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

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.

Beyond Adaptive Alloreactivity: Contribution of Innate B Cells to Allograft Inflammation and Rejection

“…61 TNFRSF13B is one of the most polymorphic genes in humans, leading Cascalho and colleagues to test whether TNFRSF13B alleles might determine the magnitude of innate B-cell responses and graft outcome. 65 Their study showed that human kidney transplant recipients with missense mutations in TNFRSF13B comprised 33% of those with AMR, but only <6% of those with stable graft function had TNFRSF13B missense mutations. These observations raised the possibility that wild-type (WT) levels of TACI were protective and, conversely, reduced TACI resulted in more aggressive alloreactivity.…”

“…To define the mechanisms for these unexpected observations, de Mattos Barbosa et al used a mouse cardiac transplant model to show that allografts in Tnfrsf13b -mutant recipients underwent early and severe AMR. 65 The increased propensity for developing AMR in Tnfrsf13b -deficient mice was not caused by increased alloantibodies but rather was associated with decreased “natural” IgM production.…”

“…Natural IgM was postulated by de Mattos Barbaso et al to be protective because of its polyreactivity results in their binding to circulating C3b, thereby preventing C3b from become activated/fixed on the membrane of eukaryotic cellular targets. 65 In Tnfrsf13b -deficient recipients, compromised complement regulation as a result of low levels of circulating “natural” IgM resulted in increased complement deposition in heart allografts and in the recipient’s kidneys. Thus, WT TACI regulated innate B-cell functions by limiting complement-associated inflammation, contrary to some common variants of Tnfrsf13b genes that intensified inflammatory responses.…”

“…Indeed, de Mattos Barbosa et al showed that transplant recipients with TNFRSF13B missense mutations had significantly lower concentrations of IgM natural antibodies and C3 in serum compared to transplant recipients with WT alleles and had an increased risk of AMR. 65 These elegant studies point to a novel and unexpectedly protective role for natural IgM produced by T-independent B cells in transplantation, and the control that TACI exerts on the levels of circulating protective natural IgM.…”

TNFRSF13B in B cell responses to organ transplantation

“…Detailed investigation further revealed that mice and human subjects with defects in or absence of TACI function exhibit defective control of T cell-dependent B cell responses [ 39 ], suggesting the receptor might act in the opposite ways in T cell-independent and T cell-dependent responses. More recent investigation reveals that TACI limits clonal expansion and affinity maturation of T cell-dependent B cell responses [ 40 ] but also that the mixture of innate and elicited B cell responses in host defense and transplantation can have a greater biological impact than the intensity of one or another type of response [ 38 , 41 ].…”