Hepatitis delta (delta) virus (HDV), a satellite virus of the hepatitis B virus (HBV), causes a severe form of viral hepatitis in humans. Here we present evidence based on electron microscopy and electrophoretic behaviour that HDV contains a single stranded circular RNA molecule. This is the first animal virus identified with a circular RNA genome. Circular RNAs have only been found in plant viruses. We have obtained a partial complementary DNA clone representing approximately 25% of the total genome of HDV. Analysis of this cDNA revealed similarity to two plant viruses that may explain the origin of the virus.

In experimental autoimmune encephalomyelitis (EAE), CD4(+) self-reactive T cells target myelin components of the CNS. However, the consequences of an autoaggressive T cell response against myelin for neurons are currently unknown. We herein demonstrate that EAE induced by active immunization with an encephalitogenic myelin basic protein peptide dramatically reduces the loss of spinal motoneurons after ventral root avulsion in rats. Both brain-derived neurotophic factor (BDNF)- and neurotrophin-3 (NT-3)-like immunoreactivities were detected in mainly T and natural killer (NK) cells in the spinal cord. In addition, very high levels of BDNF, NT-3, and glial cell line-derived neurotrophic factor mRNAs were present in T and NK cell populations infiltrating the CNS. Interestingly, bystander recruited NK and T cells displayed similar or higher neurotrophic factor levels compared with the EAE disease-driving encephalitogenic T cell population. High levels of tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) mRNAs were also detected, and both these cytokines can be harmful to several types of CNS cells, including neurons. However, treatment of embryonic motoneuron cultures with TNF-alpha or IFN-gamma only had a deleterious effect in cultures deprived of neurotrophic factors. These results suggest that the potentially neurodamaging consequences of severe CNS inflammation are curbed by the production of several potent neurotrophic factors in leukocytes.

The F, hybrids of the autoimmune New Zealand Black (NZB) mice and the phenotypically normal New Zealand White (NZW) mouse strain, develop severe systemic autoimmune disease, more fulminant than that found in the parental NZB strain . These mice manifest several immune abnormalities including antibodies to nuclear antigens and subsequent development of a fatal, immune complex-mediated glomerulonephritis with female predominance, remarkably similar to systemic lupus erythematosus (SLE) in humans.As a reflection of their autoimmune nature, both the human and murine forms of the disease show a strong association with MHC gene products . HLA DR2 and HLA DR3 individuals are at a higher risk than the general population to develop SLE (1), while in NZB/W F, mice (H-2d/°) a gene linked to the H-2u haplotype derived from the NZW parent contributes to the development of the lupus-like nephritis (2). The role of MHC genes in SLE and murine lupus is unknown. Similarly, it has been difficult to clarify the regulatory and functional abnormalities in the immune system that allow the tissue damage to occur in autoimmune disease . No doubt, with the large range of cellular interactions required for normal immunological function and tolerance, defects in the control or modulation of these interactions could occur at several levels and at any or all of these might result in reactivity to self antigens .In this study we pursue the hypothesis that IFN --t plays a crucial role in the pathogenesis of autoimmune processes. Earlier reports from this laboratory (3) and from others (4-5) have indicated that treatment of NZB/W F, mice with partially purified type I or type II interferon, resulted in an increased incidence of glomerulonephritis and death. If this hypothesis is correct, administration of IFN-y may upregulate the autoimmune process, while blocking the effect of IFN-y might downregulate such a process. We have tested this hypothesis in vivo, in the NZB X NZW/F, lupus nephritis murine model. Materials and MethodsIFN-y and Treatment Regimen . Murine IFN-y manufactured in Escherichia coli by recombinant DNA technology and of >95% purity (7 .2 X 106 U/mg) was kindly provided by Dr . H . Michael Shepard, Genentech, Inc., South San Francisco, CA . NZB/W F, female mice were given intraperitoneal injections of 5 X 10 4 U of rIFN-y or PBS three times weekly for a period of 3 mo . This work was supported by National Institutes of Health grants AI-11313 and AI-07757 . 798J . Exp . MED.

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The inflammatory response that exacerbates cerebral injury after ischemia is an attractive therapeutic target: it progresses over days and strongly contributes to worsening of the neurologic outcome. The authors show that, after transient ischemic injury to the rat brain, systemic application of interferon-beta (IFN-beta), a cytokine with antiinflammatory properties, attenuated the development of brain infarction. Serial magnetic resonance imaging (MRI) showed that IFN-beta treatment reduced lesion volume on diffusion-weighted MRI by 70% (P < 0.01) at 1 day after stroke. IFN-beta attenuated the leakage of contrast agent through the blood-brain barrier (P < 0.005), indicating a better-preserved blood-brain barrier integrity. Both control and IFN-beta-treated animals showed a similar degree of relative hyperperfusion of the lesioned hemisphere, indicating that neuroprotection by IFN-beta was not mediated by improved cerebral perfusion as assessed 24 hours after stroke onset. IFN-beta treatment resulted in an 85% reduction (P < 0.0001) in infarct volume 3 weeks later, as determined from T2-weighted MRI and confirmed by histology. This effect was achieved even when treatment was started 6 hours after stroke onset. Quantitative immunohistochemistry at 24 hours after stroke onset showed that IFN-beta almost completely prevented the infiltration of neutrophils and monocytes into the brain. Gelatinase zymography showed that this effect was associated with a decrease in matrix metalloproteinase-9 expression. In conclusion, treatment with the antiinflammatory cytokine IFN-beta affords significant neuroprotection against ischemia/reperfusion injury, and within a relatively long treatment window. Because IFN-beta has been approved for clinical use, it may be rapidly tested in a clinical trial for its efficacy against human stroke.