Innate Immunity
Usually weeks 1-2 of an immunology & genetics courseInnate immunity is where every immunology course starts because adaptive immunity makes no sense without it: the barriers, phagocytes, and complement act in minutes to hours, use germline-encoded receptors that never improve with exposure, and hand the antigen to the adaptive system. The exam lives at the checkpoints — C3 and C5 in complement, the neutrophil's oxidative burst, the NK cell's missing-self logic, and the acute-phase response driven by IL-1, IL-6, and TNF.
This guide is the frame. The exam is written from your lectures— drop this topic's slides on the dashboard to get flashcards and board-style questions from your own course, and quiz them all term (one cumulative exam rewards nothing more than early, repeated self-testing). The immunology & genetics playbook has the weekly loop.
AI-authored study notes, not faculty-reviewed and not medical advice. Verify every mechanism against your course materials and faculty; programs differ in emphasis.
High-Yield Pearl
Complement questions are trigger-and-deficiency questions: know what starts each pathway and the one-line deficiency map (early classical = lupus-like, C3 = pyogenic, C5-C9 = Neisseria, C1-INH = angioedema) and the shared middle takes care of itself.
What the exam asks
Mechanisms, patterns, and what happens when each one fails.
- Innate vs adaptive — the defining contrasts. Innate immunity is immediate (minutes to hours), uses a limited set of germline-encoded pattern-recognition receptors, responds identically on every exposure, and has no memory. Adaptive immunity takes days, uses somatically rearranged receptors of enormous diversity, and improves with repeat exposure. The two are wired together: innate cells (dendritic cells especially) present antigen and provide the costimulation and cytokines that launch the adaptive response.
- Barriers — the first line. Physical: intact skin (keratinized epithelium), mucosal epithelium with tight junctions, mucus plus the mucociliary escalator, urine flow, peristalsis. Chemical: gastric acid, lysozyme in tears and saliva (cleaves peptidoglycan), defensins and cathelicidins from epithelium, sebum's fatty acids, low vaginal pH from lactobacilli. Biologic: normal flora competing for niches — which is why broad-spectrum antibiotics invite C. difficile and Candida.
- PRRs and PAMPs. Pattern-recognition receptors are germline-encoded sensors for conserved microbial structures (PAMPs) and for damage signals (DAMPs). Toll-like receptors are the exam's favorites: TLR4 binds LPS of gram-negatives (with CD14 and MD-2), TLR5 flagellin, TLR2 gram-positive lipoteichoic acid and lipopeptides, and the endosomal TLRs 3/7/8/9 read viral RNA and unmethylated CpG DNA. Signaling (largely via NF-κB) drives inflammatory cytokines; NOD-like receptors assemble the inflammasome, activating caspase-1 to cleave pro-IL-1β.
- Complement — three pathways to one C3 convertase step. Classical: C1q binds antibody (one IgM pentamer or two adjacent IgG) on a surface → C1r/C1s → C4 and C2 → C4b2a, the classical C3 convertase. Lectin: mannose-binding lectin plus MASPs recognizes microbial mannose and generates the same C4b2a — antibody-independent. Alternative: spontaneous C3 tickover; C3b deposited on a surface binds factor B, factor D cleaves it, forming C3bBb (stabilized by properdin). All three converge on cleaving C3, then build a C5 convertase; C5b + C6-C9 assemble the membrane attack complex.
- Complement effector jobs and their fragments. C3b is the major opsonin (phagocytes carry CR1); C3a and C5a are anaphylatoxins that degranulate mast cells and increase vascular permeability, and C5a is additionally the most potent complement chemoattractant for neutrophils; C5b-9 (MAC) lyses membranes — clinically essential only against Neisseria. Regulators keep host cells safe: C1 esterase inhibitor restrains the classical pathway, and DAF (CD55) with CD59 strip convertases and block MAC on self surfaces.
- Complement deficiencies — the classic map. Early classical components (C1q, C4, C2) → impaired clearance of immune complexes and apoptotic debris → lupus-like disease; C2 deficiency is the most common. C3 deficiency → severe recurrent pyogenic infections with encapsulated bacteria (opsonization is lost). C5-C9 (terminal/MAC) deficiency → recurrent or disseminated Neisseria infections. C1 esterase inhibitor deficiency → hereditary angioedema (bradykinin-mediated, low C4, no urticaria). Loss of the GPI-anchored regulators CD55/CD59 → paroxysmal nocturnal hemoglobinuria with complement-mediated hemolysis.
- Phagocytes — neutrophils and macrophages. Neutrophils are the first cells recruited (multilobed nucleus, granules of myeloperoxidase, lysozyme, lactoferrin); they kill via the oxidative burst — NADPH oxidase makes superoxide, dismutated to H2O2, which myeloperoxidase converts to hypochlorite — and can throw NETs. Macrophages arrive later, derive from blood monocytes, persist in tissue (Kupffer cells, alveolar macrophages, microglia, osteoclasts), present antigen on MHC II, and secrete IL-1, IL-6, and TNF. Phagocytosis is amplified enormously by opsonins: C3b (CR1) and IgG Fc (FcγR).
