The role of dendritic cells in the pathogenesis of systemic lupus erythematosus

The etiology of the autoimmune disease systemic lupus erythematosus is not known, but aberrant apoptosis and/or insufficient clearance of apoptotic material have been assigned a pivotal role. During apoptosis, nucleosomes and several endogenous danger-associated molecular patterns are incorporated in blebs. Recent data indicate that apoptotic blebs induce maturation of myeloid dendritic cells, resulting in IL-17 production by T cells. In this review we summarize current knowledge on the role of dendritic cells in the pathogenesis of systemic lupus erythematosus with special emphasis on the uptake of apoptotic blebs by dendritic cells, and the subsequent induction of Th17 cells

Aberrant Mitochondrial Homeostasis in the Skeletal Muscle of Sedentary Older Adults

The role of mitochondrial dysfunction and oxidative stress has been extensively characterized in the aetiology of sarcopenia (aging-associated loss of muscle mass) and muscle wasting as a result of muscle disuse. What remains less clear is whether the decline in skeletal muscle mitochondrial oxidative capacity is purely a function of the aging process or if the sedentary lifestyle of older adult subjects has confounded previous reports. The objective of the present study was to investigate if a recreationally active lifestyle in older adults can conserve skeletal muscle strength and functionality, chronic systemic inflammation, mitochondrial biogenesis and oxidative capacity, and cellular antioxidant capacity. To that end, muscle biopsies were taken from the vastus lateralis of young and age-matched recreationally active older and sedentary older men and women (N = 10/group; ♀  =  ♂). We show that a physically active lifestyle is associated with the partial compensatory preservation of mitochondrial biogenesis, and cellular oxidative and antioxidant capacity in skeletal muscle of older adults. Conversely a sedentary lifestyle, associated with osteoarthritis-mediated physical inactivity, is associated with reduced mitochondrial function, dysregulation of cellular redox status and chronic systemic inflammation that renders the skeletal muscle intracellular environment prone to reactive oxygen species-mediated toxicity. We propose that an active lifestyle is an important determinant of quality of life and molecular progression of aging in skeletal muscle of the elderly, and is a viable therapy for attenuating and/or reversing skeletal muscle strength declines and mitochondrial abnormalities associated with aging

The interferon gamma gene in celiac disease: Augmented expression correlates with tissue damage but no evidence for genetic susceptibility

Celiac disease (CD) is a complex genetic disorder characterized by gluten intolerance. The Th1 immune response, with a key position for interferon gamma (IFN-γ), is an important determinant of intestinal remodeling in CD. We aimed at further ascertaining the role of IFN-γ, either as a genetic factor in the etiology, or as a facilitator of disease initiation/progression. Duodenal biopsies were sampled across distinct histopathological stages of the disease, including refractory CD (RCD), and used to determine IFN-γ gene (IFNG) expression by real-time RT-PCR. INFG expression correlated with the extent of tissue restructuring, reaching a 240-fold higher expression in total villous atrophy compared to healthy tissue. CD and RCD patients with similar lesions had comparable expression levels. Interestingly, patients in complete remission still had 7.6-fold residual over-expression. An INFG marker was tested in three cohorts of Dutch patients for both genetic linkage and association. Linkage analysis yielded no significant scores for IFNG or its flanking markers. In addition, IFNG allele frequencies were not differently distributed between cases and controls. Likewise, all alleles were randomly transmitted to affected children in parents-case trios. There is no evidence for IFNG as a predisposing gene in CD, despite its enhanced expression in patients in complete remission

Complementary role of HCV and HIV in T-cell activation and exhaustion in HIV/HCV coinfection.

