TNFRSF13B polymorphisms counter microbial adaptation to enteric IgA.

Jeffrey L Platt,Adam R Lefferts,Juhi Katta,Daniel Huynh,Gabriel Nunez,Cyra Kharas,Richard J Bram,Christine Marie Bassis,Peter L Freddolino,Raif Geha,Marilia Cascalho,Mayara Garcia De Mattos Barbosa,Christiane E Wobus,Nobuhiko Kamada

doi:10.1172/jci.insight.148208

Jeffrey L Platt, Adam R Lefferts + Show 12 more

Open Access

https://doi.org/10.1172/jci.insight.148208

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Abstract

TNFRSF13B encodes the transmembrane activator and CAML interactor (TACI) receptor, which drives plasma cell differentiation. Although TNFRSF13B supports host defense, dominant-negative TNFRSF13B alleles are common in humans and other species and only rarely associate with disease. We reasoned that the high frequency of disruptive TNFRSF13B alleles reflects balancing selection, the loss of function conferring advantage in some settings. Testing that concept, we investigated how a common human dominant-negative variant, TNFRSF13B A181E, imparts resistance to enteric pathogens. Mice engineered to express mono- or biallelic A144E variants of tnrsf13B, corresponding to A181E, exhibited a striking resistance to pathogenicity and transmission of Citrobacter rodentium, a murine pathogen that models enterohemorrhagic Escherichia coli, and resistance was principally owed to natural IgA deficiency in the intestine. In WT mice with gut IgA and in mutant mice reconstituted with enteric IgA obtained from WT mice, IgA induces LEE expression of encoded virulence genes, which confer pathogenicity and transmission. Taken together, our results show that C. rodentium and most likely other enteric organisms appropriated binding of otherwise protective antibodies to signal induction of the virulence program. Additionally, the high prevalence of TNFRSF13B dominant-negative variants reflects balancing selection.

Highlights

IntroductionTNFRSF13B (in humans or Tnfrsf13b in mice) encodes the transmembrane activator and CAML interactor (TACI), a member of the TNF receptor superfamily and has been considered vital to immune fitness
TNFRSF13B encodes the transmembrane activator and CAML interactor (TACI), a member of the TNF receptor superfamily and has been considered vital to immune fitness
Because gut microbiota potentially influence the virulence of C. rodentium [12], mutant and WT mice used in these experiments were cohoused for 4 weeks prior to infection to allow admixture of flora

Summary

Introduction

TNFRSF13B (in humans or Tnfrsf13b in mice) encodes the transmembrane activator and CAML interactor (TACI), a member of the TNF receptor superfamily and has been considered vital to immune fitness. Since TNFRSF13B in humans supports a key facet of immune fitness, it may be surprising that surveys of normal populations reveal extraordinary polymorphism — 951 TNFRSF13B missense and only 383 synonymous mutations (https://useast.ensembl.org/index.html) — and a high frequency of dominant-negative alleles [7]. The mechanism underlying TNFRSF13B polymorphism is unknown, missense alleles appear to have been selectively retained in populations, and the McDonald-Kreitman neutrality index indicates the locus is under strong positive selection. This is in contrast to genes encoding HLA, which are under moderate purifying pressure [10]

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