T cells, Cytokines, and Genetic Factors in Autoimmunity Studies of experimental models of arthritis and sialadenitis

Abstract: To understand the pathogenesis of autoimmune diseases we have to consider the problem from different angles. Animal models provide a tool to further understand these complex diseases, as the influence of genetic and environmental factors could be limited. Moreover, modern transgenic techniques have made it possible to study the role of certain genes and gene products in the development of diseases. To gain further knowledge about the pathogenesis and the genetic control of collagen-induced arthritis and sialadenitis (experimental models for rheumatoid arthritis and Sjögren’s syndrome respectively), we used two different approaches. The first aimed at studying the role of candidate genes such as Il10, Cd4, Cd8, Tcrb and Tcrd in arthritis, and the second to identify genetic regions that harbor arthritis and/or sialadenitis modifying genes. By investigating inbred mouse strains we showed that the genetic background had a major impact on lymphocyte subsets and cytokine production by T cells, indicating the importance of carefully phenotyping strains when using transgenic techniques in model systems. Furthermore, the complexity of cytokines in the pathogenesis of arthritis came to focus when IL-10 deficient mice were studied. The importance of IL-10 in reducing the severity of arthritis was clearly shown, but curiously IL-10 also seemed to promote arthritis as IL-10 deficiency protected against antibody-transfer induced arthritis. In addition, it was demonstrated that alfabeta T cells, especially the CD4+ T cells, were important for CIA development and the production of anti-collagen type II antibodies, whereas gammadelta T cells and CD8+ T cells were of minor importance. Finally, we identified two loci, Cia2 and Cia9, that controlled the severity of CIA and one locus, Nss1, that controlled the severity of sialadenitis in gene segregation experiments involving the B10.Q and the NOD.Q strains. These results have shed some light on the pathogenesis of arthritis and sialadenitis but further knowledge is needed to understand these complex diseases. Revealing and understanding the pathogenesis of autoimmune diseases may form a basis for new therapeutic strategies.