Abatacept modulates CD80 and CD86 expression and memory formation in human B-cells.
Abatacept
/ pharmacology
Adult
Aged
Arthritis, Rheumatoid
/ genetics
B-Lymphocytes
/ drug effects
B7-1 Antigen
/ metabolism
B7-2 Antigen
/ metabolism
Female
Gene Expression
Humans
Immunoglobulin G
/ immunology
Immunologic Memory
/ drug effects
Immunophenotyping
Lymphocyte Activation
/ drug effects
Male
Middle Aged
Abatacept
B-lymphocytes
CD80
CD86
CTLA-4
Rheumatoid arthritis
Journal
Journal of autoimmunity
ISSN: 1095-9157
Titre abrégé: J Autoimmun
Pays: England
ID NLM: 8812164
Informations de publication
Date de publication:
07 2019
07 2019
Historique:
received:
14
02
2019
revised:
12
04
2019
accepted:
15
04
2019
pubmed:
6
5
2019
medline:
21
7
2020
entrez:
6
5
2019
Statut:
ppublish
Résumé
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. To investigate direct effects of abatacept on human B-lymphocytes in vitro and in RA patients. 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 31054942
pii: S0896-8411(19)30089-7
doi: 10.1016/j.jaut.2019.04.016
pii:
doi:
Substances chimiques
B7-1 Antigen
0
B7-2 Antigen
0
Immunoglobulin G
0
Abatacept
7D0YB67S97
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
145-152Informations de copyright
Copyright © 2019. Published by Elsevier Ltd.