Identification and Characterization of Post-activated B Cells in Systemic Autoimmune Diseases
| العنوان: | Identification and Characterization of Post-activated B Cells in Systemic Autoimmune Diseases |
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| المؤلفون: | 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 |
| المصدر: | Frontiers in Immunology. 10 |
| مصطلحات موضوعية: | systemic lupus erythematosus, rheumatoid arthritis, primary Sjogren's syndrome, B cell receptor signaling, toll-like receptor 9, CD40, post-activation, anergy |
| الوصف: | Autoimmune diseases (AID) such as systemic lupus erythematosus (SLE), primary Sjogren'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-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. |
| وصف الملف: | electronic |
| URL الوصول: | https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-395436 https://doi.org/10.3389/fimmu.2019.02136 https://uu.diva-portal.org/smash/get/diva2:1366630/FULLTEXT01.pdf |
| قاعدة البيانات: | SwePub |
| DOI: | 10.3389/fimmu.2019.02136 |
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