Biology subjects

Dorjee, A. L.

Publications and source records attributed to Dorjee, A. L..

2 recordsLinked to original sources

bioRxiv2024

IFN-associated B cell hyperactivity is highly enriched in SLE patients harboring Sm/RNP antibodies

Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by an array of autoantibodies, in particular anti-nuclear antibodies (ANA). The disease is also hallmarked by an expansion of plasmablasts (PB) in peripheral blood. How these relate to autoantibody production is not clear. Here, we aimed to understand B cell alterations in SLE and their relationship to immunoglobulin levels and autoantibody production. We demonstrate that a subgroup of SLE patients is characterized by a high frequency of PB relative to memory B cells (high PB/M). Patients with this phenotype more frequently had high disease activity. Despite low overall frequencies of memory B cells, these patients exhibited an increased activation in the switched CD27+ memory compartment and a strong IFN signature in PB. Repertoire analysis revealed a highly polyclonal expansion and enrichment for IgG1 expressing PB in patients with a high PB/M ratio which was reflected in increased serum IgG levels. Importantly, the hyperactive B cell phenotype was highly enriched in patients harboring Sm/RNP autoantibodies (OR: 9.17 (2.97-26.0)). In summary, we show for the first time a direct relationship between IFN and PB expansion in a subgroup of SLE patients, highly enriched in those harboring Sm/RNP antibodies. These results provide insight into the pathways leading to B cell hyperactivity and autoantibody production which may guide the tailoring of B cell- and IFN-targeted therapies. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=156 SRC="FIGDIR/small/624119v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@1f74053org.highwire.dtl.DTLVardef@1a01da4org.highwire.dtl.DTLVardef@fa27f4org.highwire.dtl.DTLVardef@155140f_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2021

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

Fc{gamma}RIIB 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 Fc{gamma}RIIB expression on B cell activation and plasma cell differentiation. Loss of Fc{gamma}RIIB 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 Fc{gamma}RIIB and the increase in serum IgG3 was linked to increased MZ B cell signaling and activation in the absence of Fc{gamma}RIIB. Likewise, human circulating MZ-like B cells had the highest expression of Fc{gamma}RIIB, and their activation was most strongly inhibited by engaging Fc{gamma}RIIB. 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 Fc{gamma}RIIB expression in MZ B cells prevents their hyperactivation and ensuing autoimmunity. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=81 SRC="FIGDIR/small/471075v1_ufig1.gif" ALT="Figure 1"> View larger version (12K): org.highwire.dtl.DTLVardef@10bf17corg.highwire.dtl.DTLVardef@11b067aorg.highwire.dtl.DTLVardef@1465e36org.highwire.dtl.DTLVardef@d3351c_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