OBJECTIVES: To investigate whether T-cell activation and exhaustion is linked to HCV- and HIV disease parameters in HIV/HCV infected individuals, we studied T-cell characteristics in HIV/HCV coinfected patients and controls. METHODS: 14 HIV/HCV coinfected, 19 HCV monoinfected, 10 HIV monoinfected patients and 15 healthy controls were included in this cross-sectional study. Differences in expression of activation and exhaustion markers (HLA-DR, CD38, PD-1, Tim-3 and Fas) and phenotypic markers on CD4(+) and CD8(+) T-cells were analysed by flow cytometry and were related to HCV disease parameters (HCV-viremia, ALT and liver fibrosis). RESULTS: Frequencies of activated CD4(+) and CD8(+) T-cells were higher in HIV/HCV-coinfected compared to healthy controls and HCV or HIV mono-infected individuals. Coinfected patients also showed high expression of the exhaustion marker PD-1 and death receptor Fas. In contrast, the exhaustion marker Tim-3 was only elevated in HIV-monoinfected patients. T-cell activation and exhaustion were correlated with HCV-RNA, suggesting that viral antigen influences T-cell activation and exhaustion. Interestingly, increased percentages of effector CD8(+) T-cells were found in patients with severe (F3-F4) liver fibrosis compared to those with no to minimal fibrosis (F0-F2). CONCLUSIONS: HIV/HCV coinfected patients display a high level of T-cell activation and exhaustion in the peripheral blood. Our data suggest that T-cell activation and exhaustion are influenced by the level of HCV viremia. Furthermore, high percentages of cytotoxic/effector CD8(+) T-cells are associated with liver fibrosis in both HCV monoinfected and HIV/HCV coinfected patients

The effect of HIV coinfection, HAART and TB treatment on cytokine/chemokine responses to Mycobacterium tuberculosis (Mtb) antigens in active TB patients and latently Mtb infected individuals

Identification of Mtb specific induced cytokine/chemokine host biomarkers could assist in developing novel diagnostic, prognostic and therapeutic tools for TB. Levels of IFN-γ, IL-2, IL-17, IL-10, IP-10 and MIP-1α were measured in supernatants of whole blood stimulated with Mtb specific fusion protein ESAT-6/CFP-10 using xMAP technology. The study groups were HIV positive TB patients (HIV+TB+), HIV negative TB patients (HIV-TB+), HIV positive tuberculin skin test positive (TST+) (HIV+TST+), HIV negative TST+ (HIV-TST+), and HIV-TST- individuals. Compared to HIV-TST-, latent TB infection led to increased levels of IP-10, IFN-γ and IL-17, while levels of IL-2 and IP-10 were increased with active TB. Levels of IFN-γ, IL-17, MIP-1α, and IL-10 were increased in HIV-TST+ individuals compared to HIV-TB+ patients. HIV coinfection decreased the level of IFN-γ, IL-17, IP-10 and IL-2. After six months (M6) of anti-TB treatment (ATT) in HIV-TB+ patients, IFN-γ, IL-10, and MIP-1α levels normalized. After M6 and M18 of ATT plus HAART in HIV+TB+ patients, levels of MIP-1α and IL-10 normalized, while this was not the case for IFN-γ, IL-2, IL-17, and IP-10 levels. In HIV+TST+ patients on HAART, levels of IFN-γ, IL-17, IL-10 and MIP-1α normalized, while no change in the levels of IL-2 and IP-10 were observed. In conclusion, the simultaneous measurement of IFN-γ, IL-17 and IP-10 may assist in diagnosing LTBI; IL-2 and IP-10 may assist in diagnosing active TB; while IFN-γ, IL-17, MIP-1α, and IL-10 levels could help to discriminate LTBI and active TB. In addition, IL-10 and MIP-1α levels could help to monitor responses to TB treatment and HAART

The effect of HIV coinfection, HAART and TB treatment on cytokine/chemokine responses to Mycobacterium tuberculosis (Mtb) antigens in active TB patients and latently Mtb infected individuals

