ImmunologyTier 1Medical Sciences concept

Innate immune receptor defects (TLR/IRAK4/MyD88 pathway deficiencies)

Core concept

TLR (Toll-like receptor) signalling converges on MyD88 (all TLRs except TLR3) -> recruits IRAK4 -> activates NF-kB -> pro-inflammatory cytokine production (IL-1, IL-6, TNF)
IRAK4 and MyD88 deficiency produce a near-identical clinical phenotype: failure to mount effective innate response to pyogenic bacteria (Strep pneumoniae, Staph aureus, Pseudomonas)
Autosomal recessive; presents in early childhood with recurrent invasive pyogenic infection

Striking feature: blunted fever and inflammatory markers (CRP) despite severe/invasive infection -- IL-1/IL-6 production is impaired, removing the usual systemic signs of sepsis
Trap: a septic-looking child with invasive pneumococcal disease but a normal/low CRP and minimal fever -- consider IRAK4/MyD88 deficiency rather than reassurance from "unremarkable" inflammatory markers
Susceptibility improves with age -- unlike most primary immunodeficiencies, clinical severity lessens after childhood as adaptive immunity (antibody-mediated) compensates over time

Investigate with functional testing of TLR pathway response (e.g. cytokine production after TLR agonist stimulation) -- specific genetic confirmation (IRAK4/MyD88 sequencing) follows
Recurrent invasive pneumococcal/staphylococcal disease in early childhood, especially with absent fever/CRP response, should prompt primary immunodeficiency work-up alongside standard sepsis screening
Management: prophylactic antibiotics, aggressive early treatment of infection, pneumococcal/other conjugate vaccination -- no curative therapy typically required given age-related improvement

Contrast with complement deficiencies (also cause recurrent pyogenic/encapsulated organism infection) -- distinguished by normal complement levels/function testing and the blunted-fever clue specific to MyD88/IRAK4 pathway defects
TLR3 is MyD88-independent (signals via TRIF) -- TLR3/TRIF pathway defects instead cause susceptibility to HSV encephalitis, a completely different infection pattern
Fits within the broader pattern recognition receptor framework alongside NOD-like receptors and the inflammasome (autoinflammatory syndromes)

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