Apoptosis signal-regulating kinase 1 (ASK1) is an evolutionarily conserved mitogen-activated protein kinase (MAPK) kinase kinase which plays important roles in stress and immune responses. Here, we show that ASK1 deficiency attenuates neuroinflammation in experimental autoimmune encephalomyelitis (EAE), without affecting the proliferation capability of T cells. Moreover, we found that EAE upregulates expression of Toll-like receptors (TLRs) in activated astrocytes and microglia, and that TLRs can synergize with ASK1-p38 MAPK signalling in the release of key chemokines from astrocytes. Consequently, oral treatment with a specific small molecular weight inhibitor of ASK1 suppressed EAE-induced autoimmune inflammation in both spinal cords and optic nerves. These results suggest that the TLR-ASK1-p38 pathway in glial cells may serve as a valid therapeutic target for autoimmune demyelinating disorders including multiple sclerosis.

Objective. To establish a new murine model of polymyositis (PM) for the understanding of its pathologic mechanisms and the development of new treatment strategies.Methods. C protein-induced myositis (CIM) was induced by a single immunization of recombinant human skeletal C protein in C57BL/6 mice, as well as in CD4-depleted, CD8-depleted, and mutant mice as controls. Some mice were treated with high-dose intravenous immunoglobulin (IVIG) after disease induction. Muscle tissues were examined histologically.Results. In mice with CIM, inflammation was confined to the skeletal muscles. Polymyositis (PM) is a chronic autoimmune inflammatory myopathy affecting striated muscles (1). Damage of muscles results in varying degrees of muscle weakness. Dysphagia with choking episodes and respiratory muscle weakness can occur in acute cases of PM. Currently, the pathogenesis of PM is unknown, and patients are therefore treated with nonspecific immunosuppressants. High-dose corticosteroids are the first-line treatment but are not effective in all patients. Improvement of disease often depends on the dosage of corticosteroids, making a dosage reduction difficult and thus, in many cases, necessitating administration of methotrexate or other immunosuppressants as adjunctive treatment. Because these medications can elicit a wide variety of adverse drug reactions, new therapies to address the specific pathologic features of PM are needed.In affected muscles of patients with PM, infiltration of mononuclear cells leads to muscle fiber necrosis. These cells are found in the endomysial site, where non-necrotic muscle fibers are damaged, and also in the perimysial and perivascular sites of the muscles. Immunohistochemical studies have disclosed that CD8 T cells are most abundant in the endomysial site and invade

To elucidate the role of NK cells and TCR + ˇ + T cells in acute experimental autoimmune encephalomyelitis (EAE) induced in Lewis rats, the distribution, number and function of these cells were studied using several methods. Immunohistochemical and flow cytometric analysis revealed that a certain number of NK cells (17 % of the total inflammatory cells) infiltrated the central nervous system (CNS) at the peak stage of EAE and were mainly located in the perivascular region. On the other hand, virtually no TCR + ˇ + T cells were found in the CNS. NK-T (NKR-P1 + TCR § g +) cells were few and did not increase in number in the CNS and lymphoid organs. In the cytotoxic assay using YAC-1 cells, effector cells isolated from the spleen of rats at the peak of EAE showed essentially the same cytotoxicity as those isolated from normal controls although the total number of NK cells decreased to one fifth of that of normal rats. Furthermore, in vivo administration of anti-NK cell (3.2.3 and anti-asialo GM1), but not of anti-TCR + ˇ (V65), antibodies exacerbated the clinical features of EAE and induced fatal EAE in some rats. These findings suggest that NK cells play a suppressive role in acute EAE whereas TCR + ˇ + T cells are not involved in the development of or recovery from the disease.

Although multiple sclerosis is considered to be an autoimmune disease in the CNS, the immune responses that take place in the CNS and lymphoid organs remain to be elucidated. Here, we have successfully induced various subtypes of experimental autoimmune encephalitis (EAE) in LEW.1AV1 rats carrying RT1(av1) on the Lewis background genes by immunization with recombinant rat myelin oligodendrocyte glycoprotein (MOG) in various solutions with adjuvants. The purpose of the present study was to analyse in more detail the clinical and immunopathological features of MOG-induced EAE in LEW.1AV1 rats. Immunization with high doses of soluble MOG with pertussis toxin induced acute, frequently fatal EAE, whereas medium doses of partially aggregated MOG without pertussis toxin produced relapsing and remitting EAE. Secondary progressive EAE was induced in some rats by immunization with the immunization protocol having an intermediate nature between the above two. The optic nerve (approximately 60% of the immunized rats) and spinal cord (100%) were frequently involved and detectable both clinically and pathologically, while there was no lesion in the cerebrum. Histological examination revealed that, despite variety in the clinical subtypes, progression of the pathological processes was strikingly uniform, i.e. initial inflammation with minimal demyelination followed by predominant demyelination with minimal lymphocyte infiltration. These findings suggest that the lesion during the later stage is maintained by humoral factors. Taken together, this experimental system can serve as a model of neuromyelitis optica. Further analysis will provide useful information to elucidate the pathogenesis and to develop immunotherapy for neuromyelitis optica and multiple sclerosis.

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