Interplay of T lymphocytes and HLA-DR molecules in rheumatoid arthritis.
One of the genetic components of seropositive rheumatoid arthritis has been mapped to a short sequence stretch in the third hypervariable region of the HLA-DRB1 gene. A new concept has emerged, proposing that the shared-sequence motif is functional in determining the clinical patterns of rheumatoid arthritis and the severity of the disease in a codominant mode. Patients with a double dose of the shared sequence tend to have more serious disease manifestations, suggesting a model in which the genetic element is involved in perpetuating the disease. The pathogenetic model in which the shared epitope selectively binds and presents an arthritogenic peptide appears too simplistic to account for these findings. Our understanding of how the shared epitope may contribute to forming the molecular complex of the T-cell receptor, peptide, and HLA-DR molecule is advancing. Molecular analyses of the synovial T-cell infiltrate continue to define the various components involved in recruiting T cells to the site of synovial inflammation. Adhesion molecules, predominantly the endothelial cell ligands vascular adhesion molecule 1 and endothelial leukocyte adhesion molecule 1, attract phenotypically selected T cells with a wide spectrum of specificities. The rheumatoid factor-positive B cells may be important antigen-presenting cells in the joint and may activate T cells with many different specificities. Rheumatoid factor immunoglobulin genes show clear evidence of somatic mutation, indicating a T cell-dependent, antigen-driven process. Thus, multiple factors contribute to the composition of the inflammatory infiltrate and may well modulate the repertoire of T cells recruited to the tissue.(ABSTRACT TRUNCATED AT 250 WORDS)
Goronzy
J J
JJ
Department of Medicine, Mayo Clinic, Rochester, MN 55905.
Weyand
C M
CM
D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D001402:B-Lymphocytes / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D006684:HLA-DR Antigens / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism*; D012217:Rheumatoid Factor / Q000378:metabolism; D013582:Synovial Fluid / Q000166:cytology / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism*
D015815:Cell Adhesion Molecules; D006684:HLA-DR Antigens; D011948:Receptors, Antigen, T-Cell; D012217:Rheumatoid Factor