A systematic review of leukocyte telomere length and age in adults

ObjectiveTo provide a systematic review of the relationship between age and leukocyte telomere length (LTL) in adults.MethodsRelevant studies were identified by a systematic search of Medline, EMBASE and ISI Web of Knowledge databases. Key data, such as age and LTL, were extracted from the studies along with correlation coefficients and yearly attrition rates where available. Obtained data were used to calculate weighted means and correlation coefficients.ResultsOverall, 124 cross-sectional studies and 5 longitudinal studies were identified. A statistically significant inverse correlation between mean age and mean LTL across cross-sectional studies was observed for both absolute (r = ?0.338, p < 0.0001) and relative LTL (r = ?0.295, p = 0.0088). From mean LTL and ages, a yearly telomere loss of 24.7 base pairs (BP)/year was estimated by weighted linear regression. Weighted means of within study correlation of age and TL and yearly telomere loss rate estimates from cross-sectional studies were also in a similar order of magnitude (?0.380 and 21.91 BP/year). The few longitudinal studies reported somewhat higher mean telomere loss rates (between 32.2 and 45.5 BP/year).ConclusionWhile a decrease of LTL with age is out of question, data on variation of the decrease according to sex, age and other potential determinants especially from longitudinal data are still sparse.     

Pathogenic TERT promoter variants in telomere diseases

PurposeThe acquisition of pathogenic variants in the TERT promoter (TERTp) region is a mechanism of tumorigenesis. In nonmalignant diseases, TERTp variants have been reported only in patients with idiopathic pulmonary fibrosis (IPF) due to germline variants in telomere biology genes.MethodsWe screened patients with a broad spectrum of telomeropathies (n = 136), their relatives (n = 52), and controls (n = 195) for TERTp variants using a customized massively parallel amplicon-based sequencing assay.ResultsPathogenic −124 and −146 TERTp variants were identified in nine (7%) unrelated patients diagnosed with IPF (28%) or moderate aplastic anemia (4.6%); five of them also presented cirrhosis. Five (10%) relatives were also found with these variants, all harboring a pathogenic germline variant in telomere biology genes. TERTp clone selection did not associate with peripheral blood counts, telomere length, and response to danazol treatment. However, it was specific for patients with telomeropathies, more frequently co-occurring with TERT germline variants and associated with aging.ConclusionWe extend the spectrum of nonmalignant diseases associated with pathogenic TERTp variants to marrow failure and liver disease due to inherited telomerase deficiency. Specificity of pathogenic TERTp variants for telomerase dysfunction may help to assess the pathogenicity of unclear constitutional variants in the telomere diseases.     

Aberrant NKG2D expression with IL-17 production of CD4+ T subsets in patients with type 2 diabetes

Type 2 diabetes (T2D) is a systemic inflammatory disease. Although the natural killer group 2, member D (NKG2D) receptor, was not expressed normally on CD4+ T cells, the aberrant expression was found in pathological conditions such as in auto-immune diseases. However, the involvement of NKG2D in pathogenesis of T2D is unclear. We hypothesize that there is an inflammatory CD4+ T cell subpopulation expressing NKG2D and producing interleukin (IL)-17 in T2D. NKG2D expression on CD4+ T cells and their subsets were analyzed by multi-color staining using flow cytometry. Lymphocytes were activated by phorbol-12-myristate-13-acetate (PMA) and ionomycin, and were stained for intracellular IL-17. To investigate the mechanism of IL-17 production, patients’ lymphocytes were stimulated using specific anti-T cell receptor (TCR) alone, anti-NKG2D alone or a combination of the two antibodies. CD4+ T cells and particularly, CD4 + CD28^null T subset of T2D patients were highly expressed NKG2D and more prevalent compared to non-diabetic individuals (ND) (P = 0.039 and P = 0.022, respectively). Significantly higher percentages of CD4 + CD28^nullNKG2D + T cells of patients produced IL-17 when compared to those of ND (P = 0.024) and were positively correlated with the level of glycated hemoglobin A1c (HbA1c) (R² = 0.386, P = 0.041). Additionally, this cell population could be stimulated by specific monoclonal anti-NKG2D to produce IL-17. In conclusion, CD4 + CD28^nullNKG2D+ T cells were expanded in T2D, especially in patients with poor glycemic control. NKG2D may be one of the surrogate co-stimulatory receptors leading to irregular inflammatory function producing IL-17. An IL-17 producing CD4 + CD28^nullNKG2D + T cells may potentially be involved in pathogenesis and drive severity of the disease with the glycemic dependence. This particular cell type could be targeted for prognostic or therapeutic purposes.     

