STEPTRACKERIMMUNOLOGY + PATHOLOGY | INNATE IMMUNITY | HIGH-YIELD REVIEW

Barriers, Receptors & Inflammation

Innate immunity recognizes shared microbial patterns within minutes, triggers inflammation and fever, and tells the adaptive system what kind of threat it faces.

FOCUS ON
Barriers: skin, mucus, cilia, gastric acid, lysozyme, defensins, normal flora. Pattern-recognition receptors (germline-encoded) bind PAMPs and DAMPs: TLRs (TLR4 + CD14 → LPS; TLR2 → lipoteichoic acid, peptidoglycan; TLR5 → flagellin; TLR3 → dsRNA; TLR7/8 → ssRNA; TLR9 → unmethylated CpG DNA) → NF-κB and IRFs → cytokines, type I IFN. NOD-like receptors → inflammasome → caspase-1 → active IL-1β, IL-18 (gout crystals, NLRP3 gain-of-function → periodic fever). Acute-phase reactants (IL-6 → liver): ↑ CRP, ferritin, fibrinogen, hepcidin, serum amyloid A, haptoglobin, complement; ↓ albumin, transferrin. Fever: IL-1, IL-6, TNF-α → hypothalamic PGE₂.
COMPONENT
WHAT IT DOES
EXAMPLES
CLINICAL LINK
Physical & chemical barriers
Block entry, kill on contact
Keratin, tight junctions, mucus, cilia, acid, lysozyme (tears, saliva), defensins, IgA
Burns, CF, PPIs, intubation breach barriers
Normal flora
Compete for space and nutrients
Lactobacilli (vagina), gut anaerobes
Antibiotics → C difficile, Candida, BV
TLR4 (+ CD14, MD-2)
Recognizes LPS (lipid A)
Gram-negative sepsis
Septic shock: TNF-α, IL-1, IL-6, NO
TLR2 · TLR5
Lipoteichoic acid, lipoproteins, zymosan · flagellin
Gram-positive bacteria, fungi · motile bacteria
—
Endosomal TLRs (3, 7, 8, 9)
Viral dsRNA, ssRNA, CpG DNA → type I IFN
Viruses, DNA of bacteria
TLR7/9 overactivity in SLE; imiquimod is a TLR7 agonist
RIG-I / MDA5 · cGAS-STING
Sense cytoplasmic viral RNA · DNA
Type I interferon
STING gain of function → vasculopathy
Inflammasome (NLRP3)
Activates caspase-1 → cleaves pro-IL-1β and pro-IL-18; pyroptosis
Urate and cholesterol crystals, ATP, toxins
Gout; cryopyrin-associated periodic syndromes → anakinra, canakinumab
Acute-phase reactants
IL-6 drives hepatic synthesis
↑ CRP (opsonin), ferritin, fibrinogen (↑ ESR), hepcidin, SAA, haptoglobin · ↓ albumin, transferrin, transthyretin
Anemia of chronic disease (hepcidin) · AA amyloidosis (SAA)
Fever
Pyrogens → COX-2 → PGE₂ in hypothalamus raises set point
IL-1, IL-6, TNF-α; LPS
NSAIDs, acetaminophen lower it
Vascular phase of inflammation
Vasodilation (redness, heat), ↑ permeability (swelling)
Histamine, bradykinin, PGI₂, NO, C3a/C5a
Pain: bradykinin, PGE₂
Cellular phase
Neutrophils (first hours), then macrophages (2–3 days)
Chemokines: IL-8, C5a, LTB₄, bacterial peptides
See 2.03
Interferons α/β
Made by infected cells and plasmacytoid DCs; induce antiviral state (↓ protein synthesis, RNase L), ↑ MHC I, activate NK
Viral infection
Flu-like symptoms of viral illness; interferonopathies

Mechanism — from LPS to shock

LPS binds LBP → CD14 → TLR4
→
MyD88 → NF-κB
→
TNF-α, IL-1, IL-6, iNOS
→
Vasodilation, leak, DIC, feverSeptic shock

Innate vs adaptive

FEATURE
INNATE
ADAPTIVE
Speed
Minutes–hours
Days
Receptors
Germline PRRs
Rearranged TCR, BCR
Specificity
Patterns (PAMPs)
Precise epitopes
Memory
None (limited "trained")
Yes
Cells
Neutrophils, macrophages, DCs, NK, mast cells
T and B cells

How it's tested

COMMON CONFUSIONCRP and ESR both rise with inflammation, but ESR rises because fibrinogen makes RBCs stack (rouleaux); it is also high in anemia and myeloma.
THE TRAPFerritin is an acute-phase reactant — normal or high ferritin doesn't exclude iron deficiency in an inflamed patient.
YOUR APPROACHMicrobial pattern → receptor → signaling pathway → cytokine → clinical sign (fever, shock, acute-phase change).

If you see… think…

Receptor for LPS → TLR4 with CD14
Receptor for flagellin → TLR5
Unmethylated CpG DNA sensor → TLR9
Topical drug that activates TLR7 for warts → imiquimod
Caspase-1 activation in gout → NLRP3 inflammasome → IL-1β
Cytokine driving acute-phase proteins → IL-6
Iron trapped in macrophages with inflammation → hepcidin
Proteins that fall in inflammation → albumin, transferrin
Fever mediator in the hypothalamus → PGE₂
Antiviral state, ↑ MHC I, NK activation → IFN-α/β