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

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.

• Autores: Rincón Arévalo, Héctor Julián; Szelinski, Franziska; Schrezenmeier, Eva; Stefanski, Ana Luisa; Wiedemann, Annika; Weißenberg, Sarah Y.; Welle, Anna; Jungmann, Annemarie; Nordström, Karl; Walter, Jörn; Imgenberg Kreuz, Juliana; Nordmark, Gunnel; Rönnblom, Lars; Rönnblom, Lars; Catalina, Michelle D.; Grammer, Amrie C.; Lipsky, Peter E.; Lino, Andreia C.; Dörner, Thomas
• Tipo de recurso: Article of investigation
• Fecha de publicación: 2019
• Institución: Universidad de Antioquia
• Repositorio: Repositorio UdeA
• Idioma: eng
• OAI Identifier: oai:bibliotecadigital.udea.edu.co:10495/43130
• Acceso en línea: https://hdl.handle.net/10495/43130
• Palabra clave: Agammaglobulinemia Tirosina Quinasa - inmunología; Agammaglobulinaemia Tyrosine Kinase - immunology; Enfermedades Autoinmunes; Autoimmune Diseases; Linfocitos B; B-Lymphocytes; Proteínas Tirosina Fosfatasas - inmunología; Protein Tyrosine Phosphatases - immunology; Receptores de Antígenos de Linfocitos B - inmunología; Receptors, Antigen, B-Cell - immunology; Quinasa Syk - inmunología; Syk Kinase - immunology; Lupus Eritematoso Sistémico; Lupus Erythematosus, Systemic; Antígenos CD40; CD40 Antigens; Receptor Toll-Like 9; Toll-Like Receptor 9; https://id.nlm.nih.gov/mesh/D000077329; https://id.nlm.nih.gov/mesh/D001327; https://id.nlm.nih.gov/mesh/D001402; https://id.nlm.nih.gov/mesh/D017027; https://id.nlm.nih.gov/mesh/D011947; https://id.nlm.nih.gov/mesh/D000072377; https://id.nlm.nih.gov/mesh/D008180; https://id.nlm.nih.gov/mesh/D019013; https://id.nlm.nih.gov/mesh/D051217
• Rights: openAccess
• License: https://creativecommons.org/licenses/by/4.0/