A Decreased Frequency of Regulatory T Cells in Patients with Common Variable Immunodeficiency

Introduction: Common variable immunodeficiency disorder (CVID) is a heterogeneous syndrome, characterized by deficient antibody production and recurrent bacterial infections in addition abnormalities in T cells. CD4(+)CD25(high) regulatory T cells (Treg) are essential modulators of immune responses, including down-modulation of immune response to pathogens, allergens, cancer cells and self-antigens.Objective: in this study we set out to investigate the frequency of Treg cells in CVID patients and correlate with their immune activation status.Materials and Methods: Sixteen patients (6 males and 10 females) with CVID who had been treated with regular intravenous immunoglobulin and 14 controls were enrolled. Quantitative analyses of peripheral blood mononuclear cells (PBMC) were performed by multiparametric flow cytometry using the following cell markers: CD38, HLA-DR, CCR5 ( immune activation); CD4, CD25, FOXP3, CD127, and OX40 (Treg cells); Ki-67 and IFN-gamma (intracellular cytokine).Results: A significantly lower proportion of CD4(+)CD25(high) FOXP3 T cells was observed in CVID patients compared with healthy controls (P<0.05). in addition to a higher proportion of CD8(+) T cells from CVID patients expressing the activation markers, CD38(+) and HLA-DR(+) (P<0.05), we observed no significant correlation between Tregs and immune activation.Conclusion: Our results demonstrate that a reduction in Treg cells could have impaired immune function in CVID patients.Universidade Federal de São Paulo, São Paulo, BrazilUniversidade Federal de São Paulo, São Paulo, BrazilWeb of Scienc

Invariant Natural Killer T-cells and their subtypes may play a role in the pathogenesis of endometriosis

Objective: To evaluate the frequencies of iNKT cells and their subsets in patients with deep endometriosis. Methods: A case-control study was conducted between&nbsp;2013 and&nbsp;2015, with&nbsp;73&nbsp;patients distributed into two groups: 47&nbsp;women with a histological diagnosis of endometriosis and&nbsp;26&nbsp;controls. Peripheral blood, endometriosis lesions, and healthy peritoneal samples were collected on the day of surgery to determine the frequencies of iNKT cells and subtypes via flow cytometry analysis. Results: The authors observed a lower number of iNKT (p&nbsp;=&nbsp;0.01) and Double-Negative (DN) iNKT cells (p&nbsp;=&nbsp;0.02) in the blood of patients with endometriosis than in the control group. The number of DN iNKT IL-17+ cells in the secretory phase was lower in the endometriosis group (p&nbsp;=&nbsp;0.049). There was an increase in the secretion of IL-17 by CD4+ iNKT cells in the blood of patients with endometriosis and severe dysmenorrhea (p&nbsp;=&nbsp;0.038), and severe acyclic pelvic pain (p&nbsp;=&nbsp;0.048). Patients with severe dysmenorrhea also had a decreased number of CD4+ CCR7+ cells (p&nbsp;=&nbsp;0.022). Conclusion: The decreased number of total iNKT and DN iNKT cells in patients with endometriosis suggests that iNKT cells play a role in the pathogenesis of endometriosis and can be used to develop new diagnostic and therapeutic agents

Lower numbers of natural killer T cells in HIV-1 and Mycobacterium leprae co-infected patients

Natural killer T (NKT) cells are a heterogeneous population of lymphocytes that recognize antigens presented by CD1d and have attracted attention because of their potential role linking innate and adaptive immune responses. Peripheral NKT cells display a memory-activated phenotype and can rapidly secrete large amounts of pro-inflammatory cytokines upon antigenic activation. In this study, we evaluated NKT cells in the context of patients co-infected with HIV-1 and Mycobacterium leprae. The volunteers were enrolled into four groups: 22 healthy controls, 23 HIV-1-infected patients, 20 patients with leprosy and 17 patients with leprosy and HIV-1-infection. Flow cytometry and ELISPOT assays were performed on peripheral blood mononuclear cells. We demonstrated that patients co-infected with HIV-1 and M.leprae have significantly lower NKT cell frequencies [median 0.022%, interquartile range (IQR): 0.0070.051] in the peripheral blood when compared with healthy subjects (median 0.077%, IQR: 0.0320.405, P &lt; 0.01) or HIV-1 mono-infected patients (median 0.072%, IQR: 0.0300.160, P &lt; 0.05). Also, more NKT cells from co-infected patients secreted interferon-? after stimulation with DimerX, when compared with leprosy mono-infected patients (P = 0.05). These results suggest that NKT cells are decreased in frequency in HIV-1 and M.leprae co-infected patients compared with HIV-1 mono-infected patients alone, but are at a more activated state. Innate immunity in human subjects is strongly influenced by their spectrum of chronic infections, and in HIV-1-infected subjects, a concurrent mycobacterial infection probably hyper-activates and lowers circulating NKT cell numbers.National Institutes of Health [R01-AI52731, AI060379]Fogarty International Center [D43 TW00003]Fundacao de Amparo a Pesquisa do Estado de Sao Paulo [04/15856-9/Kallas, 2010/05845-0/Kallas]Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)Brazilian Ministry of Science and Technology [484230/2011-5]New York Community Trus

Expansion of a subset of CD14(high)CD16(neg)CCR2(low/neg) monocytes functionally similar to myeloid-derived suppressor cells during SIV and HIV infection

