Spontaneous myopathy in the SJL/J mouse: pathology and strength loss.

Myopathy has been found to develop spontaneously in 100% of SJL/J mice between 6 and 8 months of age. Extent of muscular involvement and mouse strength were quantified in SJL/J mice and Balb/c control mice 2-16 months old. Muscle from young SJL/J mice exhibited histopathological abnormalities and occasional inflammatory infiltrate. By 6 months, 78% of SJL/J mice had developed active myopathy. By 8 months, all SJL/J mice examined had active disease with a mean of 12.9% of muscle fibers affected. Replacement of muscle fibers by fat and/or collagen began at 10 months and was pronounced by 14 months. Significant decreases in strength scores (total body pulling force) at 6 months and 10 months of age reflected the onset of active myopathy and the onset of muscle degeneration, respectively. The spontaneous onset and 100% incidence of myopathy in the SJL/J mouse line should provide a useful model for idiopathic myopathy.

Nitric oxide production in relation to spontaneous B-cell lymphoma and myositis in SJL mice.

SJL mice spontaneously develop B cell lymphomas (historically described as reticulum cell sarcomas) by 12 months of age and inflammatory muscle disease (myositis) by 6 months of age. Tumors originate in mesenteric lymph nodes and in Peyer's patches and resemble human germinal center lymphomas. The growth of reticulum cell sarcomas is completely dependent on cytokine production by normal T cells. The spontaneous myositis, which resembles human idiopathic myositis, is characterized by various abnormalities in skeletal muscle, including infiltration with inflammatory cells consisting primarily of macrophages. The participation of different cytokines in the pathogenesis of the lymphoma and the massive invasion of macrophages into muscle tissues led us to investigate the possible involvement of nitric oxide (NO.), which is known to be synthesized by activated macrophages under inflammatory conditions. Elevated NO. production, measured by urinary nitrate excretion, by SJL mice in comparison with BALB/c control mice was observed as early as 7 weeks of age. Both aging and degree of spontaneous myositis correlated with increased nitric oxide production. Oral administration of N-monomethyl-L-arginine, an inhibitor of nitric oxide synthase (NOS), reduced urinary nitrate excretion and also the severity of myositis. Immunohistochemical analysis revealed the presence of inducible NOS (iNOS) in cells in the spleen, lymph nodes, and skeletal muscle. The iNOS is primarily responsible for the enhanced nitric oxide production. Morphology of cells that stained positive for iNOS was similar to that of macrophages infiltrating into the affected tissues. Chronic production of elevated amounts of nitric oxide by the SJL mice, therefore, provides a useful in vivo model for future studies of cellular damage resulting from endogenously produced NO.in combination with oxygen radicals.

Polyclonal immunoglobulin therapy protects against cardiac damage in experimental coxsackievirus-induced myocarditis.

Balb/c male mice infected i.p. with 2 x 10(5) plaque forming units (PFU) of coxsackievirus B3 (CVB3) develop severe myocarditis 7 days later. Studies were performed to determine whether therapy with normal polyclonal immunoglobulin would prevent cardiac inflammation. Partially purified immunoglobulin was derived from pooled mouse serum by ammonium sulphate precipitation. Infected animals given either 100 or 1000 micrograms of this preparation for 2 days prior to infection showed greater than 50% reduction in myocarditis compared to control animals which were infected and given either phosphate buffered saline, human immunoglobulin or monoclonal mouse IgG to an extraneous antigen. Protection did not depend upon inhibition of virus infection since cardiac viral titres were frequently equivalent in control and immunoglobulin-treated groups.

Coxsackievirus-B3-induced myocarditis: virus receptor antibodies modulate myocarditis.

Two variants of coxsackievirus group B, type 3 (CVB3) differ in ability to induce myocarditis in Balb/cCUM mice. Infection with the highly pathogenic variant (CVB3M) stimulates autoimmunity to normal cardiocyte antigens, and tissue injury results primarily from an autoreactive cytolytic T lymphocyte (ACTL). Animals infected with the less pathogenic CVB3o variant do not develop ACTL, although CVB3o replicates to high titers in the heart and polyclonal neutralizing antisera fail to distinguish between the two variant virions. The present study uses two IgM mAb derived by fusing spleen cells from CVB3M-infected mice with NS-1 cells. These mAb investigate important differences between the virus variants that may explain why only selected infections trigger autoimmunity. mAb 8A6 is a virus-neutralizing antibody that prevents infection of HeLa cells and cultured cardiocytes by attaching to the virus. mAb 10A1 also interferes with infection but presumably reacts to the virus receptor on the susceptible cells and shows little or no binding to the virions. While 8A6 is equally effective in neutralizing both CVB3o and CVB3M, suggesting that antigenic epitopes on both variants are either identical or highly cross-reactive, 10A1 distinguishes between the variants, suggesting that the pathogenic and less pathogenic viruses use distinct cell surface receptors. Competitive binding studies using radiolabeled CVB3M and either of the unlabeled variants confirm this hypothesis. Both mAb effectively prevent CVB3M-induced cardiac damage in vivo. mAb 10A1 also inhibits autoreactive ACTL lysis of cardiocytes, indicating that the autoimmune effectors may recognize the virus receptor, and that the receptor utilized by a virus may prove important in triggering auto-sensitization.