enzymes.
• Defensins — cationic antimicrobial peptides (α-defensins from neutrophils/Paneth cells, β-defensins from epithelium) that punch holes in microbial membranes.
• Lactoferrin & transferrin — iron sequestration (nutritional immunity).
• Normal/commensal flora — colonisation resistance.

High-yield: Lysozyme is most effective against gram-positive bacteria because their thick exposed peptidoglycan is accessible; gram-negatives are protected by the outer membrane.

2. Cellular components

Cell	Lineage	Key role	Exam pearl
Neutrophil	Myeloid	First responder; phagocytosis; NETs	Most abundant WBC; "pus" cell
Macrophage	Myeloid (monocyte-derived)	Phagocytosis, antigen presentation, cytokines	Tissue-fixed (Kupffer, alveolar, microglia, osteoclast)
Dendritic cell	Myeloid/lymphoid	Professional APC; bridges innate→adaptive	Most potent APC
NK cell	Lymphoid	Kills virus-infected & tumour cells; ADCC	No memory; "missing-self"
Mast cell/basophil	Myeloid	Histamine; allergy & antiparasitic	IgE-mediated
Eosinophil	Myeloid	Antiparasitic (helminths); allergy	Major basic protein

Phagocytosis — stepwise

Chemotaxis → Recognition/attachment (opsonin–receptor) → Engulfment (pseudopodia) → Phagosome formation → Phagolysosome fusion → Killing & digestion → Antigen presentation.

• Opsonins that enhance attachment: IgG (Fc receptor), C3b (CR1), and mannose-binding lectin / CRP.
• Oxygen-dependent killing (respiratory/oxidative burst): NADPH oxidase generates superoxide → H₂O₂ → myeloperoxidase + Cl⁻ → hypochlorous acid (HOCl), the most potent microbicidal product.
• Oxygen-independent killing: lysozyme, defensins, lactoferrin, hydrolytic enzymes.

High-yield: Chronic granulomatous disease (CGD) = defective NADPH oxidase → failed respiratory burst. Diagnose with Nitroblue Tetrazolium (NBT) test (no colour change/abnormal) or the more sensitive Dihydrorhodamine (DHR) flow cytometry. Patients get recurrent infections with catalase-positive organisms (Staphylococcus aureus, Aspergillus, Burkholderia, Serratia, Nocardia — mnemonic "Cats Need PLACESS").

Natural Killer (NK) cells

• Large granular lymphocytes; CD16⁺ CD56⁺, CD3⁻ (no TCR).
• Recognise "missing self" — loss of MHC class I (e.g. virus-infected/tumour cells downregulate MHC-I to escape T cells, but this triggers NK killing).
• Balance of signals: inhibitory receptors (KIRs binding MHC-I) vs activating receptors. Loss of inhibition → killing.
• Kill via perforin + granzymes and Fas–FasL.
• Mediate ADCC (antibody-dependent cell-mediated cytotoxicity) via the CD16 (FcγRIII) receptor binding IgG-coated targets.
• Activated by IL-12, IL-15, IFN-α/β; secrete IFN-γ (activates macrophages).

High-yield: NK cell killing is regulated by the balance between activating and inhibitory receptors; the inhibitory KIRs recognise self MHC class I. NK is the principal innate defence against herpesviruses (severe disseminated HSV/VZV/CMV in NK deficiency).

3. Pattern recognition receptors (PRRs)

PRRs recognise conserved PAMPs (pathogen-associated molecular patterns) and DAMPs (damage-associated molecular patterns from injured host cells).

TLR	Ligand (PAMP)	Location	Microbe
TLR2 (with 1/6)	Lipopeptides, peptidoglycan, lipoteichoic acid	Surface	Gram-positive bacteria
TLR3	dsRNA	Endosome	Viruses
TLR4	LPS (endotoxin)	Surface	Gram-negative bacteria
TLR5	Flagellin	Surface	Motile bacteria
TLR7/8	ssRNA	Endosome	Viruses
TLR9	Unmethylated CpG DNA	Endosome	Bacteria/viruses

• Other PRR families: NLRs (cytoplasmic; form the inflammasome), RIG-I-like receptors (cytoplasmic viral RNA), C-type lectin receptors (mannose receptor, dectin-1 for fungal β-glucan).
• Signalling: most TLRs use the MyD88 adaptor → NF-κB activation → pro-inflammatory cytokines (TNF-α, IL-1, IL-6). TLR3 (and TLR4 partly) use TRIF → IRF3 → type I interferons.
• Inflammasome (NLRP3): activates caspase-1, which cleaves pro-IL-1β and pro-IL-18 into active forms.

High-yield: TLR4 = LPS/endotoxin sensor and is central to gram-negative sepsis/septic shock. TLR3, 7, 8, 9 are endosomal and sense nucleic acids. Mnemonic for endosomal nucleic-acid TLRs: "3-7-8-9 live in the endosome."

