Abatacept modulates CD80 and CD86 expression and memory formation in human B-cells

• Autores: Lorenzetti, Raquel; Janowska, Iga; Smulski, Cristian Roberto; Frede, Natalie; Henneberger, Nadine; Walter, Lea; Schleyer, Marei-Theresa; Hüppe, Janika M.; Staniek, Julian; Salzer, Ulrich; Venhoff, Ana; Troilo, Arianna; Voll, Reinhard Edmund; Venhoff, Nils; Thiel, Jens; Rizzi, Marta
• Año de publicación: 2019
• Idioma: inglés
• Tipo de recurso: artículo
• Materia: ABATACEPT; B-LYMPHOCYTES; CD80; CD86; CTLA-4; RHEUMATOID ARTHRITIS
• Institución: Consejo Nacional de Investigaciones Científicas y Técnicas

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 hypothesize that B-cells are a direct target of abatacept. Objectives: To investigate direct effects of abatacept on human B-lymphocytes in vitro and in RA patients. Methods: The effect of abatacept on healthy donor B-cells’ phenotype, activation and CD80/CD86 expression was studied in vitro. Nine abatacept-treated RA patients were studied. Seven of these were followed up to 24 months, and two up to 12 months only and treatment response, immunoglobulins, ACPA, RF concentrations, B-cell phenotype and ACPA-specific switched memory B-cell frequency were assessed. Results: B-cell development was unaffected by abatacept. Abatacept treatment resulted in a dose-dependent decrease of CD80/CD86 expression on B-cells in vitro, which was due to dynamin-dependent internalization. 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. Conclusions: Abatacept directly targets B-cells by reducing CD80/CD86 expression. Impairment of antigen presentation and T-cell activation may result in altered B-cell selection, providing a new therapeutic mechanism and a base for abatacept use in B-cell mediated autoimmunity.
Fil: Lorenzetti, Raquel. Albert Ludwigs University of Freiburg; Alemania
Fil: Janowska, Iga. Albert Ludwigs University of Freiburg; Alemania
Fil: Smulski, Cristian Roberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte; Argentina. Comisión Nacional de Energía Atómica. Centro Atómico Bariloche; Argentina. Comisión Nacional de Energía Atómica. Gerencia del Área de Energía Nuclear. Instituto Balseiro; Argentina
Fil: Frede, Natalie. Albert Ludwigs University of Freiburg; Alemania
Fil: Henneberger, Nadine. Albert Ludwigs University of Freiburg; Alemania
Fil: Walter, Lea. Albert Ludwigs University of Freiburg; Alemania
Fil: Schleyer, Marei-Theresa. Albert Ludwigs University of Freiburg; Alemania
Fil: Hüppe, Janika M.. Albert Ludwigs University of Freiburg; Alemania
Fil: Staniek, Julian. Albert Ludwigs University of Freiburg; Alemania
Fil: Salzer, Ulrich. Albert Ludwigs University of Freiburg; Alemania
Fil: Venhoff, Ana. Albert Ludwigs University of Freiburg; Alemania
Fil: Troilo, Arianna. Albert Ludwigs University of Freiburg; Alemania
Fil: Voll, Reinhard Edmund. Albert Ludwigs University of Freiburg; Alemania
Fil: Venhoff, Nils. Albert Ludwigs University of Freiburg; Alemania
Fil: Thiel, Jens. Albert Ludwigs University of Freiburg; Alemania
Fil: Rizzi, Marta. Albert Ludwigs University of Freiburg; Alemania