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Nurture trumps nature!

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Science Immunology  07 Apr 2017:
Vol. 2, Issue 10, eaan2236
DOI: 10.1126/sciimmunol.aan2236

Abstract

Mutation-associated infections in one individual are prevented in relatives with the same mutation by a compensatory adaptive immune response.

A mutation linked to a clear disease phenotype in some people can be present in others who lack this phenotype. It is generally argued that differences in “background” genes or environmental factors are responsible for these seeming discrepancies.

Israel and colleagues provide an intriguing explanation for such discordant genotype-phenotype associations observed in members of a consanguineous family. Their story begins with a 3-month-old child admitted to the intensive care unit with a life-threatening Staphylococcus aureus infection. After ruling out known genetic causes of primary immunodeficiency, Israel et al. identified a homozygous arginine to tryptophan substitution at position 121 (R121W) in the Toll-like receptor (TLR) signaling adaptor TIRAP (TIR domain-containing adaptor protein). The authors show that the cellular localization of R121W TIRAP is altered and that this mutation abolishes the TIR domain-mediated TLR2-TIRAP-MyD88 interaction that is normally required for signaling downstream of many TLRs. The authors also tested a panel of TLR ligands to demonstrate defective responses downstream of TLR1/2, TLR2/6, and TLR4 in cells homozygous for R121W TIRAP.

Notably, seven other relatives of the proband who were also homozygous for the R121W TIRAP allele had no history of staphylococcal infections. Although most ligands for TLR2/6 elicited defective signaling responses in all homozygous R121W TIRAP individuals, responses to lipoteichoic acid (LTA) were uniquely abolished only in the proband. This finding, and earlier studies showing that anti-LTA antibodies can enhance TLR2/6 responses to LTA, raised the intriguing possibility that anti-LTA responses might compensate for the absence of TIRAP signaling in the seven unaffected R121W TIRAP homozygotes. Indeed, this was shown to be the case. Only the proband lacked LTA-specific antibodies, and that child’s defective in vitro signaling response to LTA could be rescued by spiking in anti-LTA.

Like any good study, the report concludes by asking some provocative questions. It is currently unclear why the proband did not acquire maternal anti-LTA antibodies or generate her own. Further, the authors wonder whether other congenital innate immune deficiencies are accompanied by similar compensatory responses in adaptive immunity. Indeed, “nurtured” adaptive immune responses might more broadly compensate for other innate immune defects, perhaps explaining the clinical improvement seen in some immunodeficient kids as they age.

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