New models for relapsing polychondritis and rheumatoid arthritis : focus on the tissue specific immune response

Detta är en avhandling från Medical Inflammation Research, I11 BMC, 221 84 Lund

Sammanfattning: Relapsing polychondritis (RP) and rheumatoid arthritis (RA) are autoimmune diseases where an inappropriate immune response destroys cartilage. In RP, the ears, larynx, nose and joints are affected, while the most prominent sign of RA is arthritis. For ethical reasons many experiments can not be performed in man, and consequently animal models are needed. To investigate the complexity of the tissue specific immune response in cartilage, we developed new animal models for RP and RA. The models were induced by immunization with two cartilage proteins; matrilin-1, mainly expressed in tracheal cartilage, and COMP, detected in tracheal as well as joint cartilage. The new models were named matrilin-1 induced relapsing polychondritis (MIRP) and cartilage oligomeric matrix protein induced arthritis (COMPIA). Contrary to all of the previously published models for RP, the MIRP model reflects symptoms from the larynx, nose and kidneys, like in patients with RP. This model was dependent on alphabeta T cells (rats), B cells (mice) and MHC- as well as non-MHC genes (rats). Furthermore, when matrilin-1 specific monoclonal antibodies were injected into mice, we could induce an erosive inflammation in the cartilage of the respiratory tract which indicated that the antibodies were pathogenic. We could also demonstrate that the extraarticular cartilage was affected in the collagen induced arthritis (CIA), but not in the pristane induced arthritis (PIA), both models commonly used to mimic RA. Our COMPIA model differed in several aspects to the CIA and the PIA. The main difference being that the E3 rat strain, known as a non-responder in other RA models, was susceptible to immunization. The results from the MIRP model were followed up in patients with RP. We detected antibodies to matrilin-1 in sera from 13 out of 97 RP patients. Through injecting patient sera into mice and through inhibition assays, we concluded that the antibodies to matrilin-1 detected in the RP patients were specific and bound murine cartilage of the respiratory tract. Our findings will be valuable for future investigations on the pathogenesis of rheumatic diseases and of diseases where the respiratory tract is affected by inflammation. Our results may also be useful in developing strategies for protecting a selected cartilage tissue from an autoimmune attack.

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