Role of innate immunity on initiation of autoimmune diseases and its regulation

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Pathogen recognition by Toll-like receptors (TLRs) on dendritic cells (DCs) leads to DC maturation, the initiation of adaptive immunity and/or autoimmune response. In the present study, we investigated the role of innate immunity on initiation of autoimmune diseases. HTLV-1 has been identified as a causative agent which initiates and/or perpetuates the process of Sjogren's syndrome (SS) and rheumatoid arthritis (RA). At first, we analyzed the relationship between the expression of interferon (IFN)-γ and HTLV-1 p19 antigen and activation of p38 MAPK in HTLV-1-infected T cell lines and peripheral blood CD4^+T cells from patients with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). It is suggested that activation of p38 MAPK signaling pathway might be involved in the up-regulation of IFN-γ expression with high HTLV-1 proviral load in HAM/TSP patients. Furthermore, we demonstrated that Tax-mediated Bcl-xL expression inhibited apoptosis of activated T lymphocytes in HTL … More V-1-seropositive subjects. These results consequently promotes the onset of autoimmune disorders such as SS and RA. Next, we showed the expression of TLR2, TLR3 and TLR4 on the acinal and ductal cells, and infiltrated mononuclear cells from minor salivary glands of SS. When a human salivary glands (HSG) were stimulated by peptidoglycan (PDG), poly I : C, or lipopolysaccharide (LPS), HSG cell line augmented the expression of CD54 and production of IL-6, through the phosphorylation of MAP kinase. We found autoantibodies in sera from primary SS patients that specifically recognize fragments of the La protein that are produced by the granzyme B protease. NK cell number, NK cell killing activity, and the expression of activating receptor CD2 and NKG2D were significantly decreased, and the expression of NKp36, as well as the percentage of apoptotic NK cells were significantly increased in primary SS patients compared with healthy controls. Our data suggest that reduced NK cell numbers, a probably result of apoptotic death, may contribute to impaired NK cell activity in patients with primary SS. It was undertaken to investigate the phenotypic characteristics of peripheral blood dendritic cells (DCs) in SLE patients. Both myeloid DCs (CD11c^+, CD11c-BDCA-3^+) and plasmacytoid DC (BDCA-2^+) were reduced in SLE patients. These altermations of the DC subset may drive the autoimmune in SLE. Subcutaneous injections of DCs infected with recombinant adenovirus expressing the TSHR in syngeneic female mice inuced Graves'-like hyperthyroidism. IFN-γ secretion and induction of antibodies and disease were almost completely suppressed by co-administration of alum pertussis toxin, whereas polyribocytidytic acid (poly I : C) enhanced splenocyte secretion of IFN-γ without changing disease incidence. Finally, we report that the elimination of CTL epitope from B : 9-23 peptide by aminoacid substitution at position B : 16 and 19 (A^<16,19> altered peptide ligand (APL)), or truncation of the C-terminal aminoacids from the peptide (B : 9-21), both of which lacks binding to the K^d molecule, provided significant intranasally induced suppression of diabetes when co-administrated with a potent mucosal adjuvant cholera toxin (CT). These study indicated that elimination of the CTL epitope from B : 9-23 peptide was critically important for mucosally induced diabetes prevention. A^<16,19> APL uniquely suppresses anti-islet humoral and cellular autoimmunity with protection and remission of diabetes. Our present study contributes the clarification of etiology and/or pathogenesis, and leads to new strategies for treatments in autoimmune diseases. Less