Systemic lupus erythematosus (SLE) is a CD4+ T cell–dependent, immune complex–mediated, autoimmune disease that primarily affects women of childbearing age. Generation of high-titer affinity-matured IgG autoantibodies, specific for double-stranded DNA and other nuclear antigens, coincides with disease progression. Current forms of treatment of SLE including glucocorticosteroids are often inadequate and induce severe side effects. Immunological approaches for treating SLE in mice using anti-CD4 mAb’s or CTLA4-Ig and anti-CD154 mAb’s have proven to be effective. However, like steroid treatment, these regimens induce global immunosuppression, and their withdrawal allows for disease progression. In this report we show that lupus-prone NZB × NZW F1 mice given three injections of anti-CD137 (4-1BB) mAb’s between 26 and 35 weeks of age reversed acute disease, blocked chronic disease, and extended the mice’s lifespan from 10 months to more than 2 years. Autoantibody production in recipients was rapidly suppressed without inducing immunosuppression. Successful treatment could be traced to the fact that NZB × NZW F1 mice, regardless of their age or disease status, could not maintain pathogenic IgG autoantibody production in the absence of continuous CD4+ T cell help. Our data support the hypothesis that CD137-mediated signaling anergized CD4+ T cells during priming at the DC interface

Thrombospondins are extracellular-matrix glycoproteins implicated in the control of synaptogenesis and neurite growth. Previous microarray studies suggested that one gene of this family, thrombospondin 4 (THBS4), was upregulated during human brain evolution. Using independent techniques to examine thrombospondin expression patterns in adult brain samples, we report approximately 6-fold and approximately 2-fold greater expression of THBS4 and THBS2 messenger RNA (mRNA), respectively, in human cerebral cortex compared with chimpanzees and macaques, with corresponding differences in protein levels. In humans and chimpanzees, thrombospondin expression differences were observed in the forebrain (cortex and caudate), whereas the cerebellum and most nonbrain tissues exhibited similar levels of the 2 mRNAs. Histological examination revealed THBS4 mRNA and protein expression in numerous pyramidal and glial cells in the 3 species but humans also exhibited very prominent immunostaining of the synapse-rich cortical neuropil. In humans, additionally, THBS4 antibodies labeled beta-amyloid containing plaques in Alzheimer's cases and some control cases. This is the first detailed characterization of gene-expression changes in human evolution that involve specific brain regions, including portions of cerebral cortex. Increased expression of thrombospondins in human brain evolution could result in changes in synaptic organization and plasticity, and contribute to the distinctive cognitive abilities of humans, as well as to our unique vulnerability to neurodegenerative disease.

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Infection of pig-tailed macaques with the simian immunodeficiency virus (SIV) isolate SIVsmmFGb frequently results in SIV encephalitis (SIVE) in addition to immunodeficiency and acquired immune deficiency syndrome. We used in situ hybridization to quantitate the number of SIV-infected cells in brain parenchyma, choroid plexus, and meninges from 17 macaques that developed acquired immune deficiency syndrome after infection with SIVsmmFGb. SIV-infected cells and histopathological lesions of SIVE were identified in 15 of 17 animals (88.2%), including 12 of 12 rapid progressors (RP) and 3 of 5 slow progressors (SP). The parenchymal virus burden was much greater in RP macaques than in the three SP macaques with SIVE (median values of 24.3 versus 0.3 infected cells/mm(2), respectively; P < 0.05). Viral load differences between RP and SP with SIVE were less marked in choroid plexus (29.6 versus 12.8 infected cells/mm(2), respectively) and meninges (133.0 versus 34.2 infected cells/mm(2), respectively). A significant negative correlation was observed between the magnitude of the anti-SIV antibody titer at 1 month after inoculation and brain virus burden at necropsy (r = -0.614; P < 0.01). The close association between immune response and SIVE in this model should prove useful for identifying correlates of immune protection against primate lentiviral encephalitis.

Chimpanzees are susceptible to infection with human immunodeficiency virus (HIV)-1; however, infected animals usually maintain normal numbers of CD4(+) T lymphocytes and do not develop immunodeficiency. We have examined 10 chronically infected HIV-1-positive chimpanzees for evidence of progressive infection. In addition to 1 animal that developed AIDS, 3 chimpanzees exhibit evidence of progressive HIV infection. All progressors have low CD4(+) T cell counts (<200 cells/microL), severe CD4:CD8 inversion, and marked reduction in interleukin-2 receptor expression by CD4(+) T cells. In comparison with HIV-positive nonprogressor chimpanzees, progressors have higher plasma and lymphoid virus loads, greater CD38 expression in CD8(+)/HLA-DR(+) T cells, and greater serum concentrations of soluble tumor necrosis factor type II receptors and beta2-microglobulin, all markers of HIV progression in humans. These observations show that progressive HIV-1 infection can occur in chimpanzees and suggest that the pathogenesis of progressive infection in this species resembles that in humans.