Artikel
Abatacept modulates CD80 and CD86 expression in human B cells and ACPA specific memory in RA patients
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Veröffentlicht: | 8. Oktober 2019 |
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Gliederung
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Background: Cytotoxic T lymphocyte antigen-4 (CTLA-4) limits T-cell activation and is expressed on T-regulatory cells. Human CTLA-4 deficiency results in severe immune dysregulation. Abatacept (CTLA-4 Ig) is approved for the treatment of rheumatoid arthritis (RA) and its mechanism of action is attributed to effects on T-cells. It is known that CTLA-4 modulates the expression of its ligands CD80 and CD86 on antigen presenting cells (APC) by transendocytosis. As B-cells express CD80/CD86 and function as APC, we hypothesized that B-cells are a direct target of abatacept.
Methods: In vitro, kinetic of CD80 and CD86 expression was measured by flow cytometry on isolated B cells after stimulation via CD40 and IL-21R in presence and absence of abatacept. In vivo, nine abatacept-treated RA patients were followed up to 12 months, and seven up to 24 months and treatment response, immunoglobulins, ACPA, RF concentrations, B-cell phenotype and ACPA-specific switched memory B-cell frequency were assessed.
Results: Abatacept treatment in vitro resulted in a dose-dependent decrease of CD80/CD86 expression on B-cells by dynamin-dependent internalization, without influencing B-cell development. In vivo, RA patients treated with abatacept showed a progressive decrease in plasmablasts and serum IgG. While ACPA-titers only moderately declined, the frequency of ACPA-specific switched memory B-cells significantly decreased in response to treatment.
Conclusion: Abatacept directly targets B-cells by reducing of CD80/CD86 expression. The consequent impairment of antigen presentation and T-cell activation may result in altered B-cell selection and control of the generation of ACPA-specific memory B-cells providing a new therapeutic mechanism and a base for abatacept use in B-cell mediated autoimmunity.