*Purpose: The TNFRSF13B gene is among the 5% most polymorphic genes in humans. The phenotypes of the most frequent TNFRSF13B variants in humans and mice suggest the gene contributes to important facets of B cell responses, such as plasma cell differentiation, affinity maturation of antibodies and innate B cell functions. Since donor-specific (DS) B cell responses are thought to figure in the fate of organ transplants, we asked whether and how TNFRSF13B genotypes might determine graft health in recipients of kidney transplants.

*Methods: PBMCs from kidney recipients were isolated and cultured in plates coated with donor fibroblasts. DNA of adherent DS B cells was obtained, and the five exons of TNFRSF13B and Ig heavy and light chain (IgH+L) genes were amplified and sequenced. B cell clones were identified by unique CDR3. Mutations were identified by alignment to reference sequences.

*Results: Our results show that 33.82% of 167 kidney transplant recipients that were unsensitized at transplant developed AMR within 3 years had missense mutations TNFRSF13B while only 5.88% of 119 recipients with healthy grafts had mutant TNFRSF13B (P<0.0001). We hypothesized that TNFRSF13B polymorphisms determine outcomes in transplantation by modifying properties of DS B cell responses. The sequences of Ig genes of DS memory B cells isolated from the blood of 4 recipients with C104R, A181E, P251L and V220A variants revealed accumulation of somatic mutations (>15%) in persistently utilized Ig variable heavy chain (IgVH). In contrast, the Ig genes of 4 recipients expressing the WT alleles exhibited rapid turnover of IgH segments and relative scarcity of mutations (<7% in IgVH).

*Conclusions: Our results suggest that TNFRSF13B alleles shape the immune response to transplantation in at least two important ways. In one, the persistence VH utilization with accumulation of mutations, i.e. somatic hypermutation, suggests affinity maturation of DS Ig responses that might in turn lead to AMR. On the other hand, the rapid turnover of DS B cell clones with unmutated germline IgVH sequences in recipients with wild type TNFRSF13B is consistent with production of non-pathogenic or less pathogenic natural antibodies and hence with absence of AMR. Thus, TNFRSF13B genotype and characteristics of VH utilization and mutation might confer risk of antibody-mediated pathology, possibly by controlling inflammation and/or propensity for development of accommodation.

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