Abstract:
BACKGROUND:Autoreactive B cells are crucial players in the pathogenesis of rheumatoid arthritis (RA). Autoantibodies specific for citrullinated proteins (ACPA), present in the serum of approximately 60-70 % of patients, have a pathogenic role in the disease. B cell depleting therapies may result in a transient immunosuppression, increasing the risk of infections. Our aim was to develop a new therapeutic approach to selectively deplete the ACPA producing autoreactive B cells. METHODS:To target B cells synthetic citrullinated peptide derived from the β chain of fibrin, β60-74Cit 60,72,74 (β60-74Cit), the predominant epitope recognized by ACPA was used. Complement dependent cytotoxicity (CDC) was induced by a modified peptide derived from gp120 of HIV-1. To trigger CDC both the targeting peptide and the complement activating peptide were covalently coupled in multiple copies to the surface of poly (DL-lactic-co-glycolic acid) nanoparticles (NPs). Ex vivo antibody synthesis was examined by ELISA and ELISpot. CDC was tested after dead cell staining by flow cytometry. RESULTS:The β60-74Cit peptide was selectively recognized by a small subset of B cells from RA patients having high level of peptide specific serum antibody, suggesting that the peptide can target diseased B cells. The modified gp120 peptide covalently coupled to NPs induced the formation of the complement membrane attack complex, C5b-9 in human serum. We show here for the first time that bifunctional NPs coupled to multiple copies of both the targeting peptide and the complement activating effector peptide on their surface significantly reduce β60-74Cit peptide specific ex vivo ACPA production, by inducing complement dependent lysis of the citrullinated peptide specific B cells of seropositive RA patients. CONCLUSIONS:Bifunctional NPs covalently coupled to autoantigen epitope peptide and to a lytic peptide activating complement may specifically target and deplete the peptide specific autoreactive B-cells.
journal_name
Arthritis Res Therjournal_title
Arthritis research & therapyauthors
Pozsgay J,Babos F,Uray K,Magyar A,Gyulai G,Kiss É,Nagy G,Rojkovich B,Hudecz F,Sármay Gdoi
10.1186/s13075-016-0918-0subject
Has Abstractpub_date
2016-01-16 00:00:00pages
15eissn
1478-6354issn
1478-6362pii
10.1186/s13075-016-0918-0journal_volume
18pub_type
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