Characterization of CD4/CD8+ αβ and Vγ2Vδ2+ T cells in HIV-negative individuals with different Mycobacterium tuberculosis infection statuses

BackgroundThe immune responses of T cell subsets among patients with different Mycobacterium tuberculosis (M.tb) infection statuses [i.e., active tuberculosis (ATB), latent tuberculosis infection (LTBI) and non-infection (healthy control, HC)] have not been fully elucidated in HIV-negative individuals. Specifically, data are limiting in high tuberculosis epidemic regions in China. To investigate the distributions and functions of T cell subsets (i.e., CD3+, CD4+, CD8+ αβ and Vγ2Vδ2+ T cells) in HIV-negative subjects with different M.tb infection statuses, we conducted a case-control study that enrolled 125 participants, including ATB patients (n = 46), LTBI subjects (n = 34), and HC (n = 45).ResultsAn IFN-γ release assay (IGRA) was employed to screen LTBI subjects. Whole blood cell surface staining and flow cytometry were used to detect phenotypic distributions of T cells in the peripheral blood mononuclear cells (PBMCs) and tuberculous pleural fluid mononuclear cells (PFMCs). PPD and the phosphorylated antigen HMBPP were employed as stimulators for the detection of M.tb antigen-specific T cell functions via intracellular cytokine staining (ICS). The absolute numbers of T cell subsets, including CD3+ CD4+, CD3+ CD8+ αβ and Vγ2Vδ2+ T cells, were significantly reduced in active tuberculosis compared with latent tuberculosis or the healthy controls. Importantly, PPD-specific CD3+ CD4+ and CD3+ CD8+ αβ T cells and HMBPP-specific Vγ2Vδ2+ T cells in ATB patients were also significantly reduced compared to the LTBI/HC subjects (P < 0.05). In contrast, the proportion of CD4+ T cells in PFMCs was higher compared to PBMCs, while CD8+ and Vγ2Vδ2+ T cells in PFMCs were lower compared to PBMCs (all P < 0.05). PPD-specific CD4+ T cells predominated among CD3+ T cells in PFMCs.ConclusionsCellular immune responses are impaired in ATB patients. Antigen-specific CD4+ T cell may migrate from the periphery to the lesion site, where they exert anti-tuberculosis functions.     

Prognostic value of telomere length in acute coronary syndrome

Telomere and telomerase are involved in cellular and organismal ageing and have been related to human diseases. Coronary artery disease is one of the most common age-related health problems in developed countries. Nevertheless, the specific role of cellular ageing in this process is still unclear. In this study, we analyze the possible prognostic value of telomere length and telomerase polymorphisms in a population of 150 middle aged males (mean age 62 ± 7) admitted for acute coronary syndrome who were followed up for more than 600 days. Peripheral blood samples were obtained and relative and comparative qPCR was used to measure telomere length and real time PCR to study the polymorphisms. Two prognostic combined events were defined. Long telomere length was revealed as an independent predictor (protector) of combined event presentation during long term follow up in our patients.     

Assessment of candidate ocular biomarkers of ageing in a South African adult population: Relationship with chronological age and systemic biomarkers

Certain anatomic and functional parameters of the eye change with increasing chronological age. They may, therefore, serve as potential biomarkers of ageing. We investigated associations between four such ocular parameters (lens density, retinal vessel calibre, corneal endothelial cells and retinal nerve fibre layer thickness) and two ‘cellular’ biomarkers of ageing (leukocyte telomere length and CDKN2A expression), with frailty (a clinical correlate of biological ageing) in a population of South African adults. All ocular parameters revealed an association with either telomere length or CDKN2A expression. However, lens density was most strongly correlated with age, increased CDKN2A expression, and with frailty (p = 0.05 and 0.03, respectively). Narrow retinal arteriolar diameter, associated with increased chronological age, was also associated with increased CDK2NA expression (0.42 vs. 0.31, p = 0.02) but not with frailty. Ocular parameters may aid in determining biological age, warranting investigation in longitudinal studies.     