Identification of Mtb specific induced cytokine/chemokine host biomarkers could assist in developing novel diagnostic, prognostic and therapeutic tools for TB. Levels of IFN-γ, IL-2, IL-17, IL-10, IP-10 and MIP-1α were measured in supernatants of whole blood stimulated with Mtb specific fusion protein ESAT-6/CFP-10 using xMAP technology. The study groups were HIV positive TB patients (HIV+TB+), HIV negative TB patients (HIV-TB+), HIV positive tuberculin skin test positive (TST+) (HIV+TST+), HIV negative TST+ (HIV-TST+), and HIV-TST- individuals. Compared to HIV-TST-, latent TB infection led to increased levels of IP-10, IFN-γ and IL-17, while levels of IL-2 and IP-10 were increased with active TB. Levels of IFN-γ, IL-17, MIP-1α, and IL-10 were increased in HIV-TST+ individuals compared to HIV-TB+ patients. HIV coinfection decreased the level of IFN-γ, IL-17, IP-10 and IL-2. After six months (M6) of anti-TB treatment (ATT) in HIV-TB+ patients, IFN-γ, IL-10, and MIP-1α levels normalized. After M6 and M18 of ATT plus HAART in HIV+TB+ patients, levels of MIP-1α and IL-10 normalized, while this was not the case for IFN-γ, IL-2, IL-17, and IP-10 levels. In HIV+TST+ patients on HAART, levels of IFN-γ, IL-17, IL-10 and MIP-1α normalized, while no change in the levels of IL-2 and IP-10 were observed. In conclusion, the simultaneous measurement of IFN-γ, IL-17 and IP-10 may assist in diagnosing LTBI; IL-2 and IP-10 may assist in diagnosing active TB; while IFN-γ, IL-17, MIP-1α, and IL-10 levels could help to discriminate LTBI and active TB. In addition, IL-10 and MIP-1α levels could help to monitor responses to TB treatment and HAART

Pegylated interferon-alpha monotherapy leads to low response rates in HIV-infected patients with acute hepatitis C

Background: Despite a rising incidence of acute HCV in patients infected with HIV, the optimal therapeutic strategy (pegylated interferon-alpha [PEG-IFN-alpha] monotherapy or in combination with ribavirin) is still under debate. Methods: A total of 23 HIV-infected patients were prospectively diagnosed with acute HCV and treated with PEG-IFN-alpha 2a monotherapy (180 mu g/week) for 24 or 48 weeks. Add-on ribavirin was allowed from week 4 of therapy onwards. There were three patients who were not included for different reasons. Blood samples were routinely drawn for viral load measurement and IL28B polymorphism analysis. Results: Spontaneous viral clearance occurred in 1 (4%) patient. Nineteen patients (13 genotype 1 and 6 genotype 4) received treatment with PEG-IFN-alpha monotherapy (3 with add-on ribavirin) resulting in a rapid virological response (HCV RNA Conclusions: PEG-IFN-alpha monotherapy resulted in a low SVR rate and a high percentage of null-response, whereas non-SVR was associated with a polymorphism in the IL28B gene (rs8099917)

Changes in CD8⁺ effector and memory phenotype in all patients and healthy controls.

<p>A: representative plots of a healthy control, HIV-HCV coinfected, HCV monoinfected and HIV- mono patient showing naïve (right lower quadrant), central memory (right upper quadrant), effector memory (left upper quadrant) and effector (left lower quadrant) CD8⁺ T-cells by CD27 and CD45RO staining. B: pie charts of mean percentages of naïve (light grey), central memory (CM; light blue), effector memory (EM; dark blue) and effector (orange) CD8⁺ T-cells in 42 patients and 3 healthy controls. C: relative increase of median percentages of memory subsets compared to healthy controls. D: box plot showing percentages of effector CD8⁺ T-cells in HCV-monoinfected (left) or HIV/HCV-coinfected patients (right) with fibrosis scores F0–F2 (yellow) versus F3–F4 (red). The depicted p-value was calculated with two way ANOVA and indicates statistical significant difference in percentages of effector CD8⁺ T cells in F0–F2 fibrosis compared to F3–F4 fibrosis, independent of coinfection with HIV. Liver fibrosis was assessed with Fibroscan in 74% of HCV monoinfected patients and 71% of HIV/HCV coinfected patients. E: correlation of staining for perforin (Y-axis) with effector phenotype (X-axis) in CD8⁺ T-cells. Box-plots show median, quartiles and range. Line represents linear regression. P-values are depicted as: * (<0.05) and ** (p-value <0.01).</p

Correlations of clinical parameters and T cell markers.

<p>Spearman correlations of HCV-RNA and ALT with expression of activation and exhaustion markers and median expression of these markers in patients with F0–F2 versus F3–F4 fibrosis in all HCV-monoinfected and HIV/HCV-coinfected patients.</p