Rheumatoid Arthritis (Collagen-Induced Arthritis, TTP Deficiency, K/BxN Model)
RA is a systemic autoimmune disease characterized by prominent joint involvement. Arthritis is typically associated with erosion of cartilage and subchondral bone, formation of an inflammatory tissue, consisting of activated macrophages, T cells, fibroblasts, and other immune cells (pan-nus). This can ultimately result in joint destruction and significant joint deformi-ties. In addition to the joints, RA can cause vasculitis, splenomegaly, and leukopenia (Felty’s syndrome), interstitial lung dis-ease, and other abnormalities. Rheuma-toid factor (an autoantibody against the Fc portion of immunoglobulin) and anti-bodies against citrulline-modified proteins or peptides (usually detected as antibod-ies against an artificially produced cyclic citrullinated peptide, or CCP) are typical serological findings in RA, although not all patients exhibit these abnormalities. Several animal models of RA exist, but they do not precisely reproduce the clinical and laboratory abnormalities.
Immunization of susceptible rodent strains with type II collagen (CII) leads to the development of a severe polyarticular arthritis resembling human RA. Although induced by heterologous CII, immuniza-tion leads to a response against autologous CII. CIA can be induced in susceptible strains of mice, rats, and primates. Histo-logically, both RA and CIA are character-ized by an intense synovitis accompanied by erosion of cartilage and subchon-dral bone by a pannuslike tissue. Unlike human RA, CIA is monophasic. In addi-tion, there are important serological differ-ences. In general, rheumatoid factor is not produced in CIA and antibodies against CCP are absent.
Tristetraprolin (TTP) is a transcription factor that can bind to and destabilize mRNAs encoding TNF-α and granu-locyte-macrophage colony-stimulating factor (GM-CSF). Mice deficient in TTP develop a complex syndrome character-ized by cachexia, polyarticular arthritis, dermatitis, autoimmunity, and myeloid hyperplasia accompanied by extramedul-lary hematopoiesis (erythrocyte produc-tion outside of the bone marrow). TTP knockout mice exhibit exuberant inflam-matory pannus and bony erosions. These mice also produce high titers of anti-DNA, and ANAs; however, rheumatoid factors are absent.
Although RA has been considered pri-marily a type IV autoimmune reaction for many years, the finding that autoantibod-ies against glucose-6-phosphate isomerase (GPI) can transfer RA-like joint disease to normal mice has rekindled interest in the possibility that antibody-mediated auto-immune mechanisms (type II or type III) could play a role in the pathogenesis of RA. K/BxN T-cell-receptor transgenic mice express a transgenic T-cell receptor specific for a peptide of the ubiquitously expressed self-protein GPI. Arthritis in this model is initiated by antibodies against GPI. The resulting synovitis is chronic, erosive, and associated with pannus formation. Para-doxically, although the GPI antigen is ubiq-uitous, autoimmunity is focused on the joints. It appears that the GPI protein, not a cross-reactive synovial antigen, is the tar-get of the pathogenic antibodies. Although the histological appearance of the affected joints is reminiscent of RA, there is no evi-dence that RA in humans can be caused by antibodies against GPI. The classic sero-logical abnormalities, rheumatoid factor, and anti-CCP antibodies are not seen, and anti-TNF-α antibodies have little effect in this model.