Weißenberg, Sarah Y. Szelinski, Franziska Schrezenmeier, Eva Stefanski, Ana-Luisa Wiedemann, Annika Rincon-Arevalo, Hector Welle, Anna Jungmann, Annemarie Nordström, Karl Walter, Jörn Imgenberg-Kreuz, Juliana Nordmark, Gunnel Rönnblom, Lars Bachali, Prathyusha Catalina, Michelle D. Grammer, Amrie C. Lipsky, Peter E. Lino, Andreia C. Dörner, Thomas Table_4_Identification and Characterization of Post-activated B Cells in Systemic Autoimmune Diseases.DOCX <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> systemic lupus erythematosus;rheumatoid arthritis;primary Sjögren's syndrome;B cell receptor signaling;toll-like receptor 9;CD40;post-activation;anergy 2019-09-24
    https://frontiersin.figshare.com/articles/dataset/Table_4_Identification_and_Characterization_of_Post-activated_B_Cells_in_Systemic_Autoimmune_Diseases_DOCX/9895265
10.3389/fimmu.2019.02136.s010