Effects of type II collagen epitope carbamylation and citrullination in human leucocyte antigen (HLA)-DR4+ monozygotic twins discordant for rheumatoid arthritis. (25th July 2016)

• Record Type: Journal Article
• Authors: De Santis, M; Ceribelli, A; Cavaciocchi, F; Generali, E; Massarotti, M; Isailovic, N; Crotti, C; Scherer, H U; Montecucco, C; Selmi, C
• Is Part Of: Clinical and experimental immunology. Volume 185:Number 3(2016:Sep.)
• Page Start: 309
• Page End: 319
• Publication Date: 2016-07-25
• Subjects: carbamylation -- citrullination -- rheumatoid arthritis -- type II human collagen; Immunopathology -- Periodicals; 616.079
• DOI: 10.1111/cei.12825
• Languages: English
• ISSNs: 0009-9104

Abstract

Summary: The aim of this study is to investigate the effect of the native, citrullinated or carbamylated type II human collagen T cell- and B cell-epitopes on the adaptive immune response in rheumatoid arthritis (RA). Peripheral blood T and B cells obtained from a human leucocyte D4-related (antigen DR4 − HLA-DR4) + woman with early RA, her healthy monozygotic twin and an unrelated HLA-DR3 + woman with early RA were analysed for activation (CD154/CD69), apoptosis (annexin/7-aminoactinomycin), cytokine production [interferon (IFN)γ/interleukin (IL)−17/IL-4/IL-10/IL-6] and functional phenotype (CD45Ra/CCR7) after stimulation with the collagen native T cell epitope (T261-273), the K264 carbamylated T cell epitope (carT261–273), the native B cell epitope (B359–369) or the R360 citrullinated B cell epitope (citB359–369), and the combinations of these. The T cell memory compartment was activated by T cell epitopes in both discordant DR4 + twins, but not in the DR3 + RA. The collagen-specific activation of CD4 + T cells was induced with both the native and carbamylated T cell epitopes only in the RA twin. Both T cell epitopes also induced IL-17 production in the RA twin, but a greater IL-4 and IL-10 response in the healthy twin. The citrullinated B cell epitope, particularly when combined with the carbamylated T cell epitope, induced B cell activation and an increased IL-6/IL-10 ratio in the RA twin compared to a greater IL-10 production in the healthy twin. Our data suggest that circulating collagen-specific T and B cells are found in HLA-DR4 + subjects, but only RA activated cells express co-stimulatory molecules and produce proinflammatory cytokines. Carbamylation and citrullination further modulate the activation and cytokine polarization of T and B cells.