TNFRSF13B genotypes control immune-mediated pathology by regulating the functions of innate B cells.

Mayara Garcia De Mattos Barbosa,Marilia Cascalho,Jenna Barnes,Jeffrey L Platt,Beverly Fu,Hui Liu,Yu Zhang,Milagros Samaniego,Adam R Lefferts,Richard J Bram,Ariella Shikanov,Evan A Farkash,Daniel Huynh,Raif S Geha,Eline T Luning Prak

doi:10.1172/jci.insight.150483

Abstract

Host genes define the severity of inflammation and immunity but specific loci doing so are unknown. Here we show that TNF receptor superfamily member 13B (TNFRSF13B) variants, which enhance defense against certain pathogens, also control immune-mediated injury of transplants, by regulating innate B cells’ functions. Analysis of TNFRSF13B in human kidney transplant recipients revealed that 33% of those with antibody-mediated rejection (AMR) but fewer than 6% of those with stable graft function had TNFRSF13B missense mutations. To explore mechanisms underlying aggressive immune responses, we investigated alloimmunity and rejection in mice. Cardiac allografts in Tnfrsf13b-mutant mice underwent early and severe AMR. The dominance and precocity of AMR in Tnfrsf13b-deficient mice were not caused by increased alloantibodies. Rather, Tnfrsf13b mutations decreased “natural” IgM and compromised complement regulation, leading to complement deposition in allografted hearts and autogenous kidneys. Thus, WT TNFRSF13B and Tnfrsf13b support innate B cell functions that limit complement-associated inflammation; in contrast, common variants of these genes intensify inflammatory responses that help clear microbial infections but allow inadvertent tissue injury to ensue. The wide variation in inflammatory reactions associated with TNFRSF13B diversity suggests polymorphisms could underlie variation in host defense and explosive inflammatory responses that sometimes enhance morbidity associated with immune responses.

Highlights

Immunity and tolerance are governed at least in part by highly polymorphic genes of the MHC [1, 2], first appreciated as inherited determinants of the ability to produce antibodies against and reject foreign cells and tissues [3, 4]
That the extraordinary polymorphism of TNFRSF13B has been maintained across mammalian species likely suggests the aggressive, highly inflammatory responses confer host defense; our results show this benefit is balanced by the risk that immunity will eventuate in unbridled inflammatory reactions severe enough to destroy an organ
We reasoned that if functions imparted by TNFRSF13B were of consequence for the biological impact of antibody responses, the frequency of TNFRSF13B missense mutations might differ in transplant recipients with antibody-mediated rejection (AMR) and recipients free of rejection

Summary

Introduction

Immunity and tolerance are governed at least in part by highly polymorphic genes of the MHC [1, 2], first appreciated as inherited determinants of the ability to produce antibodies against and reject foreign cells and tissues [3, 4]. Having recently discovered that a highly polymorphic gene (TNF receptor superfamily member 13B, TNFRSF13B) remote from MHC determines the character of primary immunity to enteric pathogens and whether immunity confers protection [9], we wondered whether and how variants of that gene could explain the not uncommon dissociation between transplant immunity and rejection of transplants and more broadly whether polymorphism at this locus could explain profoundly divergent impact of immunity and inflammation. TNFRSF13B could govern the balance between immunity and tolerance [16]

Methods

Results

Conclusion