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de Mattos Barbosa MG, Lefferts AR, Huynh D, et al. TNFRSF13B genotypes control immune-mediated pathology by regulating the functions of innate B cells. JCI Insight. 2021;6(17)doi: 10.1172/jci.insight.150483.
de Mattos Barbosa, M. G., Lefferts, A. R., Huynh, D., Liu, H., Zhang, Y., Fu, B., Barnes, J., Samaniego, M., Bram, R. J., Geha, R. S., Shikanov, A., Prak, E. T. L., Farkash, E. A., Platt, J. L., & Cascalho, M. (2021). TNFRSF13B genotypes control immune-mediated pathology by regulating the functions of innate B cells. JCI insight, 6(17), . https://doi.org/10.1172/jci.insight.150483
de Mattos Barbosa, Mayara Garcia, et al. "TNFRSF13B genotypes control immune-mediated pathology by regulating the functions of innate B cells." JCI insight vol. 6,17 (2021). doi: https://doi.org/10.1172/jci.insight.150483
de Mattos Barbosa MG, Lefferts AR, Huynh D, Liu H, Zhang Y, Fu B, Barnes J, Samaniego M, Bram RJ, Geha RS, Shikanov A, Prak ETL, Farkash EA, Platt JL, Cascalho M. TNFRSF13B genotypes control immune-mediated pathology by regulating the functions of innate B cells. JCI Insight. 2021 Sep 08;6(17). doi: 10.1172/jci.insight.150483. PMID: 34283811; PMCID: PMC8492324.
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JCI Insight. 2021 Sep 08;6(17). doi: 10.1172/jci.insight.150483.

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

JCI insight

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

Affiliations

  1. Department of Surgery.
  2. Department of Pathology, and.
  3. Department of Medicine, University of Michigan, Ann Arbor, Michigan, USA.
  4. Department of Pediatric and Adolescent Medicine and Department of Immunology, Mayo Clinic, Rochester, Minnesota, USA.
  5. Division of Immunology, Boston Children's Hospital, Boston, Massachusetts, USA.
  6. Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
  7. Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan, USA.
  8. Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
  9. Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, USA.

PMID: 34283811 PMCID: PMC8492324 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.

Keywords: Genetic variation; Genetics; Immunoglobulins; Inflammation; Mouse models

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