CD8+-dependent CNS demyelination following ocular infection of mice with a recombinant HSV-1 expressing murine IL-2

Demyelinating diseases comprise a spectrum of immunopathologic syndromes in which myelin, the fatty covering of nerve cell fibers in the brain and spinal cord, is destroyed. In this study, we have shown for the first time that ocular infection of BALB/c mice with a recombinant herpes simplex virus type 1 (HSV-1) expressing IL-2 (HSV-IL-2) results in CNS demyelination as determined by light microscopy and EM. The demyelinated lesions involve periventricular white matter, brain stem, and spinal cord white matter. Demyelination was detected in the CNS of infected mice up to 75 days (the longest time point tested) post HSV-IL-2 infection. In contrast, mice infected with HSV-IFN-gamma or HSV-IL-4, which are identical to HSV-IL-2 but express IFN-gamma or IL-4 instead of IL-2, did not exhibit demyelination. Control mice infected with wild-type HSV-1 or parental virus also remained free of these symptoms. During early times (days 3-7), post-infection with HSV-IL-2 virus, a T(H)1 + T(H)2 pattern of cytokines was produced by lymphocytes of infected mice while mice infected with HSV-IFN-gamma or control viruses produced a T(H)1 pattern of cytokine. By day 21 post-infection, all infected groups exhibited a T(H)1 pattern of response. Immunohistochemistry and FACS analyses of infiltrates in the brains and spinal cords of HSV-IL-2-infected mice showed elevations in CD4+ and CD8+ T cells and macrophages. However, T cell depletion studies suggest that only central memory CD8+ T cells are directly involved in the demyelination process, with macrophages being involved through a bystander effect.     

Effects of mood state and psychosocial functioning on plasma Interleukin-6 in adult patients before cardiac surgery

OBJECTIVE: The purpose of this study was to examine the potential effect of mood states and psychosocial functioning during the waiting weeks prior to major cardiac surgery on the plasma Interleukin-6 (IL-6) levels in 236 patients immediately before their operation. METHOD: The sample was recruited from patients at the cardiac clinic of the University of Michigan Medical Center (Ann Arbor). Two weeks before cardiac surgery, trained research assistants conducted a face-to-face interview with these middle-aged and older patients on their preoperative physical examination date at the clinic. Standardized instruments were used to assess mood states and psychosocial functioning. The blood samples of 236 patients, obtained on the morning of the operation, were analyzed for plasma IL-6. RESULTS: In bivariate analysis, poor psychological functioning and anxiety, as well as bodily pain and body mass index (BMI), were correlated with plasma IL-6 (p < .05), but sociodemographics, chronic illness and use of psychotropic medications were not. When the effect of bodily pain and BMI were taken into account, partial correlation analysis showed that psychological functioning continued to be associated with plasma IL-6 (p < .05); the association of IL-6 with depression now became significant (p < .05), whereas that with anxiety became even more significant (p < .001). CONCLUSIONS: Preoperative psychological disturbances during the waiting weeks before cardiac surgery may influence the plasma levels of IL-6 immediately prior to the procedure. The clinical implications of these findings remain to be determined.     

RSA 2004: combined basic research satellite symposium - session four: hepatitis virus and alcohol interactions in immunity and liver disease

This article summarizes the proceedings of the RSA 2004 Combined Basic Research Satellite Meeting convened at the Westin Bayshore Resort and Marina, Vancouver, CA. The session "Hepatitis virus and alcohol interactions in immunity and liver disease" featured four speakers and was chaired by Drs. Diane Lucas and Samuel French. The presentations were 1) Mitochondrial effects of HCV proteins and alcohol by Steve Weinman, 2) Chronic alcohol consumption accelerates viral hepatitis and T-cell hepatitis via dysregulation of cytokine signaling by Bin Gao 3) Interactions between alcohol, hepatitis C virus and innate defense pathways by Steve Polyak and 4) Scavenger Receptor-mediated modulation of the innate and adaptive immune responses following chronic ethanol consumption by Geoffrey Thiele.     