Altered phenotype and function of NK cells infiltrating Human Papillomavirus (HPV)-associated genital warts during HIV infection

HIV-infected individuals experience more persistent HPV infections and are less likely to resolve genital warts. This study compared phenotype and functions of NK and T cells from genital warts and blood from 67 women. We compared in vitro functional responses of NK and T cells by multiparametric flow cytometry. HIV + women had significantly lower frequencies of CD4 T cells in warts (p = 0.001) and blood (p = 0.001). While the distribution of NK cell subsets was similar, HIV + women tended to have lower frequencies of CD56^Dim NK cells in both blood (p = 0.0001) and warts (p = 0.006) than HIV − women. Wart NK cells from HIV + women expressed significantly lower CD107a and produced IFN-γ. HAART status was not associated with differences in NK cell functionality. We conclude that wart NK cells from HIV + women have defects in their ability to degranulate and/or secrete IFN-γ, which may provide insights into why HIV + women fail to spontaneously resolve genital warts.     

High expression of OX40 (CD134) and 4-1BB (CD137) molecules on CD4+CD25high cells in children with type 1 diabetes

PurposeDespite the rapidly rising incidence of diabetes in children, with the highest rise in children < 5 years of age, data on mechanisms that trigger severe beta-cells damage are limited. The aim of the study was to assess the frequency of OX40 (CD134) or 4-1BB (CD137) positive cells in the peripheral blood of children with newly diagnosed type 1 diabetes (T1D) in comparison to healthy controls.Material/methodsThe study included 33 children (mean age 7.3 ± 5.4 years) with newly diagnosed T1D and 39 age-matched healthy controls. Separate analysis was performed in children < 5 years. Flow cytometric analysis was performed using the following markers: CD4, CD25, CD137, and CD134. Fasting C-peptide level was assessed as well.ResultsThe frequency of CD4⁺CD25^highOX40⁺ was higher in T1D children than in controls (median value 3.58% vs. 1.1%, respectively; p = 0.003). Moreover, T1D children had higher frequency of CD4⁺CD25^high4-1BB⁺ cells than healthy subjects (median value 5.76% vs. 3.74%, respectively; p = 0.037). A significant correlation was noted between the age of diabetic children and the C-peptide level (r = 0.54, 95% CI [0.19–0.77], p = 0.004). In comparison with age-matched controls, children < 5 years had higher frequency of CD4⁺CD25^highOX40⁺ (p = 0.004) and CD4⁺CD25^high4-1BB⁺ cells (p = 0.079).ConclusionsOur study showed higher frequency of both OX40 and 4-1BB positive cells in T1D children in comparison to controls. It seems that observed differences might be more pronounced in children < 5 years of age than in older subjects. Further clinical studies are needed to determine the age-related differences in the immune system, in the pathogenesis of T1D.     

Exploration on the effect of predeposit autotransfusion on bone marrow hematopoiesis after femoral shaft fracture

ObjectiveBy observing the changes in the number and activity of CD34+ cells in bone marrow after predeposit autotransfusion (PAT) to patients with femoral shaft fracture (FSF), to evaluate the effects of PAT on hematopoietic function and hematopoietic stem cells in bone marrow.MethodsSelected FSF patients were randomly divided into 2 groups: the control group (patients did not receive blood transfusion after surgery) and PAT group (patients received PAT after surgery). The content of RBC and Plt in blood samples were counted by blood routine. The cell cycle and proportion of CD34+ myelinated cells in blood samples was analyzed by flow cytometry. The telomere DNA length of hematopoietic stem cells (HSCs) in the control groups and PAT group at postoperation 24 was analyzed by southern blot.ResultsThe content of RBC and Plt in postoperation 6 h and 24 h in the control group was evidently higher compared to that in PAT group, while Hb content in control group was significantly lower compared to that in PAT group. The proportion of CD34+ myelinated cells in post-transfusion 6 h and postoperation 24 h in PAT group was evidently higher compared to that in the control group. In PAT group, S phase at postoperation 24 h was significantly larger compared to that at post-transfusion 6 h. The telomere DNA length of HSCs in PAT group was longer than that in the control group.ConclusionPAT can increase the number of HSC, while does not cause the abnormal aging of HSCs. PAT is suitable for postoperative blood transfusion of patients with FSF.     

