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2-Glycoprotein I-specific T cells are associated with epitope spread to lupus-related autoantibodies

Salem, D;Subang, R;Okazaki, Y;Laplante, P;Levine, JS;Kuwana, M;Rauch, J;

Systemic lupus erythematosus (SLE) is a prototypic model for B cell epitope spread in autoimmunity. Autoantibodies to numerous and molecularly distinct self-antigens emerge in a sequential manner over several years, leading to disease manifestations. Among the earliest autoantibodies to appear are those targeting the apoptotic cell-binding protein 2-glycoprotein I (2GPI). Notably, mice immunized with 2GPI and LPS display a remarkably similar pattern of autoantibody emergence to that seen in human SLE. Here, we used this model to investigate whether epitope spread to SLE-related autoantibodies is associated with a unique or limited 2GPI-specific T cell response. We ask whether MHC class II haplotype and its associated T cell epitope restriction impact epitope spread to SLE-related autoantibodies. We found that 2GPI/LPS-immunized mice produced similar SLE-related autoantibody profiles regardless of their 2GPI T cell epitope specificity or MHC class II haplotype. Although 2GPI T cell epitope specificity was clearly determined by MHC class II haplotype, a number of different 2GPI T cell epitopes were associated with epitope spread to SLE-related autoantibodies. Notably, one 2GPI T cell epitope (peptide 23, NTGFYLNGADSAKCT) was also recognized by T cells from an HLA-DRB1*0403(+) autoimmune patient. These data suggest that the generation of a 2GPI-reactive T cell response is associated with epitope spread to SLE-related autoantibodies, independent of epitope specificity or MHC class II restriction. On the basis of these findings, we propose that factors enabling a 2GPI-reactive T cell response may predispose individuals to the development of SLE-related autoantibodies independent of their MHC class II haplotype.