During Inflammation, Some Proteins Undergo Modification, Converting Arginine Residues in Their

During inflammation, some proteins undergo modification, converting arginine residues in their sequences to citrulline. In smokers, an increased level of protein citrullination has been detected in cells of the lung, an observation that has been proposed as one explanation for the strong association between smoking and the autoimmune disease, rheumatoid arthritis. To determine a potential mechanism by which protein citrullination might lead to autoimmunity, studies were performed in mice. These mice were transgenic for the human MHC class II molecule, HLA DR4, the allele showing strong association with rheumatoid arthritis in humans. These mice were immunized with a peptide derived from the self-antigen vimentin (Vim_65-77), or with a variant Vim_65-77 peptide in which the arginine at position 70 of this peptide was converted to citrulline (Vim_65-77(R70Cit)). Ten days later, T cells were isolated from draining lymph nodes of the immunized mice, and were stimulated in vitro with APCs plus each vimentin peptide. After three days of culture, IFN- $\gamma$ levels in the supernatants of the cultures were measured, as shown in Figure Q1)18). To confirm that the T cell responses were directed at vimentin peptides bound to DR4, duplicate in vitro cultures received anti-DR4 blocking antibody. What hypothesis is suggested by these data to account for how protein citrullination might lead to autoimmunity?