Hepatitis C Virus (HCV) Evades NKG2D-Dependent NK Cell Responses through NS5A-Mediated Imbalance of Inflammatory Cytokines

Understanding how hepatitis C virus (HCV) induces and circumvents the host's natural killer (NK) cell-mediated immunity is of critical importance in efforts to design effective therapeutics. We report here the decreased expression of the NKG2D activating receptor as a novel strategy adopted by HCV to evade NK-cell mediated responses. We show that chronic HCV infection is associated with expression of ligands for NKG2D, the MHC class I-related Chain (MIC) molecules, on hepatocytes. However, NKG2D expression is downmodulated on circulating NK cells, and consequently NK cell-mediated cytotoxic capacity and interferon-γ production are impaired. Using an endotoxin-free recombinant NS5A protein, we show that NS5A stimulation of monocytes through Toll-like Receptor 4 (TLR4) promotes p38- and PI3 kinase-dependent IL-10 production, while inhibiting IL-12 production. In turn, IL-10 triggers secretion of TGFβ which downmodulates NKG2D expression on NK cells, leading to their impaired effector functions. Moreover, culture supernatants of HCV JFH1 replicating Huh-7.5.1 cells reproduce the effect of recombinant NS5A on NKG2D downmodulation. Exogenous IL-15 can antagonize the TGFβ effect and restore normal NKG2D expression on NK cells. We conclude that NKG2D-dependent NK cell functions are modulated during chronic HCV infection, and demonstrate that this alteration can be prevented by exogenous IL-15, which could represent a meaningful adjuvant for therapeutic intervention

Cerebral Amyloid Angiopathy Related Inflammation With Prominent Meningeal Involvement. A Report of 2 Cases

International audienceCerebral amyloid angiopathy related inflammation (CAA-RI) is a rare form of CAA characterized by subacute encephalitic symptoms (cognitive decline, seizures, focal deficits) associated with extensive and confluent white matter lesions co-localizing with lobar microbleeds on brain MRI. We report two cases of unusual CAA-RI mimicking meningoencephalitis but without typical brain lesions on FLAIR and T2* sequences. These 2 cases may extend the clinical spectrum of CAA-RI by suggesting the possible occurrence of quite purely meningeal forms of CAA-RI

Relapsing polychondritis can be characterized by three different clinical phenotypes: analysis of a recent series of 142 patients

Relapsing polychondritis (RP) is a rare condition characterized by recurrent inflammation of cartilaginous tissue and systemic manifestations. Data on this disease remain scarce. This study was undertaken to describe patient characteristics and disease evolution, identify prognostic factors, and define different clinical phenotypes of RP.METHODS:We performed a retrospective study of 142 patients with RP who were seen between 2000 and 2012 in a single center.RESULTS:Of the 142 patients, 86 (61%) were women. The mean ± SD age at first symptoms was 43.5 ± 15 years. Patients had the following chondritis types: auricular (89%; n = 127), nasal (63%; n = 89), laryngeal (43%; n = 61), tracheobronchial (22%; n = 32), and/orcostochondritis (40%; n = 57). The main other manifestations were articular (69%; n = 98), ophthalmologic (56%; n = 80), audiovestibular (34%; n = 48), cardiac (27%; n = 38), and cutaneous (28%; n = 40). At a mean ± SD followup of 13 ± 9 years, the 5- and 10-year survival rates were 95 ± 2% and 91 ± 3%, respectively. Factors associated with death on multivariable analysis were male sex (P = 0.01), cardiac abnormalities (P = 0.03), and concomitant myelodysplastic syndrome (MDS) (P = 0.004) or another hematologic malignancy (P = 0.01). Cluster analysis revealed that separating patients into 3 groups was clinically relevant, thereby separating patients with associated MDS, those with tracheobronchial involvement, and those without the 2 features in terms of clinical characteristics, therapeutic management, and prognosis.CONCLUSION:This large series of patients with definite RP revealed an improvement in survival as compared with previous studies. Factors associated with death were male sex, cardiac involvement, and concomitant hematologic malignancy. We identified 3 distinct phenotypes

Expression of major histocompatibility complex class I chain-related molecule A, NKG2D, and transforming growth factor-beta in the liver of humans with alveolar echinococcosis: new actors in the tolerance to parasites?