Testostérone libre ou biodisponible : dosages ou calculs. Comparaison critique de différents modes d'approche

The aim of the study is to find the most reliable practical approach to the estimation of free or bioavailable serum testosterone. We compare assayed values of bioavailable testosterone (T Bio), Free testosterone DPC (Free T DPC), total testosterone (Ttot) and calculated Free Androgen Index FAI = [Ttot/SHBG] × 100, calculated Free Testosterone using the equation derived from the law of mass action for the model: two binding proteins (SHBG, Albumin) and two ligands (T,E₂) (FTc_II Södergaard) or one ligand (T) (Ftc_I Kaufman and Fiers). Serum SHBG, Albumin, E₂ are determined exprimentally in every sample. The bioavailable (or non-SHBG bound) T correlates well with Free T by ultrafiltration (r = 0.96; P < 0.01), is easy to perform, reliable and sensitive if a particular care is ensured in the purification of the tracer. Assayed women values of T Bio agreed well with calculated values for FTc _II or FTc _I (r = 0.93; P < 0.01) using the laws of mass action. In contrast, the ratios of FTc _II/T Bio and FTc _I/T Bio (which should be constant if indexes reflect T Bio) remain negatively SHBG dependent for women and positively SHBG dependent for men confirming that the assumptions of the model are too simplified and the association constants Ka values too approximative. Calculated FTc is an acceptable substitute for an estimation of bioavailable T if we presume women with standard SHBG binding conditions and sera free of significant amounts of substances or steroids that could occupy the binding sites in the SHBG moiety and invalidate the calculation. Although showing a good correlation (r = 0.89; P < 0.01) with T Bio, FAI is not a useful index: the FAI/T Bio ratio is negatively correlated (r = –0.86 P < 0.001) with SHBG and overestimate strongly the SHBG binding capacity contribution for a reliable quantification of the non-SHBG bound T. The Free T DPC is inaccurate, not sufficiently sensitive, not free of proteins effects and less correlated with T Bio (r = 0.49; P < 0.05) than Ttot (r = 0.64; P < 0.01) for women!     

Effect of IL6 and IL23 on double negative T cells and anti ds-DNA in systemic lupus erythematosus patients

Several evidences suggest that DN T cells, IL23 and IL6 play a role in the pathogenesis of SLE. This study aimed to evaluate the frequency of DN T cells in SLE patients and the relation to their activity also to assess the possible role of IL6 and IL23 on DN T cells. Thirty patients with SLE and sixteen healthy blood donor females were enrolled. There was a significant increase in DN T cells in patients than controls (P = 0.001). These cells had a significant positive correlation with SLEDAI (r = 0.486, P = 0.006). DN T cells from SLE patient samples were expanded when stimulated in vitro with RhIL6 or RhIL23 in patients than controls. Furthermore, anti ds-DNA level was found to be increased in supernatant of PBMCs when stimulated by these cytokines in different concentrations. Our findings suggest that IL6 and IL23 may play role in SLE pathogenesis through their effect on DN T cells and anti ds-DNA.     

