期刊
ANNALS OF THE RHEUMATIC DISEASES
卷 81, 期 8, 页码 1096-1105出版社
BMJ PUBLISHING GROUP
DOI: 10.1136/annrheumdis-2021-220371
关键词
Arthritis; Rheumatoid; Synovial fluid; T-Lymphocyte subsets; Autoimmunity
类别
资金
- ANID, Chile [Fondecyt 1181853, Fondef-IDeA ID15I10080, Fondef-IDeA ID15I20080, Fondef-IDeA ID18I10243, REDES 180028]
- Spanish Ministry of Science [RTI2018-097414-B-I00]
- ANID-PFCHA/National Doctoral Scholarship 2018 [21181538]
This study analyzed the HLA-DR-associated peptidome of synovial tissue and dendritic cells in rheumatoid arthritis patients, aiming to identify potential T-cell epitopes. The researchers discovered six new epitopes recognized by CD4 + T cells and found a correlation between the frequency of IFN-gamma-producing CD4 + T cells specific for a certain peptide and disease activity.
Objective Rheumatoid arthritis (RA) immunopathogenesis revolves around the presentation of poorly characterised self-peptides by human leucocyte antigen (HLA)-class II molecules on the surface of antigen-presenting cells to autoreactive CD4 +T cells. Here, we analysed the HLA-DR-associated peptidome of synovial tissue (ST) and of dendritic cells (DCs) pulsed with synovial fluid (SF) or ST, to identify potential T-cell epitopes for RA. Methods HLA-DR/peptide complexes were isolated from RA ST samples (n=3) and monocyte-derived DCs, generated from healthy donors carrying RA-associated shared epitope positive HLA-DR molecules and pulsed with RA SF (n=7) or ST (n=2). Peptide sequencing was performed by high-resolution mass spectrometry. The immunostimulatory capacity of selected peptides was evaluated on peripheral blood mononuclear cells from patients with RA (n=29) and healthy subjects (n=12) by flow cytometry. Results We identified between 103 and 888 HLA-DR-naturally presented peptides per sample. We selected 37 native and six citrullinated (cit)-peptides for stimulation assays. Six of these peptides increased the expression of CD40L on CD4 +T cells patients with RA, and specifically triggered IFN-gamma expression on RA CD4 +T cells compared with healthy subjects. Finally, the frequency of IFN-gamma-producing CD4 +T cells specific for a myeloperoxidase-derived peptide showed a positive correlation with disease activity. Conclusions We significantly expanded the peptide repertoire presented by HLA-DR molecules in a physiologically relevant context, identifying six new epitopes recognised by CD4 +T cells from patients with RA. This information is important for a better understanding of the disease immunopathology, as well as for designing tolerising antigen-specific immunotherapies.
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