ABSTRACT
Rheumatoid arthritis (RA) is associated with the presence of certain HLA class II genes. However, why some individuals carrying RA non-associated alleles develop arthritis is still unexplained. The trans-heterodimer between two RA non-associated HLA genes can render susceptibility to develop arthritis in humanized mice, DQA1*0103/DQB1*0604, suggesting a role for DQ α chains in pathogenesis. In this study we determined the role of DQA1 in arthritis by using mice expressing DQA1*0103 and lacking endogenous class II molecules. Proximity ligation assay showed that DQA1*0103 is expressed on the cell surface as a dimer with CD74. Upon immunization with type II collagen, DQA1*0103 mice generated an antigen-specific cellular and humoral response and developed severe arthritis. Structural modelling suggests that DQA1*0103/CD74 form a pocket with similarity to the antigen binding pocket. DQA1*0103 mice present type II collagen-derived peptides that are not presented by an arthritis-resistant DQA1*0103/DQB1*0601 allele, suggesting that the DQA1*0103/CD74 dimer may result in presentation of unique antigens and susceptibility to develop arthritis. The present data provide a possible explanation by which the DQA1 molecule contributes to susceptibility to develop arthritis.
Subject(s)
Antigens, Differentiation, B-Lymphocyte/metabolism , Arthritis, Experimental/metabolism , HLA-DQ alpha-Chains/metabolism , Histocompatibility Antigens Class II/metabolism , Spleen/metabolism , Animals , Antigen Presentation , Antigens, Differentiation, B-Lymphocyte/chemistry , Antigens, Differentiation, B-Lymphocyte/immunology , Arthritis, Experimental/chemically induced , Arthritis, Experimental/immunology , Binding Sites , Cell Membrane/immunology , Cell Membrane/metabolism , Cell Proliferation , Cells, Cultured , Collagen Type II , Female , HLA-DQ alpha-Chains/chemistry , HLA-DQ alpha-Chains/genetics , HLA-DQ alpha-Chains/immunology , Histocompatibility Antigens Class II/chemistry , Histocompatibility Antigens Class II/immunology , Humans , Immunity, Cellular , Immunity, Humoral , Lymphocyte Activation , Male , Mice, Transgenic , Molecular Docking Simulation , Protein Binding , Protein Interaction Domains and Motifs , Protein Interaction Mapping , Protein Multimerization , Spleen/immunology , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Time FactorsABSTRACT
The antigenic proteins of Mycobacterium tuberculosis (Mtb) have been defined. We used synthetic peptides of secreted antigens, early secreted antigenic target 6 (ESAT-6) and cultural filtrate protein-10 (CFP-10), of Mtb and characterized the immune response in context of HLA genes. Humanized mice lacking endogenous class II molecules but expressing various human DR and DQ HLA transgenes singly or as a haplotype were used to study the HLA-mediated immune response to peptides. Our observations showed that the overall response to the promiscuous ESAT-6 31-45 peptide may be dependent on the HLA haplotype rather than a single DR or DQ molecule. Further, our data showed that HLA transgenes generated a highly variable TH response to this promiscuous peptide. This provides an explanation for the variability of the bacillus Calmette-Guerin (BCG) vaccine. Our data highlights the use of HLA transgenic mice for determining the pathogenicity or therapeutic nature of a peptide in the context of HLA alleles.
