TNFRSF13B Diversification Fueled by B Cell Responses to Environmental Challenges-A Hypothesis

Abstract

B cell differentiation and memory are controlled by the transmembrane activator and CAML interactor (TACI), a receptor encoded by TNFRSF13B. TNFRSF13B mutations are frequently found in common variable immunodeficiency (CVID) and in IgA -deficiency; yet, ~98% of those with mutant TNFRSF13B are healthy. Indeed, TNFRSF13B is among the 5% most polymorphic genes in man. Other mammals evidence polymorphism at comparable loci. We hypothesize that TNFRSF13B diversity might promote rather than detract from well-being by controlling key elements of innate immunity. We shall discuss how extraordinary diversity of TNFRSF13B could have evolved and persisted across diverse species of mammals by controlling innate and adaptive B cell responses in apparently paradoxical ways.

Keywords: B-lymphocyte; T cell-dependent antibody response; T cell-independent antibody responses; TNFRSF13B; antibodies.

Figure 1

Diversity of TNFRSF13B in host response to environmental challenges. TNFRSF13B encodes a receptor (TACI) through to support the maturation of B cells, yet the gene is among the most polymorphic in the genome and polymorphism is maintained across mammalian species. The authors speculate that polymorphism of TNFRSF13B reflects balancing selection—balancing benefits and disadvantages of signals the receptor delivers but also manifold intermediate functions the protein and its neighbors in cell membrane confer. The figure depicts two hypothetically distinct regions of the protein that confer phenotypically distinct properties. The balancing of complex sets of phenotypic properties that presumably impact all mammals could underlie extraordinary diversity of the gene across species. CVID, Common Variable Immunodeficiency.