- Neutrophil recruitment — the adhesion cascade. Margination → rolling on endothelial selectins (E- and P-selectin binding sialyl-Lewis X) → chemokine-triggered activation → firm adhesion via integrins (LFA-1/Mac-1 binding endothelial ICAM-1) → transmigration (diapedesis, PECAM-1) → chemotaxis along C5a, LTB4, IL-8, and bacterial formyl peptides. Leukocyte adhesion deficiency type 1 is a CD18 integrin defect: recurrent bacterial infections, no pus, poor wound healing, delayed umbilical cord separation, marked neutrophilia.
- NK cells and missing self. NK cells are lymphocytes of the innate system — no rearranged antigen receptor, no memory in the classic sense. They kill by the balance of signals: inhibitory receptors read MHC class I, so a virally infected or tumor cell that downregulates MHC I loses the 'self' brake and is lysed via perforin and granzymes. They also perform antibody-dependent cellular cytotoxicity through CD16 (FcγRIII) and are activated by IL-12, IFN-α/β, and IL-15; their signature product is IFN-γ, which activates macrophages.
- Acute inflammation, fever, and acute-phase reactants. The cardinal signs — rubor, calor, tumor, dolor, functio laesa — come from histamine- and prostaglandin-driven vasodilation and permeability plus cellular infiltrate. IL-1, IL-6, and TNF from macrophages act on the hypothalamus (via PGE2 raising the set point — fever; NSAIDs block the COX step) and on the liver, which reprograms protein synthesis: positive acute-phase reactants rise (CRP — an opsonin and complement activator, ferritin, fibrinogen — the reason ESR rises, hepcidin — which sequesters iron and drives anemia of chronic disease, serum amyloid A, haptoglobin) while albumin and transferrin fall (negative reactants).
Worth drilling · 24 concepts
Each with the one fact that identifies it. Your course's slides are the authority; use this to check your list against.
- 1Neutrophil — first cell on scene in acute inflammation; multilobed nucleus, myeloperoxidase granules
- 2Macrophage — tissue-resident phagocyte from a blood monocyte; presents antigen and secretes IL-1, IL-6, TNF
- 3NK cell — lymphocyte that lyses cells missing MHC class I, using perforin and granzymes
- 4Dendritic cell — the bridge to adaptive immunity; the most potent activator of naive T cells
- 5TLR4 — surface receptor for gram-negative LPS, working with CD14 and MD-2
- 6TLR5 — surface receptor that recognizes bacterial flagellin
- 7Endosomal TLRs 3/7/9 — read viral dsRNA, ssRNA, and unmethylated CpG DNA from inside the cell
- 8Inflammasome — NLRP3/caspase-1 platform that cleaves pro-IL-1β to its active form
- 9C1q — starts the classical pathway by binding the Fc of surface-bound IgM or paired IgG
- 10Mannose-binding lectin — starts the antibody-independent pathway using MASPs to cleave C4 and C2
- 11C3b — the major opsonin; phagocytes grab it through CR1
- 12C5a — the most potent complement chemoattractant for neutrophils; also an anaphylatoxin
- 13Membrane attack complex — C5b-9 pore; its loss means recurrent Neisseria infections
- 14Properdin — the one positive regulator, stabilizing the alternative-pathway convertase C3bBb
- 15C1 esterase inhibitor — its deficiency causes hereditary angioedema with a low C4 and no urticaria
- 16CD55/CD59 — GPI-anchored self-protectors; their loss causes paroxysmal nocturnal hemoglobinuria
- 17NADPH oxidase — generates the respiratory burst; defective in chronic granulomatous disease
- 18Myeloperoxidase — converts H2O2 to hypochlorite inside the phagolysosome
- 19Selectins — mediate leukocyte rolling by catching sialyl-Lewis X
- 20LFA-1 (CD18 integrin) — mediates firm adhesion to ICAM-1; defective in leukocyte adhesion deficiency
- 21C-reactive protein — liver-made acute-phase opsonin driven by IL-6; the fast-moving inflammation marker
- 22Hepcidin — acute-phase hormone that locks iron away, producing anemia of chronic disease
- 23Lysozyme — enzyme in tears and saliva that cleaves bacterial peptidoglycan
- 24Interferon-α/β — the antiviral state cytokines from virally infected cells
Practice it
Active recall over the drill list — flip and claim, match the pairs, produce the answers cold, fill in the diagram.
Every concept on the drill list, one card at a time — the name up front, the fact that identifies it on the flip. Claim each card honestly and the deck learns what to lead with next time. Progress lives in this browser only.
What everyone misses
The distinctions that lose points on this material, year after year.
- The lectin pathway is not the classical pathway. Both build the same C4b2a convertase, so students merge them. The discriminator is the trigger: antibody bound to a surface = classical (C1q); microbial mannose with no antibody anywhere in the stem = lectin (MBL/MASPs). If the vignette never mentions antibody, don't pick classical.
