Big Picture: Why Innate Immunity Exists
Concept
- Job #1: buy time and limit damage before the adaptive system (B/T cells) ramps up over days.
- Fully functional from birth — no prior exposure needed.
- Fixed recognition repertoire, germline-encoded — same intensity every exposure, no memory.
- Adaptive system: >10⁹ possible receptor specificities via gene rearrangement; much slower to deploy.
Pathogen breaches surface→
Barrier + resident sensor response→
Local inflammation→
Systemic signaling→
Adaptive handoff if needed
One-line exam fact: innate immunity has no memory and no affinity maturation — that's the adaptive system's job.
Barriers: Stopping Entry Before It Starts
Anatomic + Chemical
Skin
- Intact keratinized epithelium = mechanical wall.
- Mildly acidic surface pH slows bacterial growth.
- Ciliary escalator physically clears microbes.
- Mucus + antimicrobial enzymes trap and degrade organisms.
GI tract
- Mucous membrane similar to airway.
- Gastric acid is a major chemical kill step before reaching the gut.
- Epithelia secrete defensins + interferons at baseline.
- γδ T cells sit within epithelia — innate-like, recognize shared microbial patterns only.
| Category | Examples | Mechanism |
|---|---|---|
| Physical | Skin, cilia, mucus | Block or sweep away organisms |
| Temperature | Core body temp; fever | Many pathogens grow poorly above normal range |
| Chemical | Lysozyme, defensins | Lysozyme cleaves peptidoglycan; defensins punch membrane pores |
| Enzymatic/pH | Gastric acid, skin pH | Direct killing / growth suppression |
Sensing Danger: How Innate Cells "See" a Threat
PRRs · PAMPs · DAMPs
- Pattern recognition receptors (PRRs) are germline-encoded — not rearranged like B/T cell receptors.
- Two signal categories they detect:
- PAMPs — conserved microbial motifs (e.g., LPS, flagellin, viral RNA).
- DAMPs — self molecules released by damaged/dying cells (e.g., ATP, uric acid crystals).
- Innate recognition capacity is limited (roughly <1,000 patterns) vs. adaptive receptor diversity (>10⁹).
| Family | Location | Detects | Result |
|---|---|---|---|
| Toll-like receptors (extracellular) | Cell surface | Bacterial lipopeptides, peptidoglycan, LPS, flagellin | NF-κB activation → cytokines, adhesion molecules |
| Toll-like receptors (endosomal) | Endosome | Viral dsRNA, ssRNA, unmethylated CpG DNA | Antiviral gene induction |
| NOD-like receptors | Cytosol | Bacterial peptidoglycan fragments | NF-κB → macrophage activation |
| Inflammasome sensor (e.g., NLRP3) | Cytosol | Microbial products + DAMPs (ATP, urate crystals, ROS) | Caspase-1 activation → mature IL-1β / IL-18 |
| RIG-like receptors | Cytoplasm | Viral RNA | Interferon production |
Sensor + adaptor→Pro-caspase-1→Active caspase-1→Cleaves pro-IL-1β→IL-1β released→Acute inflammation
Exam trap: gain-of-function inflammasome mutations don't just cause infection susceptibility — they drive gout, atherosclerosis, and type II diabetes via excess IL-1β.
Cellular Players and What Marks Them
Myeloid + NK
Macrophage polarization
| Cell | Where found | Key marker/look | Main job |
|---|---|---|---|
| Neutrophil | Blood, first into tissue | Multilobed nucleus | Rapid phagocytosis, short-lived |
| Monocyte → Macrophage | Blood → tissue | Kidney-bean nucleus → ruffled membrane | Prolonged defense, cytokine release, cleanup/repair |
| Dendritic cell | All epithelia/tissues | Long cytoplasmic processes | Antigen capture + bridges to adaptive response |
| Mast cell | Skin, mucosa | Granule-packed cytoplasm | Histamine release — innate TLR or IgE-triggered |
| NK cell | Blood, lymphoid tissue | CD16+ CD56+, large granular lymphocyte | Kills infected/transformed cells, secretes IFN-γ |
M1 (classical): driven by TLR signals + IFN-γ → pro-inflammatory, phagocytic.