Effect of treatment interruption monitored by CD4 cell count on mitochondrial DNA content in HIV-infected patients: a prospective study

BACKGROUND: HIV infection per se and HAART can alter mitochondrial functionality, leading to a decrease in mitochondrial DNA content. OBJECTIVE: To evaluate whether treatment interruption monitored by CD4 cell count can restore mitochondrial DNA content in peripheral blood lymphocytes. METHODS: Mitochondrial DNA content was measured in platelet-free CD4 and CD8 T cells by real-time polymerase chain reaction; flow cytometry was used to identify and quantify activated CD4 and CD8 T lymphocytes. RESULTS: The 30 patients had been treated for a mean of 107 months (range, 27-197). Median CD4 cell count at discontinuation was 702 cells/microl (range, 547-798). Median observational time from HAART discontinuation was 11.3 months (range, 4-26). Discontinuation of treatment provoked significant increases in mitochondrial DNA in CD8 T cells, which started only 6 months after therapy discontinuation [5.12 copies/cell per month from 0 to 6 months (P = 0.37) and 26.96 copies/cell per month from 6 to 12 months (P < 0.0001)]. CONCLUSIONS: This study is the first showing that mitochondrial DNA content can increase in peripheral blood lymphocytes during treatment interruption, but only after at least 6 months of interruption. Consequently, interruptions of shorter periods, whether by clinician or patient decision, are unlikely to allow restoration of mitochondrial DNA and so decrease HAART-related toxicity.     

Alcohol exacerbates murine pulmonary tuberculosis

Alcohol consumption has been described as a risk factor for infection with Mycobacterium tuberculosis, but its contribution to tuberculosis has been difficult to isolate from other adverse socioeconomic factors. Our objective was to evaluate the impact of alcohol consumption on pulmonary infection with M. tuberculosis in a murine model. BALB/c mice were maintained on the Lieber-DeCarli liquid ethanol diet or a liquid control diet and infected intratracheally with low-dose M. tuberculosis H37Rv. Lung organism burdens, lung and lung-associated lymph node CD4⁺- and CD8⁺- lymphocyte numbers and rates of proliferation, and CD4⁺-lymphocyte cytokine production levels were compared between the groups. The alcohol-consuming mice had significantly higher lung organism burdens than the control mice, and the CD4⁺- and CD8⁺-lymphocyte responses to pulmonary infection with M. tuberculosis were blunted in the alcohol group. Lymphocyte proliferation and production of gamma interferon were decreased in the CD4⁺ lymphocytes from the alcohol-consuming mice. Additionally, lung granulomas were significantly smaller in the alcohol-consuming mice. In conclusion, murine alcohol consumption is associated with decreased control of pulmonary infection with M. tuberculosis, which is accompanied by alterations in the region-specific CD4⁺- and CD8⁺-lymphocyte responses and defective lung granuloma formation.     

Neither neutrophils nor reactive oxygen species contribute to tissue damage during Pneumocystis pneumonia in mice

Neutrophils are implicated in the damage of lung tissue in many disease states, including infectious diseases and environmental insults. These effects may be due to oxidative or nonoxidative functions of the neutrophil or both. We examined the role of neutrophils in pulmonary damage during infection with the opportunistic fungal pathogen Pneumocystis sp. in four mouse models of neutrophil dysfunction. These were (i) a knockout of the gp91(phox) component of NADPH oxidase, in which reactive oxygen species (ROS) production is greatly reduced; (ii) a double knockout of gp91(phox) and inducible nitric oxide synthase, in which ROS and nitric oxide production is greatly decreased; (iii) a knockout of the chemokine receptor CXCR2, in which accumulation of intra-alveolar neutrophils is severely diminished; and (iv) antibody depletion of circulating neutrophils in wild-type mice with the monoclonal antibody RB6. Surprisingly, in each case, indicators of pulmonary damage (respiratory rates, arterial oxygen partial pressures, and intra-alveolar albumin concentrations) were the same in knockout mice and comparable wild-type mice. Therefore, whereas neutrophils are a valid correlative marker of lung damage during Pneumocystis infection, neither neutrophils nor ROS appear to be the causative agent of tissue damage. We also show that there is no difference in Pneumocystis burdens between wild-type and knockout mice, which supports the idea that neutrophils do not have a major role in the clearance of this organism.