The DNA mismatch repair enzyme PMS1 is a myositis-specific autoantigen
Article first published online: 28 FEB 2001
Copyright © 2001 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 44, Issue 2, pages 389–396, February 2001
How to Cite
Casciola-Rosen, L. A., Pluta, A. F., Plotz, P. H., Cox, A. E., Morris, S., Wigley, F. M., Petri, M., Gelber, A. C. and Rosen, A. (2001), The DNA mismatch repair enzyme PMS1 is a myositis-specific autoantigen. Arthritis & Rheumatism, 44: 389–396. doi: 10.1002/1529-0131(200102)44:2<389::AID-ANR58>3.0.CO;2-R
- Issue published online: 28 FEB 2001
- Article first published online: 28 FEB 2001
- Manuscript Accepted: 18 SEP 2000
- Manuscript Received: 12 JUL 2000
- SLE Foundation
- Scleroderma Research Foundation
- NIH. Grant Numbers: AR-44684, AR-43727, DE-12354
- Arthritis Foundation Arthritis Investigator Award
- Burroughs Wellcome Fund Translational Research Award
- Johns Hopkins University Outpatient Clinical Research Center
The specificity of the autoantibody response in different autoimmune diseases makes autoantibodies useful for diagnostic purposes. It also focuses attention on tissue- and event-specific circumstances that may select unique molecules for an autoimmune response in specific diseases. Defining additional phenotype-specific autoantibodies may identify such circumstances. This study was undertaken to investigate the disease specificity of PMS1, an autoantigen previously identified in some sera from patients with myositis.
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 antigens recognized by PMS1-positive sera were further characterized in terms of their susceptibility to cleavage by apoptotic proteases.
PMS1, a DNA mismatch repair enzyme, was identified as a myositis-specific 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 enzymes (PMS2, MLH1) were targeted, apparently independently. Sera recognizing PMS1 also recognized several other proteins involved in DNA repair and remodeling, 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 death.
PMS1 autoantibodies are myositis specific. The striking correlation between an immune response to a group of granzyme B substrates (functioning in DNA repair and remodeling) and the myositis phenotype strongly implies that tissue- and event-specific biochemical events play a role in selecting these molecules for an autoimmune response. Understanding the role of granzyme B cleavage in this response is an important priority.