4. Acute-phase reactants

Hepatocyte-derived plasma proteins whose concentration shifts ≥25% during inflammation; driven mainly by IL-6 (also IL-1, TNF-α).

Positive acute-phase reactants (rise):

• C-reactive protein (CRP) — binds phosphocholine on microbes/dead cells; opsonin + complement activator; rises within 6–8 h, peaks ~48 h. Best marker of acute inflammation.
• Serum amyloid A (SAA) — precursor of AA amyloid (secondary amyloidosis).
• Fibrinogen — drives rouleaux formation → raised ESR.
• Hepcidin — blocks ferroportin → traps iron → anaemia of chronic disease.
• Procalcitonin — relatively specific for bacterial sepsis.
• Haptoglobin, ceruloplasmin, ferritin, complement, α1-antitrypsin.

Negative acute-phase reactants (fall): Albumin, transferrin, transthyretin (prealbumin).

High-yield: IL-6 is the master inducer of the hepatic acute-phase response. CRP rises and falls faster than ESR, making it better for monitoring response to treatment. Procalcitonin distinguishes bacterial from viral infection and guides antibiotic stewardship.

The complement system

A cascade of ~30 plasma proteins (synthesised mainly by the liver) that opsonise pathogens, recruit inflammatory cells, and lyse microbes. C3 is the central, most abundant component and the convergence point of all three pathways.

Three activation pathways → one common terminal pathway

Pathway	Trigger / initiator	C3 convertase	Distinguishing point
Classical	Antigen–antibody complex (IgM > IgG); C1q binds Fc	C4b2a (older notation C4b2b)	Requires antibody → links to adaptive; needs Ca²⁺ & Mg²⁺
Alternative	Spontaneous C3 hydrolysis on microbial surfaces (LPS, zymosan)	C3bBb (stabilised by properdin)	Antibody-independent; amplification loop; needs Mg²⁺ only
Lectin (MBL)	Mannose/mannan on microbe surface bound by MBL/ficolins → MASPs	C4b2a (like classical)	Antibody-independent but uses classical components

Common terminal sequence: C3 convertase cleaves C3 → C3b + C3a → C5 convertase → C5 → C5b → C5b + C6,7,8,9 → Membrane Attack Complex (MAC, C5b–9) → osmotic lysis.

Key complement fragments and functions

• Anaphylatoxins → C3a, C4a, C5a — mast cell degranulation, vasodilation, smooth muscle contraction. C5a is also the most potent chemotactic factor for neutrophils.
• Opsonin → C3b (binds CR1); central role in clearance.
• Membrane Attack Complex → C5b–9 — pore formation, lysis.
• Immune complex clearance — C3b/CR1 on RBCs ferry complexes to spleen/liver.

High-yield mnemonic: "Complement does OIL" — Opsonisation (C3b), Inflammation/anaphylatoxins (C3a, C5a), Lysis (MAC C5b-9). C5a = strongest chemoattractant.

Complement regulators (and their disease links)

• C1 inhibitor (C1-INH) — deficiency → Hereditary Angioedema (recurrent non-pitting, non-pruritic angioedema; ↑ bradykinin; C4 is low). Treat with C1-INH concentrate, icatibant (bradykinin B2 antagonist), ecallantide; NOT antihistamines/adrenaline-responsive like allergic angioedema.
• DAF (CD55) & CD59 (MIRL) — GPI-anchored; absent in Paroxysmal Nocturnal Haemoglobinuria (PNH) due to PIGA mutation → complement-mediated intravascular haemolysis. Treat with eculizumab (anti-C5). Diagnose by flow cytometry (FLAER).
• Factor H / Factor I — deficiency/dysfunction → atypical HUS.

Complement deficiencies — disease associations (very high-yield)

Deficient component	Clinical consequence
C1, C4, C2 (early classical)	SLE-like autoimmune disease, immune-complex disease; C2 most common inherited complement deficiency
C3	Severe recurrent pyogenic (encapsulated) infections + immune complex disease
C5–C9 (MAC) & Properdin	Recurrent Neisseria infections (meningococcal, gonococcal)
C1-INH	Hereditary angioedema
DAF/CD59	PNH
MBL	Increased infections in infancy

High-yield: Terminal complement (C5–C9) or properdin deficiency → recurrent Neisseria (meningococcal) infection. These patients must receive meningococcal vaccination, and it is also the reason eculizumab users need meningococcal vaccine before therapy. C2 deficiency is the commonest hereditary complement defect and presents with SLE-like illness.

