Proteoglycan (aggrecan)-induced progressive polyarthritis is a novel, autoimmune animal model which shows many similarities to human rheumatoid arthritis and ankylosing spondylitis, as indicated by clinical assessments and histopathologic studies of diarthrodial joints and spine. The disease is induced by intraperitoneal immunization of BALB/c mice with a select group of proteoglycans isolated from human, dog and swine cartilages. Proteoglycans from other species tested to date do not induce arthritis. The development of the disease in genetically susceptible BALB/c mice is dependent upon the expression of both cell-mediated and humoral immunities to host mouse cartilage proteoglycans. The glycosaminoglycan side chains of the proteoglycans most likely are not included in the """"""""arthritogenic"""""""" epitopes, but their presence significantly inhibits the immune recognition of core protein epitopes. Recently, (1) the applicants isolated core protein fragments from canine articular cartilage and localized an arthritogenic segment at the N- terminal end of the interglobular domain. (2) generated aggrecan- specific T cell hybridomas, one of which is arthritogenic (5/4E-810), if injected with autoantibodies to mouse proteoglycan. (3) selected autoreactive monoclonal antibodies to mouse aggrecan which induce arthritis, if a pool of these antibodies are injected with T lymphocytes from arthritic animals. Thus, the investigators hypothesize that (1) there exist more than one autoimmune epitope in arthritogenic proteoglycans, which may be different for T and B lymphocytes and (2) both T- and B-cell mediated autoimmune responses are required for the development of the disease. They propose to investigate this hypothesis by determining the primary structure of arthritogenic epitopes which are most likely located in relatively short segments of the core protein of the aggrecans. This proposal is a continuation of the current project and will focus upon a few as yet unknown aspects of proteoglycan-induced arthritis: (1) What are the common amino acid sequences of arthritogenic (fetal human, canine and mouse) cartilage PGs which are absent (or different) in non- arthritogenic (e.g., bovine and rat chondrosarcoma) PGs? (2) Are these """"""""common"""""""" structures able to induce an autoimmune response and/or arthritis in BALB/c mice? (3) Is there any yet unidentified alternative splicing or polymorphism at the level of the genes coding for arthritogenic PGs? (4) Is there any link between autoimmune responses in arthritis and alternative splicing events of cartilage PGs? Answers to these questions are important for the understanding of autoimmunity to cartilage matrix components responsible for human rheumatoid joint diseases, may facilitate the development of early diagnosis of such diseases and may suggest prospective gene therapy regimens for use in susceptible individuals.
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