Artikel
Differential phenotypes of disease-specific auto-reactive B cell responses in patients with Systemic Sclerosis
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Veröffentlicht: | 9. September 2020 |
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Gliederung
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Introduction: 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. To address this question, we here delineated 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. ATA- and ACA-IgG and -IgA as well as total IgG and IgA were measured in culture supernatants by ELISA. In addition, PBMC were depleted of circulating plasmablasts (CD19+CD20-CD27++) by fluorescence activated cell sorting (FACS), and isolated plasmablasts were cultured separately. B cell subsets were defined by flow cytometry. PBMCs and B cell subsets from 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 despite comparable levels of total IgA. 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. In contrast to the ACA response, the remarkable ATA-IgA secretion points towards a mucosal origin of the ATA response.
Disclosures: None declared