Immunomodulation and immunopathogenesis in autoimmune disease with emphasis on autoimmune neuritis and arthritis

Abstract

Experimental autoimmune neuritis (EAN) and arthritis are CD4+ T cell mediated autoimmune animal models for the study of immunomodulation and immunopathogenesis of human Guillain-Barré syndrome (GBS) and rheumatoid arthritis (RA). Inflammatory cell infiltration and cytokine production in the target organs are characteristic features of both diseases, suggesting a role of cytokine production in the pathogenesis.

A significant reduction in the incidence and severity of EAN and a delayed time of onset of EAN were found in IL-12 deficient (IL-12-/-), as compared to wild type mice. The clinical symptoms were associated with a reduced IFN-gamma and TNF-alpha, while enhanced IL-4 production in the sciatic nerve as well as significantly suppressed levels of anti-PO peptide IgG2b antibody in serum suggested that IL-12 has a major role in the initiation, enhancement and perpetuation of pathogenic events in EAN by promoting a Th1 cell-mediated immune response and suppressing the Th2 response. These results demonstrate that IIL-12 may play a critical role in the pathogenesis of EAN.

Tumor necrosis factor receptor I (TNFR I) is thought to mediate the majority of TNF activities. When administered soluble TNFR I (sTNFR I) to mice immunized with PO peptide the severity and the duration of EAN were decreased. This was accompanied in vitro by a marked reduction in antigen-specific T cell proliferation and IFN-gamma synthesis by spleen cells in sTNFR I treated mice. Immunohistochemical analysis revealed a strong decrease in the number of infiltrating macrophages, CD4+ T cells and CD8+ T cells in the sciatic nerve. These data directly demonstrate a pivotal role for TNF in the development of EAN and also suggest that sTNFR I may have a therapeutic potential in human GBS.

CC chemokine receptor 5 deficient (CCR5-/-) mice showed a significant reduction in the incidence of collagen-induced arthritis in comparison to wild-type (CCR5+/+) mice. However, the severity score once they developed arthritis showed clinical features similar to wild-type mice. There were significantly lower levels of antibodies against CH in CCR5-/- mice compared to wild- type mice, especially IgG2a and IgG2b, and obviously higher levels of EL10 in CCR5-/- mice. There was overproduction of MIP-1beta in serum and culture supernatant of spleen cells in CCR5 deficient mice after CH-immunization that might partly have contributed to the severity of arthritis. Our results indicate that CCR5 plays a role in the pathogenesis of arthritis, but its role can probably be substituted by other factors.

Changes of glia and cytokine expression were found in the spinal cord of adjuvantinduced arthritic (AIA) rats. Macroglia and MHC class 11 immunostaining were enhanced, and the numbers and immunostaining intensity of astrocytes expressing GFAP were increased. Using in situ hybridization and immunohistochemical methods, both mRNA and protein levels of IL-1beta, IL-6 and TNF-alpha were significantly increased in the spinal cord of arthritic rats. Higher levels of cytokine expression were noted in reactive astrocytes and microglia.