Natural IgA and TNFRSF13B polymorphism: a double edged sword fueling balancing selection

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 the high frequency of disruptive TNFRSF13B alleles reflects balancing selection, the loss of function conferring advantage in some settings. Testing that concept, we asked whether and how a common human dominant negative variant, TNFRSF13B A181E, imparts resistance to enteric pathogens. Mice engineered to express mono-allelic or bi-allelic A144E variants of tnrsf13B, corresponding to A181E exhibited striking resistance to pathogenicity and transmission of C. rodentium, a murine pathogen that models enterohemorrhagic E. coli, and resistance was principally owed to deficiency of natural IgA in the intestine. In wild type mice with gut IgA and in mutant mice fed IgA, binding of Ig induces expression of LEE encoded virulence genes, which confer pathogenicity and transmission. C. rodentium and probably some other enteric organisms thus appropriated binding of otherwise protective antibodies to signal induction of the virulence program and the high prevalence of TNFRSF13B dominant negative variants thus reflects balancing selection.