Experimental autoimmune sialadenitis : studies of immunopathogenesis, cellular signaling and MHC genetics

Abstract

Experimental autoimmune sialadenitis (EAS), an animal model for Sjogren´s syndrome (SS) in humans, develops spontaneously in certain mouse strains. A major feature of EAS and SS is infiltration of exocrine glands by mononuclear cells (MNC), and functional impairment of predominantly salivary and lachrymal glands leading to mouth and eye dryness. This thesis focused on cytokines and chemokines as immune effector molecules in the submandibular glands (SMG) of mice with EAS. Insulin-like growth factor-1 receptor (IGF-1R) cellular signaling, and major histocompatibility complex association with EAS were also evaluated.

To study immune activation in EAS, phenotypes of the infiltrating MNC and profiles of the proand anti-inflammatory cytokines were examined. Temporal accumulation for cells expressing mRNA for tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta IL-6, TNF-beta and IL-12 occurred during the early phase of EAS, whereas interferon (IFN)-gamma and cytolysin mRNA expressing cells accumulated gradually and peaked at the height of EAS. Low levels of IL-4, IL-10 and tumor growth factor (TGF)-beta mRNA expressing cells were observed over the course of EAS.

To investigate preferential recruitment of the MNC to SMG in EAS, the expression of selected beta-chemokines was evaluated in young and adult mice with the disease. Upregulation of mRNA expressing cells for regulated upon activation, normal T cell expressed and secreted (RANTES), macrophage inflammatory protein (MIP)-1beta and monocyte chemoattractant protein (MCP)-1 was observed in young mice with mild EAS. A pronounced up-regulation was observed for MIP-1alpha, but up-regulation was also observed for MCP-1, MIP-1beta and RANTES mRNA expressing cells in adult mice with severe EAS.

To explore mechanisms of tissue destruction in EAS, the levels of cell survival promoter insulin-like growth factor-1 receptors (IGF-1R) were evaluated in SMG in EAS. A downstream effector molecule of IGF-1 R signaling, BAD, was also evaluated. The results showed that reduction of IGF-1 Rs in SMG parallels enhancement of BAD by SMG epithelial cells.

To investigate association of major histocompatibility complex (MHC) genes with EAS, the severity of sialadenitis and the immune response in SMG of different MHC congenic nonobese diabetic (NOD) mouse strains were evaluated. The MHC determined the immune response and susceptibility to EAS in a haplotype-specific manner, such that the higher the T helper cell type 2 (Th2) response, the lower the susceptibility to EAS, and vice versa.

In conclusion: (1) TNF-alpha, IL-1beta IL-6 and IL-12 together with IFN-gamma and cytolysin may play a role in initiation and perpetuation of EAS, probably in conjunction with low production of IL-4, IL-10 and TGF-beta; (2) MCP-1, MIP-1beta and RANTES may play a role in the induction of EAS, whereas MCP-1, MIP-1beta, RANTES, and predominantly MIP-1alpha might be involved in progression and perturbation of EAS; (3) the IGF-1Rinduced defects in glandular homeostasis may enhance apoptosis and trigger autoimmunity in EAS; and (4) the variation in MHC class 11 peptide-binding ability influences the magnitude of the Th2 response and susceptibility to disease, thus suggesting an immune regulatory failure in EAS and SS.