M2 (alternative): driven by IL-4/IL-13 → tissue repair, dampens inflammation.
Macrophage/DC→IL-12→NK cell activation→IFN-γ→Feeds back to activate macrophage
Complement: Three Jobs, One Cascade
Innate pathways: Alternative + Lectin
- Liver-made plasma proteins that circulate as inactive zymogens and activate each other in sequence.
- Alternative pathway — spontaneous, antibody-independent, triggered by microbial surfaces (LPS).
- Lectin (mannose-binding) pathway — mannose-binding lectin recognizes microbial carbohydrates, feeds into the same downstream steps as the classical pathway, but without antibody.
Recruitment: C3a, C4a, C5a act as anaphylatoxins/chemoattractants.
Opsonization: C3b coats microbes and immune complexes for clearance.
Direct killing: C5b initiates assembly of the membrane attack complex (C5b-6-7-8-9), punching holes in target membranes.
Spontaneous C3b→+ Factor B, D→C3 convertase (C3bBb)→C5 convertase→C5b→Membrane attack complex
High-yield: C5a is both an anaphylatoxin AND a chemotactic factor for neutrophils — it does double duty.
The Inflammatory Cascade, Step by Step
Extravasation
- Rolling — selectins on activated endothelium loosely and transiently bind mucin-like ligands on the phagocyte; flow keeps knocking it loose, causing rolling.
- Activation — local chemoattractants (IL-8, C5a, bacterial N-formyl peptides) trigger G-protein signaling, flipping integrins into a high-affinity state.
- Firm adhesion — activated integrins bind Ig-superfamily adhesion molecules (ICAM) on endothelium, stopping the cell.
- Transmigration — the phagocyte squeezes between endothelial cells into the tissue.
| Chemoattractant | Source |
|---|---|
| IL-8 (a chemokine) | Mast cells, platelets, neutrophils, monocytes/macrophages |
| C5a | Complement activation (either innate pathway) |
| Leukotriene B4 | Arachidonic acid pathway in phagocytes/mast cells |
| N-formyl-methionyl peptides | Bacterial protein synthesis byproducts |
Clinical correlate — Leukocyte adhesion deficiency: absent CD18 (β2-integrin chain) blocks firm adhesion/transmigration. Result: high circulating neutrophil counts but no abscess or pus formation, recurrent bacterial infections, classically presenting as delayed umbilical cord separation with omphalitis. Viral susceptibility is unaffected.
Once in tissue — phagocytosis
Pseudopod extension→Engulfment into phagosome→Fusion with lysosome→Digestion→Exocytosis of debris
- Opsonization by IgG (via Fc receptor) or C3b (via complement receptor) boosts phagocytic uptake dramatically.
- Dying neutrophils release nuclear material as extracellular traps (NETs) — trap/kill pathogens but can injure surrounding tissue.
Inside the Phagolysosome: How Microbes Actually Die
Oxidative vs. non-oxidative
Oxygen-dependent (respiratory burst)
- NADPH oxidase converts O₂ → superoxide → hydroxyl radicals + H₂O₂.
- Myeloperoxidase combines H₂O₂ + chloride → hypochlorite (bleach chemistry).
- Inducible nitric oxide synthase converts arginine → nitric oxide, an antimicrobial radical.
Oxygen-independent
- Lysozyme — cleaves peptidoglycan.
- Defensins — form membrane pores.
- Lactoferrin — starves bacteria of iron.
- Other hydrolytic enzymes degrade debris.
