CD8+ T-Cell Exhaustion Phenotype in Chronic Hepatitis C Virus Infection Is Associated With Epitope Sequence Variation.

Background and Aims: During chronic hepatitis C virus (HCV) infection, CD8+ T-cells become functionally exhausted, undergoing progressive phenotypic changes, i.e., overexpression of "inhibitory" molecules such as PD-1 (programmed cell death protein 1) and/or Tim-3 (T-cell immunoglobulin and mucin domain-containing molecule-3). The extreme intrahost genetic diversity of HCV is a major mechanism of immune system evasion, facilitating epitope escape. The aim of the present study was to determine whether T-cell exhaustion phenotype in chronic HCV infection is related to the sequence repertoire of NS3 viral immunodominant epitopes. Methods: The study population was ninety prospective patients with chronic HCV genotype 1b infection. Populations of peripheral blood CD8+ T-cells expressing PD-1/Tim-3 were assessed by multiparametric flow cytometry, including HCV-specific T-cells after magnetic-based enrichment using MHC-pentamer. Autologous epitope sequences were inferred from next-generation sequencing. The correction of sequencing errors and genetic variants reconstruction was performed using Quasirecomb. Results: There was an interplay between the analyzed epitopes sequences and exhaustion phenotype of CD8+ T-cells. A predominance of NS31406 epitope sequence, representing neither prototype KLSGLGLNAV nor cross-reactive variants (KLSSLGLNAV, KLSGLGINAV or KLSALGLNAV), was associated with higher percentage of HCV-specific CD8+PD-1+Tim-3+ T-cells, P=0.0102. Variability (at least two variants) of NS31406 epitope sequence was associated with increased frequencies of global CD8+PD-1+Tim-3+ T-cells (P=0.0197) and lower frequencies of CD8+PD-1-Tim-3- T-cells (P=0.0079). In contrast, infection with NS31073 dominant variant epitope (other than prototype CVNGVCWTV) was associated with lower frequency of global CD8+PD-1+Tim-3+ T-cells (P=0.0054). Conclusions: Our results indicate that PD-1/Tim-3 receptor expression is largely determined by viral epitope sequence and is evident for both HCV-specific and global CD8+ T-cells, pointing to the importance of evaluating autologous viral epitope sequences in the investigation of CD8+ T-cell exhaustion in HCV infection.

Peroxiredoxins as Markers of Oxidative Stress in IgA Nephropathy, Membranous Nephropathy and Lupus Nephritis.

IgA nephropathy (IgAN), membranous nephropathy (MN), and lupus nephritis (LN) represent important causes of chronic kidney disease. They belong to the immune-mediated glomerulonephritis (GNs), and have distinct pathogenesis, distinct clinical courses, and variable responses to treatment. Therefore, specific diagnostic procedures are necessary for more effective patient management. Recently, a role for oxidative stress has been proposed in various renal disorders. Thus, molecules related to oxidative stress, such as 2-Cys-peroxiredoxins (PRDXs), may represent plausible candidates for biomarkers in renal pathologies. The aim of this study was to assess whether there are differences between individual GNs and healthy controls in the context of PRDXs serum concentration. We enrolled 108 patients with biopsy-proven IgAN (47), MN (26), LN (35) and 30 healthy age- and sex-matched controls. The serum concentrations of PRDX 1-5 were measured with ELISA assays and correlated with demographic and clinical data. The PRDXs' concentration varied depending on the GN type. We also observed an association of PRDXs with lower estimated glomerular filtration rates, complement, hemoglobin, and body mass index. Our study indicates that individual PRDX can play roles in pathophysiology of selected GNs and that their serum concentrations may become useful as a new supplementary diagnostic markers in IgAN, MN as well as LN. The results of this study open a new avenue for prospective research on PRDXs in renal diseases.

The clinical course and outcome of Listeria monocytogenes meningitis: A retrospective single center study.

BACKGROUND: The aim of the study was to determine clinical manifestations and outcome of Listeria monocytogenes meningitis (LM) and to compare with other forms of bacterial meningitis (BM). MATERIAL AND METHODS: We analyzed records of all adult patients with BM who were hospitalized between January 2010 and December 2017 in the largest neuroinfection center in Poland. RESULTS: Out of 343 analyzed patients with BM 24 were diagnosed to have LM. Patients with LM were older compared to patients with other forms of BM (62 years vs. 57 years, p=0.039), were more likely to have cancer (16.7% vs. 4.7%, p=0.045), receive immunosuppressive treatment (45.8% vs. 10.7%, p<0.001), or be immunocompromised in any way (62.5% vs. 35.5%, p=0.016). Blood tests showed lower WBC (10.7 × 103 cells/µl vs. 15.5 × 103 cells/µl, p=0.004), C-reactive protein (150 mg/L vs. 221 mg/L, p=0,019) and procalcitonin (1.27 ng/mL vs. 3.78 ng/mL, p=0.003) in LM group. Analysis of cerebrospinal fluid showed lower cell count (531.5 cells/µL vs. 1100 cells/µL, p<0.001) and lower chloride (113 mmol/L vs. 117 mmol/L, p=0.036) in patients with LM. In the multiple logistic regression analysis, immunosuppressive therapy was the only variable independently associated with LM (OR:8.72, CI 95%:1.41-64.34, p=0.024). CONCLUSIONS: LM is associated with older age, cancer and immunosuppressive therapy. However, in multivariate analysis only immunosuppressive therapy turned out to be an independent risk factor for LM.

