Antony Rosen, M.D., Joan Bathon, M.D., and Alan Matsumoto, M.D.
Abstract # 39 The Stess Protein BiP is Overexpressed and a Major B- and T-Cell Target in RA. S Blass, A Union, J Raymackers, U Ungethum, F Schumann, F De Keyser, J Engel and G Burmester. Germany.
This joint-specific autoantigens that are responsible for initiation and propagation of the autoimmune response in RA are incompletely defined. There is significant interest in immune responses to stress proteins as potential driving immunogens in many autoimmune diseases. These authors demonstrated that autoantibodies to BiP were present in almost 70% of patients with RA. These antibodies were present in very low frequency in other rheumatic diseases (though spondyloarthropathies and reactive arthritis were not examined) and in healthy controls. Interestingly, a BiP-specific T cell response was observed in a high proportion of RA patients (again ~70%), and never in control populations.
Editorial Comment:Perhaps most strikingly of all was the observation that the expression of BiP in RA synovium was extremely high compared to OA synvoium. The authors proposal that BiP expression in the RA joint drives the ongoing T cell and autoantibody response is a very intriguing one, which needs additional study.
Abstract # 535 Serum Anti-Cyclic Citrullinated Peptide Antibody (anti-CCP) Levels in Patients with RA: Correlation with Disease Activity During 5 Years of Follow-Up E-J Kroot, B de Jong, L van de Putte, W van Venrooij, and P van Riel. The Netherlands.
This abstract looks at the utility of the newly described anti-CCP ELISA as a tool in following patients with RA over 5 years. This antibody was positive by ELISA in 62.5% of patients with recent onset RA. In only 50% of these CCP-positive patients did the antibody stay positive over time, in ~25% antibodies disappeared permanently, and in ~25% they varied over the time of follow-up. There was only a very weak correlation between antibody positivity and disease activity.
Editorial Comment: The studies reinforce previous notions that these antibodies are EARLY markers of RA, and that their utility as diagnostic markers worsens over time. Furthermore, the studies suggest that these anti-CCP antibodies may be markers of the early pathogenic events in RA, and occur close to disease initiation. As such, they may be particularly valuable as markers to define the initiating rather than the propagating events in RA.
Abstract # 947 P53 Regulates Onset and Severity of Murine Collagen-Induced Arthritis Y Yamanishi, D Boyle, M Pinkoski, D Green, N Zvaifler, G Firestein. California.
The wild type p53 gene is a tumor suppressor gene. It is overexpressed in rheumatoid (RA) synovium. Loss of p53 function, for example through a dominant negative mutation, can result in increased proliferation and invasiveness of fibroblast-like synoviocytes in vitro. Mutations of p53 have been found in the synovia of RA patients undergoing joint replacement. To determine if the loss of p53 function plays a role in the pathogenesis of inflammatory arthritis, the investigators induced collagen arthritis in p53 Knockout (KO) mice. The p53 KO mice developed arthritis earlier and more severely than those mice expressing wild type p53. The phenotype was identical in homozygotes (p53 +/+) and heterozygotes (p53 +/-) indicating that one copy of the gene was sufficient for the modest to moderate protection against arthritis. These studies indicate that wild type p53 diminishes synovitis and joint damage in inflammatory synovitis, most likely byinducing apoptosis in the affected tissue. Thus, wild type p53 appears to confer a protective function in RA.
Editorial Comment: Some cancers are characterized by a defective p53 gene. In essence, the RA synovium may act like a cancer tissue - invading and degrading nearby bone and cartilage - perhaps as a result of p53 mutations similar to those seen in cancer.
Abstract # 295 T Cell Responses in Rheumatoid Synovitis are Dominated by CD8+ T cells Y Kang, U Wagner, H Yang, R Beckenbaugh, J Goronzy, C Weyand. Minnestota.
The association of HLA class II alleles with RA disease prevalence and severity has suggested the importance of CD4+ T cells in synovial inflammation. Although present in the inflammatory infiltrate of rheumatoid synovium, the role of CD8+ T cells is unknown. The authors present two lines of evidence for the importance of CD8+ T cells. In human synovium/SCID mouse chimeras, antibody mediated CD8+ T cell depletion caused marked decrease in IFNgand TNFamRNA levels and adoptive transfer of CD8+ T cells into autologous grafts enhanced IFNaproduction. Lymphoid follicles in rheumatoid synovium are the likely sites of antigen presentation. In human synovial biopsies, lymphoid follicles isolated by laser dissection, demonstrated restricted T cell receptor bchain usage, with the predominance of the restricted sequences from CD8+ cells.
Editorial comment: This abstract challenges the existing dogma that CD4+ T cell/HLA class II interaction is critical component of rheumatoid synovitis. In response to questioning, Dr. Weyand did not provide a mechanism how CD8+ T cells might play a role in the HLA class II association. However this intriguing information presents a challenge to look for antigens that stimulate CD8+ T cell populations and raises the possibility of the CD8+ T cells as a therapeutic target.