10.3389/fimmu.2019.02136.s010 Sarah Y. Weißenberg Sarah Y. Weißenberg Franziska Szelinski Franziska Szelinski Eva Schrezenmeier Eva Schrezenmeier Ana-Luisa Stefanski Ana-Luisa Stefanski Annika Wiedemann Annika Wiedemann Hector Rincon-Arevalo Hector Rincon-Arevalo Anna Welle Anna Welle Annemarie Jungmann Annemarie Jungmann Karl Nordström Karl Nordström Jörn Walter Jörn Walter Juliana Imgenberg-Kreuz Juliana Imgenberg-Kreuz Gunnel Nordmark Gunnel Nordmark Lars Rönnblom Lars Rönnblom Prathyusha Bachali Prathyusha Bachali Michelle D. Catalina Michelle D. Catalina Amrie C. Grammer Amrie C. Grammer Peter E. Lipsky Peter E. Lipsky Andreia C. Lino Andreia C. Lino Thomas Dörner Thomas Dörner Table_4_Identification and Characterization of Post-activated B Cells in Systemic Autoimmune Diseases.DOCX Frontiers 2019 systemic lupus erythematosus rheumatoid arthritis primary Sjögren's syndrome B cell receptor signaling toll-like receptor 9 CD40 post-activation anergy 2019-09-24 04:18:44 Dataset https://frontiersin.figshare.com/articles/dataset/Table_4_Identification_and_Characterization_of_Post-activated_B_Cells_in_Systemic_Autoimmune_Diseases_DOCX/9895265 <p>Autoimmune diseases (AID) such as systemic lupus erythematosus (SLE), primary Sjögren's syndrome (pSS), and rheumatoid arthritis (RA) are chronic inflammatory diseases in which abnormalities of B cell function play a central role. Although it is widely accepted that autoimmune B cells are hyperactive in vivo, a full understanding of their functional status in AID has not been delineated. Here, we present a detailed analysis of the functional capabilities of AID B cells and dissect the mechanisms underlying altered B cell function. Upon BCR activation, decreased spleen tyrosine kinase (Syk) and Bruton's tyrosine kinase (Btk) phosphorylation was noted in AID memory B cells combined with constitutive co-localization of CD22 and protein tyrosine phosphatase (PTP) non-receptor type 6 (SHP-1) along with hyporesponsiveness to TLR9 signaling, a Syk-dependent response. Similar BCR hyporesponsiveness was also noted specifically in SLE CD27<sup>−</sup> B cells together with increased PTP activities and increased transcripts for PTPN2, PTPN11, PTPN22, PTPRC, and PTPRO in SLE B cells. Additional studies revealed that repetitive BCR stimulation of normal B cells can induce BCR hyporesponsiveness and that tissue-resident memory B cells from AID patients also exhibited decreased responsiveness immediately ex vivo, suggesting that the hyporesponsive status can be acquired by repeated exposure to autoantigen(s) in vivo. Functional studies to overcome B cell hyporesponsiveness revealed that CD40 co-stimulation increased BCR signaling, induced proliferation, and downregulated PTP expression (PTPN2, PTPN22, and receptor-type PTPs). The data support the conclusion that hyporesponsiveness of AID and especially SLE B cells results from chronic in vivo stimulation through the BCR without T cell help mediated by CD40–CD154 interaction and is manifested by decreased phosphorylation of BCR-related proximal signaling molecules and increased PTPs. The hyporesponsiveness of AID B cells is similar to a form of functional anergy.</p>