Marchf1 Deficiency Attenuates Antibody-Mediated Rejection by Modulating B Cell Responses

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Purpose: TNFRSF13B is one of the most polymorphic genes in humans.Low function variants encoded by TNFRSF13B mutant alleles are associated with antibody mediated rejection (AMR) of kidney transplants.This association was confirmed by studies in Tnfrsf13b-deficient mice in which heterotopic cardiac allografts exhibited AMR whereas grafts in wild type controls exhibited cellular rejection.Because Tnfrsf13b-deficiency is rare we tested the impact of low function tnfrsf13b variants in murine kidney transplants.Methods: We performed H-2 F1-to-P kidney transplants in Tnfrsf13b mA114E mice, which correspond to TNFRSF13B hA181E in humans.Histologic sections obtained 15 days after transplantation, were stained for IgG, IgM and C3d deposition.We tested IgM and IgG concentrations and serum complement activity as well as IgG Fc glycosylation by gel capillary electrophoresis.Results: We observed severe AMR with deposits of IgG and C3d, and decreased C3 in serum in Tnfrsf13b mA114E mice but milder graft damage in WT recipients.The sections of kidneys excised from recipients with mono and biallelic mA1114E genotypes had more serious combined glomerulitis and peritubular capillaritis (mean BANFF grades 3.75 and 3, respectively) compared to grafts excised from recipients with WT Tnfrsf13b genotype (mean BANFF grade 1.3).Because Tnfrsf13b does not modify the level of alloantibodies, we asked what properties other than concentration of Ab produced by mutant mice might explain the more severe immunopathology.Mutant mice had decreased IgM at baseline and decreased IgM responses to alloimmunization; IgM is effective at regulating complement (C).Second, mutant mice produced more alloreactive IgG2b and IgG3, which activate C most effectively, than wild type mice.Third, mutant mice had 2-fold less sialylated IgG Fc than WT mice.Thus, IgG from mutant mice bound C1q better than WT mice and mutant mice had reduced C3 in the serum indicating Tnfrsf13b-dependent C regulation.Conclusions: AMR is a uncommon outcome of allotransplantation in humans and almost never occurs in naïve mice.Our results indicate however that functionally significant Tnfrsf13b mutations modify properties of baseline and antigen-specific IgG in ways that increase efficiency of complement fixation, and we hypothesize these changes enhance immunopathology of kidney allografts leading to a diathesis for AMR.We conclude that inherited defects in TNFRSF13B function might underlie AMR in naïve humans and mice and provide evidence the occurrence reflects increased effector function of IgG and possibly decreased regulation of C. Given the high frequency of TNFRSF13B polymorphism our results suggest screening for functionally significant mutations may be warranted in organ transplantation.

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