Association of cardiac autonomic neuropathy with alteration of sympatho-vagal balance through heart rate variability analysis

Early sub-clinical assessment of severity of cardiac autonomic neuropathy (CAN) and intervention are of prime importance for risk stratification and early treatment in preventing sudden death due to silent myocardial infarction. The Ewing battery is currently the diagnostic tool of choice but is unable to detect sub-clinical disease and requires patient cooperation. Time and frequency domain analysis have several shortcomings including sensitivity to recording length, respiratory activity and non-stationarities in the ECG signal. An important step forward is to have a non-invasive method of detecting CAN that is robust against these shortcomings and has a higher sensitivity for the presence of both sub-clinical and overt clinical disease. This study presents a novel parameter, tone–entropy (T–E) that analyses heart rate variability (HRV) of 20 min lead II ECG recordings. Tone (T) represents sympatho-vagal balance and entropy (E) the autonomic regularity activity. Thirteen normal subjects without (CAN?) and 21 with CAN (CAN+) participated in this study. Among 21 CAN+ subjects, 13 are early CAN+ (eCAN+), eight are definite CAN+ (dCAN+) according to autonomic nervous system function tests as described by Ewing. The results showed that tone was higher and the entropy was lower in the dCAN+ group (T = ?0.033 to ?0.010 and E = 1.73–2.24) compared with the eCAN+ (T = ?0.0927 to ?0.0311 and E = 2.0–2.65) and normal (T = ?0.128 to ?0.0635 and E = 2.64–3.15) group. The research verified that T–E is a suitable method to determine the presence of CAN that correctly identifies experimentally induced changes in cardiac function akin to parasympathetic and sympathetic dysfunction and differentiates between stages in CAN disease progression identified using the Ewing battery.     

CD28 and PTPN22 are associated with susceptibility to rheumatoid arthritis in Egyptians

ObjectiveLimited data are available on the genetics of rheumatoid arthritis (RA) in Egyptians. Therefore, we investigated whether the confirmed genetic risk factors for RA in Europeans and/or Asians contribute to RA susceptibility in Egyptians.Subjects and methodsA set of seven single-nucleotide polymorphisms (SNPs) in the vicinity of CD28, TNFAIP3, PTPN22, PADI4 and HLA-DRA were tested in a large multi-centric RA cohort in Egypt, consisting of 394 cases and 398 matched controls. Patients were stratified based on the positivity of either anti-citrullinated protein antibodies (ACPAs) or rheumatoid factor (RF).ResultsSignificant association was evident for three SNPs in this cohort: the CD28 (rs1980422) variant showed a strong association in the whole cohort (P = 0.000119) and in seropositive subsets of the disease (P_ACPA+ = 0.004; P_RF+ = 0.0005). Upon stratification, the PTPN22 (rs2476601) and TNFAIP3(rs5029939) variants showed association only with ACPA positive (P_ACPA+ = 0.00573) and negative (P_ACPA− = 0.00999) phenotypes, respectively.ConclusionOur results suggest that CD28(rs1980422) and PTPN22(rs2476601) contribute to RA-susceptibility in Egyptians. Failure to replicate the association of PADI4(rs2240340)/(PADI4_94) in Egyptian RA patients provides further support for the notion that genetic architecture of RA is different in multiple populations of European, Asian, African, and Middle Eastern ancestries. Further investigation using large-scale studies is thus needed to maximize the power of genetic association.     

HHV-6 cell receptor CD46 expression on various cell subsets of six blood and graft sources: A prospective series

BackgroundCord Blood (CB) are increasingly used as an alternative stem cells source in adults for allogeneic Stem Cell Transplantation (allo-SCT). The risk of human herpesvirus (HHV-6) reactivation is significantly higher after CB transplant vs unrelated peripheral blood stem cells (PBSC) allo-SCT. Higher HHV-6 cell receptor CD46 expression on progenitor cells in CB may explain this difference.ObjectivesTo prospectively compare the HHV-6 cell receptor CD46 expression on various cell subsets of three freshly harvested blood sources on one hand and of three graft sources on the other hand.Study design52 samples were used for the purpose of this study. They were issued from peripheral blood (PB, n = 10), G-CSF mobilised PB (GCSF-PB, n = 10), cord blood (CB, n = 10), unmanipulated bone marrow (uBM, n = 5), leukapheresis product (LP, n = 10) and thawed CB graft (n = 7). CD46 expression was assessed by FACS analysis on total lymphocytes, monocytes, NK cells, T and B cells subsets, plasmacytoid (pDCs) dendritic cells and stem cells.ResultsAs all cell subsets were found CD46 positive, CD46 mean fluorescence intensity (MFI) was then considered for comparison between the three blood sources and the three graft sources. The most impressive result observed was that HHV-6 cell receptor CD46 expression was significantly reduced in almost all cell components of thawed CB graft compared to other graft sources.ConclusionsThis original study shows strong differences in term of quantitative CD46 expression between several blood and grafts samples. Our results suggest that other factors than the qualitative CD46 expression play a role in the higher HHV-6 reactivation observed after CB transplant in adults.     

