TY - JOUR
T1 - TNFRSF13B genotypes control immune-mediated pathology by regulating the functions of innate B cells
AU - De Mattos Barbosa, Mayara Garcia
AU - Lefferts, Adam R.
AU - Huynh, Daniel
AU - Liu, Hui
AU - Zhang, Yu
AU - Fu, Beverly
AU - Barnes, Jenna
AU - Samaniego, Milagros
AU - Bram, Richard J.
AU - Geha, Raif S.
AU - Shikanov, Ariella
AU - Luning Prak, Eline T.
AU - Farkash, Evan A.
AU - Platt, Jeffrey L.
AU - Cascalho, Marilia
N1 - Funding Information:
The microarray analysis was performed by the Advanced Genomics Core at the University of Michigan. This work was supported by the NIH (AI117561, AI122369, and AI15158801) to MC and JLP; by EB022033, to MC and AS; by the Department of Surgery at the University of Michigan; by the Michigan Genomics Initiative; by 2 grants from the Michigan Institute for Clinical and Health Research (to MC and MGMB); and by a grant from the American Society of Transplantation Research Network (to MGMB).
Publisher Copyright:
© 2021, de Mattos Barbosa et al.
PY - 2021/9/8
Y1 - 2021/9/8
N2 - 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.
AB - 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.
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U2 - 10.1172/jci.insight.150483
DO - 10.1172/jci.insight.150483
M3 - Article
C2 - 34283811
AN - SCOPUS:85114646272
VL - 6
JO - JCI insight
JF - JCI insight
SN - 2379-3708
IS - 17
M1 - e150483
ER -