We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Identification and Characterization of Post-activated B Cells in Systemic Autoimmune Diseases.
- Authors
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
- Abstract
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− 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.
- Subjects
B cells; AUTOIMMUNE diseases; SYSTEMIC lupus erythematosus; PROTEIN-tyrosine phosphatase; B cell receptors
- Publication
Frontiers in Immunology, 2019, p1
- ISSN
1664-3224
- Publication type
Article
- DOI
10.3389/fimmu.2019.02136