Breach of autoreactive B cell tolerance by post-translationally modified proteins.
Ann Rheum Dis
; 76(8): 1449-1457, 2017 Aug.
Article
em En
| MEDLINE
| ID: mdl-28442530
ABSTRACT
OBJECTIVES:
Over 50% of patients with rheumatoid arthritis (RA) harbour a variety of anti-modified protein antibodies (AMPA) against different post-translationally modified (PTM) proteins, including anti-carbamylated protein (anti-CarP) antibodies. At present, it is unknown how AMPA are generated and how autoreactive B cell responses against PTM proteins are induced. Here we studied whether PTM foreign antigens can breach B cell tolerance towards PTM self-proteins.METHODS:
Serum reactivity towards five carbamylated proteins was determined for 160 patients with RA and 40 healthy individuals. Antibody cross-reactivity was studied by inhibition experiments. Mass spectrometry was performed to identify carbamylated self-proteins in human rheumatic joint tissue. Mice were immunised with carbamylated or non-modified (auto)antigens and analysed for autoantibody responses.RESULTS:
We show that anti-CarP antibodies in RA are highly cross-reactive towards multiple carbamylated proteins, including modified self-proteins and modified non-self-proteins. Studies in mice show that anti-CarP antibody responses recognising carbamylated self-proteins are induced by immunisation with carbamylated self-proteins and by immunisation with carbamylated proteins of non-self-origin. Similar to the data observed with sera from patients with RA, the murine anti-CarP antibody response was, both at the monoclonal level and the polyclonal level, highly cross-reactive towards multiple carbamylated proteins, including carbamylated self-proteins.CONCLUSIONS:
Self-reactive AMPA responses can be induced by exposure to foreign proteins containing PTM. These data show how autoreactive B cell responses against PTM self-proteins can be induced by exposure to PTM foreign proteins and provide new insights on the breach of autoreactive B cell tolerance.Palavras-chave
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Base de dados:
MEDLINE
Assunto principal:
Artrite Experimental
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Artrite Reumatoide
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Autoanticorpos
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Autoantígenos
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Carbamatos
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Linfócitos B
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Processamento de Proteína Pós-Traducional
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Citrulina
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article