Effects of type II collagen epitope carbamylation and citrullination in human leucocyte antigen (HLA)-DR4(+) monozygotic twins discordant for rheumatoid arthritis.
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.
Rheumatology and Clinical Immunology, Humanitas Research Hospital, Rozzano, Italy.|BIOMETRA Department, University of Milan, Milan, Italy.
M
M
De Santis
Rheumatology and Clinical Immunology, Humanitas Research Hospital, Rozzano, Italy.
A
A
Ceribelli
Rheumatology and Clinical Immunology, Humanitas Research Hospital, Rozzano, Italy.
F
F
Cavaciocchi
Rheumatology and Clinical Immunology, Humanitas Research Hospital, Rozzano, Italy.
E
E
Generali
Rheumatology and Clinical Immunology, Humanitas Research Hospital, Rozzano, Italy.
M
M
Massarotti
Rheumatology and Clinical Immunology, Humanitas Research Hospital, Rozzano, Italy.
N
N
Isailovic
Rheumatology and Clinical Immunology, Humanitas Research Hospital, Rozzano, Italy.
C
C
Crotti
Department of Rheumatology, Leiden University Medical Center, Leiden, the Netherlands.
H U
HU
Scherer
Rheumatology, Policlinico San Matteo, University of Pavia, Pavia, Italy.
C
C
Montecucco
Rheumatology and Clinical Immunology, Humanitas Research Hospital, Rozzano, Italy.|BIOMETRA Department, University of Milan, Milan, Italy.
C
C
Selmi
D056704:Adaptive Immunity; D000328:Adult; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D002219:Carbamates / Q000276:immunology / Q000378:metabolism*; D024043:Collagen Type II / Q000737:chemistry* / Q000276:immunology; D016207:Cytokines / Q000097:blood*; D018985:Epitopes, B-Lymphocyte / Q000737:chemistry / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000276:immunology*; D005260:Female; D015804:HLA-DR4 Antigen / Q000737:chemistry / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory; D016753:Interleukin-10 / Q000097:blood; D020381:Interleukin-17 / Q000097:blood; D015847:Interleukin-4 / Q000097:blood; D008213:Lymphocyte Activation; D010641:Phenotype; D011499:Protein Processing, Post-Translational; D014430:Twins, Monozygotic
D002219:Carbamates; D024043:Collagen Type II; D016207:Cytokines; D018985:Epitopes, B-Lymphocyte; D018984:Epitopes, T-Lymphocyte; D015804:HLA-DR4 Antigen; C508609:IL10 protein, human; C508598:IL4 protein, human; D020381:Interleukin-17; D016753:Interleukin-10; D015847:Interleukin-4
carbamylation; citrullination; rheumatoid arthritis; type II human collagen