The serum of most patients with rheumatoid arthritis contains immunoglobulins, or antibodies. The autoantibodies to gamma globulin (IgG) are called rheumatoid factors. The latex fixation tests commonly used in the diagnosis of rheumatoid arthritis detect only the IgM class of rheumatoid factor, which is most prevalent; however, IgG and, to a lesser extent, IgA rheumatoid factors are also found. All classes of rheumatoid factor act as antibodies to IgG (which acts as antigen) to form immune complexes. In rheumatoid arthritis, some rheumatoid factor is produced in the synovium. Some of the IgG and IgM shown in plasma cells (see Plate 5-8) consists of rheumatoid factor. Immune complexes containing rheumatoid factor, IgG, and complement are prominent in vacuoles of synovial fluid cells as well as in synovial macrophages and interstitium. The immune complexes also appear to be important in extra-articular disease because they deposit in vessel walls and cause vasculitis. The latex agglutination test of rheumatoid factor has been replaced by the enzyme-linked immunosorbent assay (ELISA) in current clinical practice.
Citrullination is the term used for the post-translational modification of the amino acid arginine into the amino acid citrulline. Cyclic citrullinated peptides (CCP) are post-transcriptionally modified peptides, and their antibodies are called anti-CCP antibodies, which were introduced into clinical use in 1997. As with rheumatoid factors, anti-CCP antibodies aid in the diagnosis of rheumatoid arthritis and may be present before the appearance of symptoms of rheumatoid arthritis. Their presence is an indicator of rheumatoid disease severity. ELISA is widely used to detect the anti-CCP antibodies, and the sensitivity and specificity of the anti-CCP antibodies are 50% to 75% and over 90%, respectively. The newer-generation assays, including the second-generation anti-CCP antibody assays (anti-CCP2), have improved sensitivity and specificity compared with the original anti-CCP assays.
A genetic predisposition is an important factor in determining the immune response to the still-unknown initiating factors. The major histocompatibility complex class II antigen HLA-DR4 (HLA-DRB1*0401 and HLA-DRB1*0404/0408 by new nomenclature) is associated with an increased incidence of rheumatoid arthritis in many populations, but it is not present in all patients with rheumatoid arthritis. PTPN22 (protein tyrosine phosphatase N22) has been associated with rheumatoid arthritis as well, although about 17% of the normal white population also have this missense gene mutation.
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