dc.contributor.author
Weißenberg, Sarah Y.
dc.contributor.author
Szelinski, Franziska
dc.contributor.author
Schrezenmeier, Eva
dc.contributor.author
Stefanski, Ana-Luisa
dc.contributor.author
Wiedemann, Annika
dc.contributor.author
Rincon-Arevalo, Hector
dc.contributor.author
Welle, Anna
dc.contributor.author
Jungmann, Annemarie
dc.contributor.author
Nordström, Karl
dc.contributor.author
Walter, Jörn
dc.contributor.author
Imgenberg-Kreuz, Juliana
dc.contributor.author
Nordmark, Gunnel
dc.contributor.author
Rönnblom, Lars
dc.contributor.author
Bachali, Prathyusha
dc.contributor.author
Catalina, Michelle D.
dc.contributor.author
Grammer, Amrie C.
dc.contributor.author
Lipsky, Peter E.
dc.contributor.author
Lino, Andreia C.
dc.contributor.author
Dörner, Thomas
dc.date.accessioned
2020-01-10T12:53:19Z
dc.date.available
2020-01-10T12:53:19Z
dc.identifier.uri
https://refubium.fu-berlin.de/handle/fub188/26374
dc.identifier.uri
http://dx.doi.org/10.17169/refubium-26135
dc.description.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.
en
dc.rights.uri
https://creativecommons.org/licenses/by/4.0/
dc.subject
B cell receptor signaling
en
dc.subject
post-activation
en
dc.subject
primary Sjögren's syndrome
en
dc.subject
rheumatoid arthritis
en
dc.subject
systemic lupus erythematosus
en
dc.subject
toll-like receptor 9
en
dc.subject.ddc
600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::610 Medizin und Gesundheit
dc.title
Identification and Characterization of Post-activated B Cells in Systemic Autoimmune Diseases
dc.type
Wissenschaftlicher Artikel
dcterms.bibliographicCitation.articlenumber
2136
dcterms.bibliographicCitation.doi
10.3389/fimmu.2019.02136
dcterms.bibliographicCitation.journaltitle
Frontiers in Immunology
dcterms.bibliographicCitation.originalpublishername
Frontiers Media S.A.
dcterms.bibliographicCitation.volume
10
refubium.affiliation
Charité - Universitätsmedizin Berlin
refubium.resourceType.isindependentpub
no
dcterms.accessRights.openaire
open access
dcterms.bibliographicCitation.pmid
31616406
dcterms.isPartOf.eissn
1664-3224