International audienceBACKGROUND: Echinococcus multilocularis growth and persistent granuloma, which lead to the development of the severe parasitic disease alveolar echinococcosis (AE), might be caused by abnormal expression of stress-induced proteins, with subsequent abnormalities in T cell activation. Similar to its involvement in tumors, the NKG2D-major histocompatability complex class I chain-related molecules A and B (MICA/B) signaling system could be involved in host-parasite interactions; however, its involvement in helminthic diseases has never been studied. METHODS: We studied MICA/B, NKG2D, and transforming growth factor-beta (TGF-beta) expression on liver sections and measured levels of soluble MICA in serum samples obtained from patients with progressive AE. Livers from healthy and cirrhotic subjects were studied as controls. RESULTS: Expression of MICA/B proteins was strongly enhanced in the hepatocytes and endothelial and bile duct cells; in the CD68+ cells of the periparasitic infiltrate, especially epithelioid and giant cells; and, also, in the metacestode germinal layer. Strong expression of MICA/B in the liver contrasted with low numbers of NK cells and lack of expression of NKG2D on the numerous CD8+ T lymphocytes of the periparasitic infiltrate, as well as with the absence of soluble MICA in serum. TGF-beta was strongly expressed by most of the infiltrating lymphocytes. CONCLUSIONS: Sustained expression of MICA/B molecules and TGF-beta might lead to modulation of NKG2D with subsequent inhibition of NKG2D-dependent cytotoxicity. Abnormalities of this signaling system could contribute to parasitic evasion of the host's immunity

Serum biomarker signature identifies patients with B-cell non-Hodgkin lymphoma associated with cryoglobulinemia vasculitis in chronic HCV infection

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von Willebrand factor/ADAMTS13 axis and venous thromboembolism in moderate‐to‐severe COVID‐19 patients

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Contrast between Prevalence of HIT Antibodies and Confirmed HIT in Hospitalized COVID-19 Patients: A Prospective Study with Clinical Implications

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Oral corticoid, aspirin, anticoagulant, colchicine, and furosemide to improve the outcome of hospitalized COVID-19 patients - the COCAA-COLA cohort study

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Epidemiology, diagnosis and treatment of chronic hepatitis B in HIV-infected patients (EPIB 2005 STUDY)

International audienceOBJECTIVE: To describe the characteristics of hepatitis B (HBV) infection in HIV-infected patients and the impact of anti-HBV treatments. PATIENTS AND METHODS: All the patients with past or present chronic HBV infection seen in October 2005 in 17 French hospitals were included. Data were retrospectively collected from their first visit in a time-dependent manner, through a detailed standardized questionnaire. RESULTS: Among 477 HBV-infected patients, 261 (55%) were co-infected with HIV. The HBV-HIV co-infected patients underwent fewer serological, virological and histological evaluations. Initial positive HBe antigenemia (HBe Ag) was more frequent in these patients (57.9 versus 28.6%; P < 10), as was cirrhosis on the initial liver biopsy (17.9 versus 7.6%; P = 0.05). Throughout the mean 5-year follow-up, HBe Ag loss was less frequent (P = 0.04), as was HBe seroconversion (incidence rate 2.6 versus 10/100 patient-years; P < 10). HBe Ag loss was associated with fibrosis improvement (METAVIR score -0.5 +/- 0.4 versus +0.2 +/- 0.6 if persistent positive HBe Ag, P = 0.01). In co-infected patients on tenofovir, adefovir or interferon, HBe seroconversions were seen in patients on combined HBV treatment, the use of which is increasing (58% in 2005). Nevertheless, no significant difference in virological, immunological or biochemical evolution was observed between these different treatments. CONCLUSIONS: In HBV-HIV co-infected patients, the assessment of HBV infection still needs to be improved, the HBV wild-type remains predominant, and HBe Ag loss is rare and associated with a better histological evolution. There is insufficient evidence of the superiority of combined HBV treatment, and this still needs be demonstrated in long term studies