{beta}2-glycoprotein I-specific T cells are associated with epitope spread to lupus-related autoantibodies [Molecular Bases of Disease]

January 2nd, 2015 by Salem, D., Subang, R., Okazaki, Y., Laplante, P., Levine, J. S., 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 β2-glycoprotein I (β2GPI). Notably, mice immunized with β2GPI and lipopolysaccharide (LPS) display a remarkably similar pattern of autoantibody emergence to that seen in human SLE. Here we use this model to investigate whether epitope spread to SLE-related autoantibodies is associated with a unique or limited β2GPI-specific T cell response. We ask whether MHC class II haplotype, and its associated T cell epitope restriction, impacts epitope spread to SLE-related autoantibodies. We found that β2GPI/LPS-immunized mice produced similar SLE-related autoantibody profiles regardless of their β2GPI T cell epitope specificity or MHC class II haplotype. While β2GPI T cell epitope specificity was clearly determined by MHC class II haplotype, a number of different β2GPI T cell epitopes were associated with epitope spread to SLE-related autoantibodies. Notably, one β2GPI 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 β2GPI-reactive T cell response is associated with epitope spread to SLE-related autoantibodies, independent of epitope specificity or MHC class II restriction. Based on these findings, we propose that factors enabling a β2GPI-reactive T cell response may predispose individuals to the development of SLE-related autoantibodies independent of their MHC class II haplotype.