- C3a/C5a vs C3b — fragment jobs get swapped. The small 'a' fragments float away as anaphylatoxins and (C5a) chemoattractants; the big 'b' fragments stay stuck to the surface as opsonins and convertase parts. An answer choice calling C3b an anaphylatoxin, or C3a an opsonin, is the trap.
- Terminal complement deficiency is Neisseria, not everything. Losing C5-C9 leaves opsonization intact, so these patients are NOT broadly infection-prone — they get recurrent Neisseria (meningococcemia, gonococcemia) specifically. Broad pyogenic and encapsulated-organism infections point to C3 deficiency instead.
- Hereditary angioedema has no hives and doesn't answer to antihistamines. C1-INH deficiency swelling is bradykinin-mediated: nonpitting edema of face, airway, and gut WITHOUT urticaria or pruritus, unresponsive to antihistamines, epinephrine, or steroids. Screening clue is a LOW C4. Students pick 'allergic reaction' because the face is swollen — the missing hives are the tell.
- CGD vs MPO deficiency vs LAD — three different neutrophil lesions. Chronic granulomatous disease = NADPH oxidase gone: no respiratory burst at all (abnormal dihydrorhodamine test; catalase-positive organisms like Staph aureus, Serratia, Aspergillus). Myeloperoxidase deficiency = usually mild and Candida-prone; the respiratory burst itself is intact (NBT normal), but the DHR test is ABNORMAL because DHR fluorescence depends on MPO — don't use DHR alone to separate it from CGD. LAD = the cells never ARRIVE (CD18 defect): neutrophilia in blood but no pus at the wound. MCQs bank on you collapsing all three into 'phagocyte problem'.
- NK cells kill what LACKS MHC I. Cytotoxic T cells need MHC I to recognize a target; NK cells kill precisely when MHC I is missing or downregulated. Choosing 'NK cells recognize antigen on MHC I' inverts the whole missing-self mechanism.
- Fever is a set-point change, not failed heat loss. Pyrogenic cytokines raise the hypothalamic set point through PGE2 — the patient shivers and vasoconstricts to reach the new target. That is why NSAIDs and acetaminophen (blocking prostaglandin synthesis) treat fever but do nothing for heat stroke, where the set point is normal and cooling has failed.
Clinical correlations
Where this topic shows up again — in clinic, on rotations, and on the boards.
- Chronic granulomatous disease. Recurrent abscesses and pneumonias with catalase-positive organisms (Staph aureus, Serratia, Burkholderia, Nocardia, Aspergillus) in a young child — NADPH oxidase can't make the oxidative burst, so phagocytes engulf but cannot kill. Diagnose with the dihydrorhodamine flow assay (replaces the old nitroblue tetrazolium test); granulomas form as the immune system walls off what it can't clear.
- Leukocyte adhesion deficiency type 1. Delayed umbilical cord separation, recurrent skin and mucosal bacterial infections WITHOUT pus, and a strikingly high blood neutrophil count — the CD18 integrin defect keeps neutrophils in circulation, unable to firmly adhere and transmigrate. Absent pus plus neutrophilia is the giveaway pairing.
- Recurrent Neisseria meningitis. A second episode of meningococcal disease, or disseminated gonococcal infection, should trigger testing of the terminal complement pathway (CH50, then C5-C9 levels). Eculizumab, which blocks C5, pharmacologically reproduces this state — hence the mandatory meningococcal vaccination before starting it.
- Hereditary angioedema attack. Recurrent nonpitting swelling of lips, face, extremities, or bowel wall (presenting as colicky abdominal pain), sometimes after dental work or trauma, no urticaria — C1-INH deficiency lets bradykinin run unchecked. Low C4 screens; treatment is C1-INH concentrate or bradykinin-pathway blockers, not epinephrine or antihistamines. ACE-inhibitor angioedema is the acquired bradykinin cousin.
- Asplenia and encapsulated organisms. The spleen's macrophages clear opsonized encapsulated bacteria (pneumococcus, H. influenzae type b, meningococcus) from the blood; after splenectomy or in sickle cell autoinfarction, overwhelming post-splenectomy sepsis can kill within hours. The fix is anticipatory: vaccinate against the encapsulated three and treat fevers as emergencies.
- Septic shock and LPS. Gram-negative endotoxin (LPS) through TLR4 drives massive macrophage release of TNF and IL-1 — vasodilation, capillary leak, warm hypotensive shock, and DIC. It is the innate response itself, not the bacterium directly, doing the systemic damage.
- CRP and ESR at the bedside. CRP (IL-6-driven, from the liver) rises and falls within hours to days — good for tracking acute infection and treatment response; ESR rises because fibrinogen makes red cells stack, moves over days to weeks, and stays a workhorse for temporal arteritis and polymyalgia rheumatica. Anemia of chronic disease follows the same biology: hepcidin traps iron, so ferritin is normal-high while serum iron and TIBC are low.