Pathogenesis of rheumatoid arthritis.
Chronicity and destructive potential are characteristic features of the inflammatory response in the synovial membrane typical for RA. The dominant paradigm has proposed that an exogenous antigen, likely an infectious organism, targets the synovia and elicits a chronic immune response. Support for this disease model has come from describing the cellular components of the inflammatory lesions, which are composed of macrophages, T cells, and B cells. The observation that HLA molecules function by specifically binding antigenic peptides and presenting them to T cells has boosted the concept of an antigen-driven response. The last decade in RA research has been dominated by a shift from premolecular to molecular techniques. A major effort has been made to determine which cytokines and inflammatory mediators are produced at the site of disease. Tissue residing and infiltrating cells secrete proinflammatory cytokines in situ, which likely have a critical role in amplifying and maintaining the inflammation. We are beginning to understand that migration of inflammatory cells into the tissue is an important component of disease, specifically because adhesion molecules not only facilitate tissue infiltration, but also affect cell activation and cell-cell and cell-matrix interactions. The paradigm that RA is an antigen-driven and thus T cell-mediated disease has brought attempts to use T cell-depleting reagents as therapeutics. Although T cells could be eliminated in the peripheral blood, overall therapeutic benefits have been minimal and accompanied by major side effects. The lack of therapeutic efficacy has been demonstrated to be combined with the persistence and the selective proliferation of T cells in the joint, reemphasizing the role of tissue-infiltrating T cells in the disease. Studies of the composition of the T cell infiltrate have demonstrated heterogeneity, indicating that disease-relevant T cells are probably low in frequency. A new perspective on the role of T cells in RA has been opened by studies establishing that RA patients select a unique repertoire of T cells in the thymus and that clonal expansion of CD4 T cells is a frequent event in RA patients. Pathology of T cell function might be much more systemic than suspected so far. RFs remain the major autoantibodies in RA patients. In the last 10 years, it has become clear that they are not exclusively built under pathologic conditions but that RF-expressing B cells are an important element of normal immune responses. All immunoglobulin isotypes are represented among RF molecules. Some of them have accumulated somatic mutations, suggesting the influence of antigen recognition and T cell help. T cell control of RF production may explain the observation that RF positivity is an HLA-dependent phenomenon. Major progress in understanding pathologic events leading to RA can be expected by abandoning single hit models, which are too simplified and underestimate the complexity of the disease. In particular, taking into account that nonimmune tissues and mechanisms might be equally important in pathogenesis will open new avenues of conceptual approaches. Cross-fertilization will likely come from genetic studies aimed at detecting underlying genetic risk factors in common genetic disease. Emerging data indicate that several genetic risk determinants, each of which is nonpathologic if occurring alone, can add up to confer disease risk. One of these genetic elements in RA has been mapped to the HLA region. A sequence polymorphism in the HLA-DR B1 gene appears to be a strong genetic risk factor in several ethnic groups. Correlation of clinical presentation of RA and the inheritance of the RA risk gene suggests that the gene product is not necessary in disease initiation but functions by modulating disease pattern and severity. The next decade in RA research will be dedicated toward unraveling how genetic determinants can introduce pathology (e.g., how HLA genes can function as progre
Weyand
C M
CM
Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA.
Goronzy
J J
JJ
D017951:Antigen Presentation / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000209:etiology* / Q000276:immunology; D001323:Autoantibodies / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000276:immunology; D002450:Cell Communication; D002455:Cell Division; D002465:Cell Movement; D016207:Cytokines / Q000276:immunology; D006680:HLA Antigens / Q000276:immunology; D006801:Humans; D007132:Immunoglobulin Isotypes / Q000276:immunology; D018836:Inflammation Mediators / Q000276:immunology; D018655:Lymphocyte Count / Q000187:drug effects; D008264:Macrophages / Q000276:immunology; D008967:Molecular Biology; D012217:Rheumatoid Factor / Q000276:immunology; D013583:Synovial Membrane / Q000276:immunology; D013585:Synovitis / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
D001323:Autoantibodies; D015815:Cell Adhesion Molecules; D016207:Cytokines; D006680:HLA Antigens; D007132:Immunoglobulin Isotypes; D018836:Inflammation Mediators; D012217:Rheumatoid Factor