β2-Glycoprotein I-specific T Cells Are Associated with Epitope Spread to Lupus-related Autoantibodies

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 β 2 -glycoprotein I (β 2 GPI). Notably, mice immunized with β 2 GPI 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 β 2 GPI-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 β 2 GPI/LPS-immunized mice produced similar SLE-related autoantibody profiles regardless of their β 2 GPI T cell epitope specificity or MHC class II haplotype. Although β 2 GPI T cell epitope specificity was clearly determined by MHC class II haplotype, a number of different β 2 GPI T cell epitopes were associated with epitope spread to SLE-related autoantibodies. Notably, one β 2 GPI 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 β 2 GPI-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 β 2 GPI-reactive T cell response may predispose individuals to the development of SLE-related autoantibodies independent of their MHC class II haplotype. Background Systemic lupus erythematosus (SLE)-related autoantibodies are of unknown origin but target multiple apoptotic cell-derived antigens. Results T cell responses to multiple epitopes on β 2 -glycoprotein I (β 2 GPI), an apoptotic cell-binding protein, were associated with SLE-related autoantibody production. Conclusion Distinct β 2 GPI-reactive T cell responses are associated with SLE-related autoantibodies. Significance Factors enabling β 2 GPI-reactive T cell responses may predispose individuals to SLE.