Chronic granulomatous disease: defective NADPH oxidase → no respiratory burst. Myeloperoxidase pathway still works IF the organism itself makes H₂O₂ (catalase-negative). Catalase-positive organisms (Staph, Klebsiella, Serratia, Aspergillus) destroy their own H₂O₂, leaving myeloperoxidase without substrate — recurrent infection with these specific organisms is the classic clue. Diagnosed by nitroblue tetrazolium or dihydrorhodamine flow cytometry testing.
From Local Fire to Whole-Body Response
IL-1, IL-6, TNF-α
| Target organ | Driven by | Effect |
|---|---|---|
| Hypothalamus | IL-1, TNF-α | Prostaglandin-mediated fever |
| Liver | IL-1, IL-6, TNF-α | Acute-phase proteins (CRP, mannose-binding protein, complement components) |
| Bone marrow | IL-1, TNF-α | Leukocytosis |
| Fat/muscle | TNF-α | Cachexia in chronic states |
| Tumor cells | TNF-α | Apoptosis |
Think of IL-1/IL-6/TNF-α as the "broadcast" cytokines — same local fire, three different downstream organs responding in parallel.
Antiviral Defense: Interferons and NK Cells
IFN-α/β + NK logic
- Type I interferons (IFN-α, IFN-β) are made by virus-infected cells themselves — not virus-specific, act on neighboring cells to shut down protein synthesis and pre-emptively limit spread.
- Two IFN-driven antiviral mechanisms: activation of an RNA endonuclease that degrades viral RNA, and phosphorylation-mediated inactivation of eIF2 to block viral translation.
- Clinical uses: IFN-α for hepatitis B/C and select cancers; IFN-β for multiple sclerosis; IFN-γ for chronic granulomatous disease (boosts macrophage oxidative killing).
- Killer activating receptors (KAR, e.g., NKG2D) bind stress ligands on infected/transformed cells → push toward killing.
- Killer inhibitory receptors (KIR) bind normal HLA-E (a non-classical MHC I molecule) on healthy cells → block killing.
- Rule: inhibitory signal always wins if both are engaged — killing only proceeds when KAR is engaged and KIR is not.
- Infected/transformed cells often downregulate MHC I, which lowers HLA-E display and removes the "don't kill me" signal — this is what tips NK cells toward killing.
- Antibody-dependent cellular cytotoxicity: NK cells engage antibody-coated targets via CD16 (FcR) using a single activating signal, since the antibody itself already confirms infection.
When Innate Immunity Fails
Correlate to organism
| Defect | Consequence |
|---|---|
| TLR signaling defects | Recurrent severe bacterial infections (e.g., pneumonia) |
| Gain-of-function inflammasome mutation | Gout, atherosclerosis, type II diabetes |
| NOD2 mutation | Inflammatory bowel disease |
| IL-12 receptor deficiency | Recurrent intracellular infections (e.g., Mycobacterium) |
| IFN-γ receptor deficiency | Same — recurrent intracellular/mycobacterial infection |
| CD18 (integrin) deficiency — LAD | No pus formation, recurrent bacterial infection, delayed cord separation |
| NADPH oxidase deficiency — CGD | Recurrent catalase-positive organism infections |
Big theme: defects in phagocyte function/recruitment predispose specifically to extracellular bacteria and fungi — not viruses.
Quick-Fire Exam Pearls
Rapid review
- Neutrophils peak in tissue within ~6 hours; monocytes/macrophages follow 5–6 hours later.
- Opsonization can boost phagocytic efficiency roughly 4,000-fold.
- PRRs are germline-encoded — no somatic recombination, unlike B/T cell receptors.
- MBP (lectin) pathway activates the classical cascade machinery but is antibody-independent, so it counts as innate.
- CD16 + CD56 = NK cell markers; no CD3, no antigen-specific receptor.
- Catalase-positive organism + recurrent infection → think CGD.
- No pus + recurrent bacterial infection + high circulating neutrophils → think LAD.