The DNA mismatch repair enzyme PMS1 is a myositis-specific autoantigen

Objective. The specificity of the autoantibody response in different autoim mune diseases makes autoantibodies useful for diagnostic purposes. It also focuses attention on tissue- and event-specific circumstances that may sele ct unique molecules for an autoimmune response in specific diseases. Defini ng additional phenotype-specific autoantibodies may identify such circumsta nces. This study was undertaken to investigate the disease specificity of P MS1, an autoantigen previously identified in some sera from patients with m yositis. Methods. We used immunoprecipitation analysis to determine the frequency of autoantibodies to PMS1 in sera from patients with myositis, systemic lupus erythematosus, or scleroderma and from healthy controls. Additional antige ns recognized by PMS1-positive sera were further characterized in terms of their susceptibility to cleavage by apoptotic proteases. Results. PMS1, a DNA mismatch repair enzyme, was identified as a myositis-s pecific autoantigen. Autoantibodies to PMS1 were found in 4 of 53 patients with autoimmune myositis (7.5%), but in no sera from 94 patients with other systemic autoimmune diseases (P = 0.016). Additional mismatch repair enzym es (PMS2, MLH1) were targeted, apparently independently. Sera recognizing P MS1 also recognized several other proteins involved in DNA repair and remod eling, including poly (ADP-ribose) polymerase, DNA-dependent protein kinase , and Mi-2. All of these autoantigens were efficiently cleaved by granzyme B, generating unique fragments not observed during other forms of cell deat h. Conclusion. PMS1 autoantibodies are myositis specific. The striking correla tion between an immune response to a group of granzyme B substrates (functi oning in DNA repair and remodeling) and the myositis phenotype strongly imp lies that tissue- and event-specific biochemical events play a role in sele cting these molecules for an autoimmune response. Understanding the role of granzyme B cleavage in this response is an important priority.