CD38 gene polymorphisms and genetic predisposition to multiple myeloma

Single nucleotide polymorphisms (SNPs) of adhesion and signaling genes may influence the etiopathogenesis of multiple myeloma (MM). CD38 molecule and its ligand CD31 are expressed and interact in malignant plasma cells and MM microenvironment. In this study we evaluated allele frequencies and distribution of two potentially functional CD38 SNPs, intronic rs6449182 (184C>G) and missense rs1800561 (418C>T, Arg¹⁴⁰Trp) in 175 Caucasian patients with MM and 207 healthy blood donors. The carriers of variant G allele of the rs6449182 SNPs were found to have significantly elevated risk of MM as compared to non-carriers; odds ratio = 5.69 (95% confidence interval = 3.7–8.7), p < 0.0001. In contrast, rs1800561 SNP minor T allele was detected at very low and comparable frequencies in patients and controls groups. In conclusion, our data suggest that inherited genetic variation in CD38 gene may impact on the risk of MM development.     

A tug-of-war between tolerance and rejection – New evidence for 3′UTR HLA-G haplotypes influence in recurrent pregnancy loss

HLA-G is a molecule essential to the maintenance of the maternal-fetal interface tolerance, thus contributing to a healthy pregnancy. Here we investigate the role of HLA-G single nucleotide polymorphisms (SNPs) and whether a specific HLA-G haplotype influence or not recurrent pregnancy loss (RPL) risk. A total of 296 DNA samples from RPL (N = 140) and controls (N = 156) were evaluated. The HLA-G 3′UTR region was sequenced and eight major SNPs were evaluated (14pb insertion/deletion, +3003T/C, +3010C/G, +3027C/A, +3035C/T, +3142G/C, +3187A/G, +3196C/G). A high linkage disequilibrium (LD) among all pairs and a perfect LD between +3010C/G and +3142G/A (D′ = 1.0, r² = 1.0) were observed. Our data showed an increased risk to +3010CC genotype carriers in comparison with control [odds ratio (OR) 2.05 95% confidence interval (CI) 1.05–4.00, p = 0.035] and to a decreased risk of RPL in +3142CC genotype carriers (OR = 0.49 95%CI 0.25–0.95, p = 0.035) and +3187AG genotype carriers (OR = 0.58 95%CI 0.35–0.94, p = 0.029). A total of eight haplotypes were observed in the sample, being UTR-1 and UTR-2 the most represented. An association between UTR-1 haplotype carriers with a reduced risk of both RPL and secondary RPL was observed. Our results indicate that the HLA-G 3′UTR plays important roles in RPL and might be an important marker of susceptibility to this, and possible to other, pregnancy disorders.     

In vivo reduction of telomere length in human antigen-reactive memory T cells

There is a reduction in the average telomere lengths of CD4+ "memory" T cells, defined by the CD45RO+ phenotype, compared to CD54RA+ "naive" T cells. However, other studies suggest that telomerase activity often is sufficient to maintain the telomere length of certain B and T cell populations following immune activation in vivo. Thus it is uncertain whether genuine memory CD4+ T cells, defined by an immune response to specific recall antigens, would display telomeres of reduced length, or whether telomere size would be maintained. Therefore, we examined the telomere lengths of T cells responding to two common recall antigens, tetanus toxoid and Candida albicans. Telomere terminal restriction fragment length was assessed by Southern blots or by flow cytometry following in situ hybridization with telomere-specific peptide nucleic acid probes. For the five subjects tested, the Candida- or tetanus-reactive memory T cell populations demonstrated a significant reduction of telomere length even when compared to the phenotypically defined memory CD45RO+ T cell populations isolated from peripheral blood mononuclear cells. This finding suggests that telomerase activity does not fully compensate for the effects of in vivo activation and proliferation of some antigen-specific CD4+ T cell populations. This may contribute to immune senescence.     

