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Identification and Characterization of Post-activated B Cells in Systemic Autoimmune Diseases
Charite Univ Med Berlin, Dept Rheumatol & Clin Immunol, Berlin, Germany; German Rheumatism Res Ctr Berlin DRFZ, Berlin, Germany.
Charite Univ Med Berlin, Dept Rheumatol & Clin Immunol, Berlin, Germany; German Rheumatism Res Ctr Berlin DRFZ, Berlin, Germany.
Charite Univ Med Berlin, Dept Rheumatol & Clin Immunol, Berlin, Germany.
Charite Univ Med Berlin, Dept Rheumatol & Clin Immunol, Berlin, Germany.
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2019 (English)In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 10, article id 2136Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2019. Vol. 10, article id 2136
Keywords [en]
systemic lupus erythematosus, rheumatoid arthritis, primary Sjogren's syndrome, B cell receptor signaling, toll-like receptor 9, CD40, post-activation, anergy
National Category
Immunology in the medical area
Identifiers
URN: urn:nbn:se:uu:diva-395436DOI: 10.3389/fimmu.2019.02136ISI: 000487582300001OAI: oai:DiVA.org:uu-395436DiVA, id: diva2:1366630
Funder
Swedish Research CouncilGerman Research Foundation (DFG), Do491/101; TR130; SFB650Swedish Society of MedicineAvailable from: 2019-10-30 Created: 2019-10-30 Last updated: 2019-10-30Bibliographically approved

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