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Identification and Characterization of Post-activated B Cells in Systemic Autoimmune Diseases

Weissenberg, Sarah Y., (författare)
Charite Univ Med Berlin, Dept Rheumatol & Clin Immunol, Berlin, Germany; German Rheumatism Res Ctr Berlin DRFZ, Berlin, Germany
Szelinski, Franziska, (författare)
Charite Univ Med Berlin, Dept Rheumatol & Clin Immunol, Berlin, Germany; German Rheumatism Res Ctr Berlin DRFZ, Berlin, Germany
Schrezenmeier, Eva, (författare)
Charite Univ Med Berlin, Dept Rheumatol & Clin Immunol, Berlin, Germany
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Stefanski, Ana-Luisa, (författare)
Charite Univ Med Berlin, Dept Rheumatol & Clin Immunol, Berlin, Germany
Wiedemann, Annika, (författare)
Charite Univ Med Berlin, Dept Rheumatol & Clin Immunol, Berlin, Germany
Rincon-Arevalo, Hector, (författare)
Charite Univ Med Berlin, Dept Rheumatol & Clin Immunol, Berlin, Germany; German Rheumatism Res Ctr Berlin DRFZ, Berlin, Germany; Univ Antioquia UdeA, Fac Med, Inst Invest Med, Grp Inmunol Celular & Inmunogenet, Medellin, Colombia
Welle, Anna, (författare)
Saarland Univ, Dept Genet & Epigenet, Saarbrucken, Germany
Jungmann, Annemarie, (författare)
Saarland Univ, Dept Genet & Epigenet, Saarbrucken, Germany
Nordström, Karl, (författare)
Saarland Univ, Dept Genet & Epigenet, Saarbrucken, Germany
Walter, Jörn, (författare)
Saarland Univ, Dept Genet & Epigenet, Saarbrucken, Germany
Imgenberg-Kreuz, Juliana, (författare)
Uppsala universitet, Science for Life Laboratory, SciLifeLab, Uppsala universitet, Reumatologi
Nordmark, Gunnel, (författare)
Uppsala universitet, Reumatologi, Uppsala universitet, Science for Life Laboratory, SciLifeLab
Rönnblom, Lars, (författare)
Uppsala universitet, Reumatologi, Uppsala universitet, Science for Life Laboratory, SciLifeLab
Bachali, Prathyusha, (författare)
RILITE Res Inst, Charlottesville, VA USA
Catalina, Michelle D., (författare)
RILITE Res Inst, Charlottesville, VA USA
Grammer, Amrie C., (författare)
RILITE Res Inst, Charlottesville, VA USA
Lipsky, Peter E., (författare)
RILITE Res Inst, Charlottesville, VA USA
Lino, Andreia C., (författare)
Charite Univ Med Berlin, Dept Rheumatol & Clin Immunol, Berlin, Germany; German Rheumatism Res Ctr Berlin DRFZ, Berlin, Germany
Dörner, Thomas, (författare)
Charite Univ Med Berlin, Dept Rheumatol & Clin Immunol, Berlin, Germany; German Rheumatism Res Ctr Berlin DRFZ, Berlin, Germany
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Uppsala universitet Science for Life Laboratory, SciLifeLab. (creator_code:org_t)
Uppsala universitet Medicinska och farmaceutiska vetenskapsområdet. Medicinska fakulteten. Institutionen för medicinska vetenskaper. Reumatologi. (creator_code:org_t)
2019
Engelska.
Ingår i: Frontiers in Immunology. - 1664-3224 .- 1664-3224. ; 10
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  • Tidskriftsartikel (refereegranskat)
Abstract Ämnesord
Stäng  
  • 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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska grundvetenskaper -- Immunologi inom det medicinska området (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Immunology in the medical area (hsv//eng)

Nyckelord

systemic lupus erythematosus
rheumatoid arthritis
primary Sjogren's syndrome
B cell receptor signaling
toll-like receptor 9
CD40
post-activation
anergy

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