Cytokines of innate immunity

Cytokine	Main source	Key action
TNF-α	Macrophages	Endothelial activation, fever, cachexia, shock in sepsis
IL-1	Macrophages	Endogenous pyrogen; fever, inflammation
IL-6	Macrophages, T cells	Acute-phase protein induction; fever
IL-12	Macrophages, DCs	NK & Th1 activation; ↑ IFN-γ
Type I IFN (α/β)	Most cells / pDCs	Antiviral state; ↑ MHC-I; activates NK
IFN-γ	NK, Th1 cells	Activates macrophages (classical M1)
IL-8 (CXCL8)	Macrophages	Neutrophil chemotaxis
IL-10, TGF-β	Treg, macrophages	Anti-inflammatory/immunosuppressive

High-yield: TNF-α and IL-1 are the principal mediators of septic shock (fever, hypotension, DIC). Type I interferons (IFN-α/β) are the key antiviral cytokines; IFN-γ is the principal macrophage-activating cytokine (basis of granuloma formation in TB).

Sepsis pathophysiology — tying it together

Gram-negative LPS → binds LBP → CD14 → TLR4 → MyD88 → NF-κB → massive TNF-α, IL-1, IL-6 release → endothelial injury, vasodilation, capillary leak, DIC, multi-organ failure. Superantigens (e.g. TSST-1 of S. aureus) bypass normal processing, cross-linking MHC-II to TCR Vβ → polyclonal T-cell activation → cytokine storm.

High-yield: The single molecule initiating gram-negative septic shock is lipid A of LPS acting through TLR4/CD14.

Key differentials & "don't confuse these"

• Hereditary angioedema (low C4, normal C1q in type I/II, ↑ bradykinin) vs acquired/allergic angioedema (histamine, urticaria, responds to antihistamines/adrenaline).
• CGD (NADPH oxidase, NBT/DHR abnormal, catalase-positive organisms) vs Chediak-Higashi (LYST gene, giant granules, defective phagolysosome fusion, partial albinism) vs Leukocyte Adhesion Deficiency (CD18/β2-integrin defect, no pus, delayed cord separation, neutrophilia).
• MPO deficiency — usually mild/asymptomatic but predisposes to Candida; NBT normal but killing of Candida impaired.
• Classical vs lectin pathway — both make C4b2a convertase and use C4/C2, but the lectin pathway is antibody-independent (innate), triggered by mannose.

Recently asked / exam angle

• TLR ligand matching is a perennial single-best-answer: TLR4–LPS, TLR3–dsRNA, TLR9–CpG DNA, TLR5–flagellin. Expect a match-the-following or "which TLR senses endotoxin."
• Most potent chemotactic complement component → C5a (frequently repeated).
• Central complement component → C3; convergence of all three pathways → C3 convertase.
• Recurrent Neisseria + which deficiency → terminal complement (C5–9) / properdin.
• NBT test interpretation and CGD with catalase-positive organism list.
• NK cell markers (CD16/CD56, CD3-negative) and "missing self" / KIR recognition of MHC-I.
• Acute-phase reactant identification — CRP/ferritin/hepcidin up, albumin/transferrin down; IL-6 as inducer.
• Hereditary angioedema — low C4, bradykinin-mediated, treatment NOT adrenaline-dependent; eculizumab + meningococcal vaccine link.
• Lysozyme mechanism (cleaves NAM–NAG β-1,4 bond) and its action on gram-positives.
• Opsonins list — C3b, IgG, MBL, CRP.

Rapid revision

1. Innate immunity = immediate, non-specific, germline-encoded receptors, no memory (except "trained immunity").
2. Lysozyme cleaves the β-1,4 NAM–NAG bond of peptidoglycan → kills gram-positives.
3. Opsonins: C3b, IgG (Fc), mannose-binding lectin, CRP.
4. Respiratory burst via NADPH oxidase; defect = CGD (NBT/DHR test, catalase-positive organisms).
5. NK cells: CD16⁺CD56⁺CD3⁻, "missing-self" via KIR–MHC-I; kill by perforin/granzyme; mediate ADCC via CD16.
6. TLR4 = LPS, TLR3 = dsRNA, TLR5 = flagellin, TLR9 = CpG DNA; endosomal nucleic-acid TLRs = 3,7,8,9.
7. Most TLRs signal via MyD88 → NF-κB; TLR3/TRIF → type I interferon.
8. C3 is the central complement component; C3 convertase is where all three pathways converge.
9. C5a = most potent neutrophil chemoattractant; anaphylatoxins = C3a, C4a, C5a; MAC = C5b–9.
10. Terminal complement (C5–9)/properdin deficiency → recurrent Neisseria; C2 deficiency = commonest, SLE-like.
11. C1-INH deficiency → hereditary angioedema (low C4, bradykinin); CD55/CD59 loss → PNH (treat eculizumab + meningococcal vaccine).
12. IL-6 drives acute-phase proteins (CRP, ferritin, hepcidin, fibrinogen up; albumin/transferrin down); TNF-α & IL-1 drive septic shock; IFN-γ activates macrophages.