SAT0297 DIFFERENTIAL PHENOTYPES OF DISEASE-SPECIFIC AUTO-REACTIVE B CELL RESPONSES IN PATIENTS WITH SYSTEMIC SCLEROSIS. (2nd June 2020)

• Record Type: Journal Article
• Authors: Wortel, C.; Van Leeuwen, N.; Boonstra, M.; Toes, R.; Huizinga, T.; De Vries-Bouwstra, J.; Scherer, H. U.
• Is Part Of: Annals of the rheumatic diseases. Volume 79(2020)Supplement 1
• Page Start: 1093
• Page End: 1094
• Publication Date: 2020-06-02
• Subjects: Rheumatism -- Periodicals; 616.723005
• DOI: 10.1136/annrheumdis-2020-eular.6049
• Languages: English
• ISSNs: 0003-4967

Abstract

Abstract : Background: Systemic Sclerosis (SSc) carries the highest mortality burden among the rheumatic diseases. >95% of SSc patients harbor autoantibodies. Anti-topoisomerase antibodies (ATA) and anti-centromere antibodies (ACA) are most prevalent, mutually exclusive in individual patients, associate with distinct disease phenotypes and predict disease. Whether and how these auto-reactive B cell responses contribute to disease, however, is currently unclear. Objectives: To delineate phenotypic and functional characteristics of anti-topoisomerase and anti-centromere specific B cell responses in individual patients with SSc. Methods: Peripheral blood mononuclear cells (PBMC) obtained from ATA- and ACA-positive SSc patients were cultured without stimulation or in the presence of CD40L-expressing fibroblasts, IL-21 and BAFF. In addition, PBMC were depleted of circulating plasmablasts (CD19+CD20-CD27++) by fluorescence activated cell sorting (FACS), and isolated plasmablasts were cultured separately. ATA- and ACA-IgG and -IgA were measured in culture supernatants by ELISA. B cell subsets were defined by flow cytometry. Healthy donors and patients with rheumatoid arthritis served as controls. Results: We observed that ATA- and ACA-positive SSc patients harbour circulating B cells that secrete either ATA-IgG or ACA-IgG upon stimulation, depending on their serotype. In addition, we noted spontaneous secretion of ATA-IgG and, more remarkably, extensive secretion of ATA-IgA in ATA-positive patients. This degree of spontaneous, antigen-specific IgA secretion was specific for the ATA response in ATA-positive patients, while spontaneous ACA-IgA secretion was undetectable in the ACA-positive patient group. FACS experiments showed that spontaneously ATA-IgA secreting B cells were primarily present in the plasmablast compartment. Conclusion: Our findings demonstrate that ATA-positive SSc patients harbour an activated ATA-IgG and ATA-IgA B cell response, as indicated by the spontaneous secretion of both ATA isotypes by circulating plasmablasts. Remarkably, the ACA B cell response was far less active and lacked the active IgA component which suggests a difference in the triggers driving these autoreactive B cell responses in patients. Moreover, the remarkable ATA-IgA secretion points towards a potential mucosal origin of the ATA response. Disclosure of Interests: Corrie Wortel: None declared, Nina van Leeuwen: None declared, Maaike Boonstra: None declared, Rene Toes: None declared, Thomas Huizinga Grant/research support from: Ablynx, Bristol-Myers Squibb, Roche, Sanofi, Consultant of: Ablynx, Bristol-Myers Squibb, Roche, Sanofi, Jeska de Vries-Bouwstra: None declared, Hans Ulrich Scherer Grant/research support from: Bristol Myers Squibb, Sanofi, Pfizer, Speakers bureau: Pfizer, Lilly, Roche, Abbvie