RT Journal Article
SR Electronic
T1 FcγRIIB regulates (auto)antibody responses by limiting marginal zone B cell activation
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.12.03.471075
DO 10.1101/2021.12.03.471075
A1 Ashley N. Barlev
A1 Susan Malkiel
A1 Annemarie L. Dorjée
A1 Jolien Suurmond
A1 Betty Diamond
YR 2021
UL http://biorxiv.org/content/early/2021/12/04/2021.12.03.471075.abstract
AB 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.Competing Interest StatementThe authors have declared no competing interest.