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FcγRIIB regulates (auto)antibody responses by limiting marginal zone B cell activation

Ashley N. Barlev, Susan Malkiel, Annemarie L. Dorjée, View ORCID ProfileJolien Suurmond, Betty Diamond
doi: https://doi.org/10.1101/2021.12.03.471075
Ashley N. Barlev
1Center of Autoimmune Musculoskeletal and Hematopoietic Diseases, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, USA
2Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, USA
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Susan Malkiel
1Center of Autoimmune Musculoskeletal and Hematopoietic Diseases, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, USA
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Annemarie L. Dorjée
3Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
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Jolien Suurmond
1Center of Autoimmune Musculoskeletal and Hematopoietic Diseases, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, USA
3Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
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  • ORCID record for Jolien Suurmond
  • For correspondence: bdiamond@northwell.edu j.suurmond@lumc.nl
Betty Diamond
1Center of Autoimmune Musculoskeletal and Hematopoietic Diseases, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, USA
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  • For correspondence: bdiamond@northwell.edu j.suurmond@lumc.nl
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Abstract

FcγRIIB is an inhibitory receptor expressed throughout B cell development. Diminished expression or function is associated with lupus in mice and humans, in particular through an effect on autoantibody production and plasma cell differentiation. Here, we analysed the effect of B cell-intrinsic FcγRIIB expression on B cell activation and plasma cell differentiation.

Loss of FcγRIIB on B cells (Fcgr2b cKO mice) led to a spontaneous increase in autoantibody titers. This increase was most striking for IgG3, suggestive of increased extrafollicular responses. Marginal zone (MZ) and IgG3+ B cells had the highest expression of FcγRIIB and the increase in serum IgG3 was linked to increased MZ B cell signaling and activation in the absence of FcγRIIB. Likewise, human circulating MZ-like B cells had the highest expression of FcγRIIB, and their activation was most strongly inhibited by engaging FcγRIIB. Finally, marked increases in IgG3+ plasma cells and B cells were observed during extrafollicular plasma cell responses with both T-dependent and T-independent antigens in Fcgr2b cKO mice. The increased IgG3 response following immunization of Fcgr2b cKO mice was lost in MZ-deficient Notch2/Fcgr2b cKO mice.

Thus, we present a model where high FcγRIIB expression in MZ B cells prevents their hyperactivation and ensuing autoimmunity.

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Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • ↵* Shared first author

  • ↵# Shared senior author

  • Conflict of interest statement The authors have declared that no conflict of interest exists.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted December 04, 2021.
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FcγRIIB regulates (auto)antibody responses by limiting marginal zone B cell activation
Ashley N. Barlev, Susan Malkiel, Annemarie L. Dorjée, Jolien Suurmond, Betty Diamond
bioRxiv 2021.12.03.471075; doi: https://doi.org/10.1101/2021.12.03.471075
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FcγRIIB regulates (auto)antibody responses by limiting marginal zone B cell activation
Ashley N. Barlev, Susan Malkiel, Annemarie L. Dorjée, Jolien Suurmond, Betty Diamond
bioRxiv 2021.12.03.471075; doi: https://doi.org/10.1101/2021.12.03.471075

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