Chronic alcohol abuse affects the clinical course and outcome of community-acquired bacterial meningitis.

The aim of the study was to determine the effect of chronic alcohol abuse on the course and outcome of bacterial meningitis (BM). We analyzed records of patients with BM who were hospitalized between January 2010 and December 2017 in the largest neuroinfection center in Poland. Out of 340 analyzed patients, 45 (13.2%) were alcoholics. Compared with non-alcoholics, alcoholics were more likely to present with seizures (p < 0.001), scored higher on the Sequential Organ Failure Assessment (SOFA) (p = 0.002) and lower on the Glasgow Coma Scale (GCS) (p < 0.001), and had worse outcome as measured by the Glasgow Outcome Score (GOS) (p < 0.001). Furthermore, alcoholics were less likely to complain of headache (p < 0.001) and nausea/vomiting (p = 0.005) and had lower concentration of glucose in cerebrospinal fluid (CSF) (p = 0.025). In the multiple logistic regression analysis, alcoholism was associated with lower GCS (p = 0.036), presence of seizures (p = 0.041), male gender (p = 0.042), and absence of nausea/vomiting (p = 0.040). Furthermore, alcoholism (p = 0.031), lower GCS score (p = 0.001), and higher blood urea concentration (p = 0.018) were independently associated with worse outcome measured by GOS. Compared with non-alcoholics, chronic alcohol abusers are more likely to present with seizures, altered mental status, and higher SOFA score and have an increased risk of unfavorable outcome. In multivariate analysis, seizures and low GCS were independently associated with alcoholism, while alcoholism was independently associated with worse outcome.

PET/CT evaluation of 18F-FDG uptake in pericoronary adipose tissue in patients with stable coronary artery disease: Independent predictor of atherosclerotic lesions' formation?

BACKGROUND: Inflammatory infiltrations in EAT which releases inflammatory cytokines correspond anatomically to the atheromatous plaques in underlying coronary vessels. However, it is unknown whether inflammatory activity of pericoronary adipose tissue (PCAT) promotes coronary atherosclerosis. METHODS AND RESULTS: 35 non-diabetic patients with confirmed CAD and 35 non-CAD controls matched for age and BMI underwent 18F-FDG-PET/CT. Maximal SUV normalized by LA blood activity was measured on the sections corresponding to the respective coronaries (RCA, LCX, LAD), as well, as in subcutaneous fat, visceral fat, and epicardial fat. Extent of CAD was determined by % stenosis in segments corresponding to 18F-FDG-PET/CT sections in coronarography using quantitative coronary analysis. PCAT SUV was significantly greater than SUV in other fat locations, as well as PCAT SUV in the controls. In CAD patients with BMI >25, PCAT SUV was positively related to % stenosis of a respective coronary artery (RCA: 0.43; P < .05; LCX 0.58; P < .05; LAD 0.65; P < .05). PCAT SUV was the only independent predictor of coronary stenosis of LAD and RCA. CONCLUSIONS: Inflammatory activity of PCAT is greater than in other fat locations, in CAD is greater than in non-CAD controls, and is independently associated with coronary stenosis. In overweight patients, PCAT SUV correlates with the extent of CAD.

Inflammatory Markers Change with Age, but do not Fall Beyond Reported Normal Ranges.

We examined the serum levels of IL-6, IL-8, TNF, IL-6R, TNF-R1, and CRP and the dynamics of changes in these levels according to age. The study included healthy individuals of 20-90 years of age. Participants were divided into subgroups based on their decade of life, and into subgroups of ≥65 or <65 years. Serum cytokine levels were assayed by ELISA, and CRP using an immunoturbidimetric method. Serum CRP levels were within the normal range for all subgroups. The 60- to 70-year age group showed higher CRP than the 20- to 30- (p = 0.003), 30- to 40- (p = 0.009), and 40- to 50- (p = 0.030) year age groups. Serum cytokine levels were low. It was greater in the 60- to 70-year age group than in the 20- to 30- (p = 0.008) and 30- to 40- (p = 0.040) year groups, and was greater in the 70- to 90-year group than the 20- to 30-year group (p = 0.043). Serum TNF-R1 level in the 70- to 90-year group was greater than in all other age groups (p = 0.000 for all comparisons). Other measured parameters did not differ between groups. Serum levels of IL-6, CRP, and TNF-R1 were greater in participants ≥65 than <65 years of age. Healthy older people showed low serum levels of CRP and pro-inflammatory cytokines, but higher than in younger population. Therefore, the adjustment of normal ranges in the elderly should be considered. Serum levels of pro-inflammatory cytokines elevated beyond normal ranges indicate particular diseases.