FIGURE 1 (Left) A section of ear from a patient with relapsing polychondritis showing necrosis of cartilage and inflammatory cell infiltration (hematoxylin-eosin, medium power). (Right) A marked loss of metachromasia is observed in cartilage from the ear, indicating disappearance or breakdown of chondroitin sulfate (azure A, medium power). Source: American College of Rheumatology.
The immunologic attack on cartilage matrix components helps to explain the distribution of tissue inflammation and clinical manifestations in patients with RP. Type II, IX, and XI collagens are only found in the fibrillar scaffolding of cartilage matrices found in the ear, nose, and joints. Furthermore, matrillin-1 is a matrix protein found only in auricular, nasal, tracheal, and costochondral cartilage. Finally, cartilage proteoglycans share potentially antigenic epitopes with a variety of tissues, including connective tissue of the aorta, anterior uveal tract, heart valves, endothelial cells, and synovium, among other sites. Primate and rodent animal models immunized with the various cartilage components develop a syndrome similar to RP. The clinical manifestations vary somewhat, depending on the matrix constituent used. For example, rats immunized with matrillin-1 were more likely to develop inspiratory stridor (15). This is notable, as matrillin-1 is found in significant amounts in the trachea. Interestingly, a recent study by Hansson et al. found that RP patients with laryngotracheal symptoms were more likely to have autoantibodies to matrillin-1 than patients without these symptoms (14).
The final result of the immunologic response to cartilage constituents is destruction of the cartilage matrix. Patients with RP have high serum levels of proinflammatory cytokines that are involved in the recruitment, accumulation, and activation of highly destructive cells (monocytes, macrophages, and neutrophils) to the local inflammatory sites (16). The neutrophils and macrophages can release oxygen metabolites, prostaglandins, and enzymes capable of destroying the cartilage matrix. Furthermore, interleukin-1 and tumor necrosis factor-a (TNF-a) from macrophages can induce chondrocytes to secrete matrix-degrading metalloproteinases (17).
Based on the current understanding of the pathogenesis of RP, a model can be proposed. The initial insult is unknown, but can include trauma, toxin, infection, or another systemic inflammatory disease. This insult results in injury to cartilage. Cartilage is avascular and consequently its tissue components can be viewed as hidden from the immune system ("immunologically privileged"). Therefore, injury to cartilage results in exposure of native or modified collagen/matrix protein antigens to the immune system. In the genetically predisposed host, a humoral and/or cell-mediated immune response could occur. The ensuing inflammatory response would result in further cartilage degradation and antigen release or modification. Due to epitope sharing with other connective tissue matrix constituents, the disease could become more widespread by affecting tissues at other sites such as the aorta and eye.
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