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Platt JL, de Mattos Barbosa MG, Huynh D, et al. TNFRSF13B polymorphisms counter microbial adaptation to enteric IgA. JCI Insight. 2021;6(14)doi: 10.1172/jci.insight.148208.
Platt, J. L., de Mattos Barbosa, M. G., Huynh, D., Lefferts, A. R., Katta, J., Kharas, C., Freddolino, P., Bassis, C. M., Wobus, C., Geha, R., Bram, R., Nunez, G., Kamada, N., & Cascalho, M. (2021). TNFRSF13B polymorphisms counter microbial adaptation to enteric IgA. JCI insight, 6(14), . https://doi.org/10.1172/jci.insight.148208
Platt, Jeffrey L, et al. "TNFRSF13B polymorphisms counter microbial adaptation to enteric IgA." JCI insight vol. 6,14 (2021). doi: https://doi.org/10.1172/jci.insight.148208
Platt JL, de Mattos Barbosa MG, Huynh D, Lefferts AR, Katta J, Kharas C, Freddolino P, Bassis CM, Wobus C, Geha R, Bram R, Nunez G, Kamada N, Cascalho M. TNFRSF13B polymorphisms counter microbial adaptation to enteric IgA. JCI Insight. 2021 Jul 22;6(14). doi: 10.1172/jci.insight.148208. PMID: 34111031; PMCID: PMC8410086.
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JCI Insight. 2021 Jul 22;6(14). doi: 10.1172/jci.insight.148208.

TNFRSF13B polymorphisms counter microbial adaptation to enteric IgA.

JCI insight

Jeffrey L Platt, Mayara Garcia de Mattos Barbosa, Daniel Huynh, Adam R Lefferts, Juhi Katta, Cyra Kharas, Peter Freddolino, Christine M Bassis, Christiane Wobus, Raif Geha, Richard Bram, Gabriel Nunez, Nobuhiko Kamada, Marilia Cascalho

Affiliations

  1. Department of Microbiology and Immunology and Department of Surgery.
  2. Department of Surgery.
  3. Department of Biological Chemistry and Department of Computational Medicine and Bioinformatics.
  4. Department of Medicine, and.
  5. Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, USA.
  6. Department of Pediatrics, Boston Children's Hospital, Boston, Massachusetts, USA.
  7. Departments of Oncology, Pediatric Hematology/Oncology, and Pediatrics, Mayo Clinic, Rochester, Minnesota, USA.
  8. Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.

PMID: 34111031 PMCID: PMC8410086 DOI: 10.1172/jci.insight.148208

Abstract

TNFRSF13B encodes the transmembrane activator and CAML interactor (TACI) receptor, which drives plasma cell differentiation. Although TNFRSF13B supports host defense, dominant-negative TNFRSF13B alleles are common in humans and other species and only rarely associate with disease. We reasoned that the high frequency of disruptive TNFRSF13B alleles reflects balancing selection, the loss of function conferring advantage in some settings. Testing that concept, we investigated how a common human dominant-negative variant, TNFRSF13B A181E, imparts resistance to enteric pathogens. Mice engineered to express mono- or biallelic A144E variants of tnrsf13B, corresponding to A181E, exhibited a striking resistance to pathogenicity and transmission of Citrobacter rodentium, a murine pathogen that models enterohemorrhagic Escherichia coli, and resistance was principally owed to natural IgA deficiency in the intestine. In WT mice with gut IgA and in mutant mice reconstituted with enteric IgA obtained from WT mice, IgA induces LEE expression of encoded virulence genes, which confer pathogenicity and transmission. Taken together, our results show that C. rodentium and most likely other enteric organisms appropriated binding of otherwise protective antibodies to signal induction of the virulence program. Additionally, the high prevalence of TNFRSF13B dominant-negative variants reflects balancing selection.

Keywords: Bacterial infections; Genetic variation; Immunoglobulins; Immunology; Microbiology

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