IL28B gene variants and glucose metabolism in Type 2 Diabetes

Type 2 Diabetes (T2D) develops, when β-cell insulin response fails to compensate for insulin resistance. Recent studies reported associations between the IL28B polymorphisms (rs12979860 and rs8099917) and T2D development in Hepatitis C virus (HCV) patients. To identify possible association with T2D independent from virus infection, we investigated both IL28B polymorphisms in T2D patients and healthy controls (HC). No association was found comparing the genotype and allele frequencies of both IL28B polymorphisms between T2D patients and HC. However, higher glucose levels were found in T2D patients carrying the IL28B CT/TT rs12979860 and GT/GG rs8099917 HCV risk genotypes compared to those with the protective CC and TT genotype (p = 0.06 and p = 0.02, respectively). Moreover, T2D patients with CT/TT rs12979860 HCV risk genotypes possessed significantly higher HbA1c levels than CC carriers (p = 0.04). In conclusion, the IL28B HCV risk genotypes may influence glucose homeostasis in T2D patients without HCV.     

A dual role for Mannan-binding lectin-associated serine protease 2 (MASP-2) in HIV infection

BackgroundMannan-binding lectin (MBL) – associated serine protease 2 (MASP-2) co-activates the lectin pathway of complement in response to several viral infections. The quality of this response partly depends on MASP2 gene polymorphisms, which modulate MASP-2 function and serum levels. In this study we investigated a possible role of MASP2 polymorphisms, MASP-2 serum levels and MBL-mediated complement activation in the susceptibility to HIV/AIDS and HBV/HCV coinfection.MethodsA total of 178 HIV patients, 89 (50%) coinfected with HBV/HCV, 51.7% female, average age 40 (12–73) years, and 385 controls were evaluated. MASP-2 levels and MBL-driven complement activation were evaluated by enzyme-linked immunosorbent assay and 11 MASP2 polymorphisms from the promoter to the last exon were haplotyped using multiplex sequence-specific PCR.ResultsGenotype distribution was in Hardy-Weinberg equilibrium and differed between HIV+ patients and controls (P = 0.030), irrespective of HBV or HCV coinfection. The p.126L variant, which was associated with MASP-2 levels <200 ng/mL (OR = 5.0 [95%CI = 1.3–19.2] P = 0.019), increased the susceptibility to HIV infection (OR = 5.67 [95%CI = 1.75–18.33], P = 0.004) and to HIV + HBV+ status (OR = 6.44 [95%CI = 1.69–24.53, P = 0.006). A similar association occurred with the ancient haplotype harboring this variant, AGCDV (OR = 2.35 [95%CI = 1.31–4.23], P = 0.004). On the other hand, p.126L in addition to other variants associated with low MASP-2 levels—p.120G, p.377A and p.439H, presented a protective effect against AIDS (OR = 0.25 [95%CI = 0.08–0.80], P = 0.020), independently of age, sex, hepatic function and viral load. MASP-2 serum levels were lower in HIV+ and HIV + HBV+ patients than in controls (P = 0.0004). Among patients, MASP-2 levels were higher in patients with opportunistic diseases (P = 0.001) and AIDS (P = 0.004). MASP-2 levels correlated positively with MBL/MASP2-mediated C4 deposition (r = 0.29, P = 0.0002) and negatively with CD4+ cell counts (r = −0.21, P = 0.018), being related to decreased CD4+ cell counts (OR = 5.8 [95%CI = 1.23–27.5, P = 0.026).ConclusionsGenetically determined MASP-2 levels seem to have a two-edge effect in HIV and probably HCV/HBV coinfection, whereas low levels increase the susceptibility to infection, but on the other side protects against AIDS.