Monocytes have been categorized in three main subpopulations based on CD14 and CD16 surface expression. Classical monocytes express the CD14(++)CD16(-) CCR2(+) phenotype and migrate to inflammatory sites by quickly responding to CCL2 signaling. Here, we identified and characterized the expansion of a novel monocyte subset during HIV and SIV infection, which were undistinguishable from classical monocytes, based on CD14 and CD16 expression, but expressed significantly lower surface CCR2. Transcriptome analysis of sorted cells demonstrated that the CCR2(low/neg) cells are a distinct subpopulation and express lower levels of inflammatory cytokines and activation markers than their CCR2(high) counterparts. They exhibited impaired phagocytosis and greatly diminished chemotaxis in response to CCL2 and CCL7. In addition, these monocytes are refractory to SIV infection and suppress CD8(+) T cell proliferation in vitro. These cells express higher levels of STAT3 and NOS2, suggesting a phenotype similar to monocytic myeloid-derived cells, which suppress expansion of CD8(+) T cells in vivo. They may reflect an antiproliferative response against the extreme immune activation observed during HIV and SIV infections. In addition, they may suppress antiviral responses and thus, have a role in AIDS pathogenesis. Antiretroviral therapy in infected macaque and human subjects caused this population to decline, suggesting that this atypical phenotype is linked to viral replication. J. Leukoc. Biol. 91: 803-816; 2012.National Institutes of HealthNational Institutes of Health [MH070306, NS055648, MH085554]Ministry of Health [914/BRA/3014-UNESCO/Kallas]Ministry of HealthSao Paulo City Health Department [2004-0.168.922-7/Kallas]Sao Paulo City Health DepartmentFundacao de Amparo a Pesquisa do Estado de Sao PauloFundacao de Amparo a Pesquisa do Estado de Sao Paulo [04/15856-9/Kallas]Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES)Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES)Brazilian Ministry of EducationBrazilian Ministry of EducationBrazilian Program for STD and AIDSBrazilian Program for STD and AID

HTLV-1 Tax Specific CD8+ T Cells Express Low Levels of Tim-3 in HTLV-1 Infection: Implications for Progression to Neurological Complications

The T cell immunoglobulin mucin 3 (Tim-3) receptor is highly expressed on HIV-1-specific T cells, rendering them partially “exhausted” and unable to contribute to the effective immune mediated control of viral replication. To elucidate novel mechanisms contributing to the HTLV-1 neurological complex and its classic neurological presentation called HAM/TSP (HTLV-1 associated myelopathy/tropical spastic paraparesis), we investigated the expression of the Tim-3 receptor on CD8+ T cells from a cohort of HTLV-1 seropositive asymptomatic and symptomatic patients. Patients diagnosed with HAM/TSP down-regulated Tim-3 expression on both CD8+ and CD4+ T cells compared to asymptomatic patients and HTLV-1 seronegative controls. HTLV-1 Tax-specific, HLA-A*02 restricted CD8+ T cells among HAM/TSP individuals expressed markedly lower levels of Tim-3. We observed Tax expressing cells in both Tim-3+ and Tim-3− fractions. Taken together, these data indicate that there is a systematic downregulation of Tim-3 levels on T cells in HTLV-1 infection, sustaining a profoundly highly active population of potentially pathogenic T cells that may allow for the development of HTLV-1 complications

Skewed Distribution of Circulating Activated Natural Killer T (NKT) Cells in Patients with Common Variable Immunodeficiency Disorders (CVID)

Common variable immunodeficiency disorder (CVID) is the commonest cause of primary antibody failure in adults and children, and characterized clinically by recurrent bacterial infections and autoimmune manifestations. Several innate immune defects have been described in CVID, but no study has yet investigated the frequency, phenotype or function of the key regulatory cell population, natural killer T (NKT) cells. We measured the frequencies and subsets of NKT cells in patients with CVID and compared these to healthy controls. Our results show a skewing of NKT cell subsets, with CD4+ NKT cells at higher frequencies, and CD8+ NKT cells at lower frequencies. However, these cells were highly activated and expression CD161. The NKT cells had a higher expression of CCR5 and concomitantly expression of CCR5+CD69+CXCR6 suggesting a compensation of the remaining population of NKT cells for rapid effector action

Sequence analysis of 5' regulatory regions of the Machado-Joseph Disease gene (ATXN3)

Machado–Joseph disease (MJD) is a late-onset autosomal dominant neurodegenerative disorder, which is caused by a coding (CAG)n expansion in the ATXN3 gene (14q32.1). The number of CAG repeats in the expanded alleles accounts only for 50 to 75 % of onset variance, the remaining variation being dependent on other factors. Differential allelic expression of ATXN3 could contribute to the explanation of different ages at onset in patients displaying similar CAG repeat sizes. Variation in 5′ regulatory regions of the ATXN3 gene may have the potential to influence expression levels and, ultimately, modulate the MJD phenotype. The main goal of this work was to analyze the extent of sequence variation upstream of the ATXN3 start codon. A fragment containing the core promoter and the 5′ untranslated region (UTR) was sequenced and analyzed in 186 patients and 59 controls (490 chromosomes). In the core promoter, no polymorphisms were observed. In the 5′ UTR, only one SNP (rs3814834) was found, but no improvements on the explanation of onset variance were observed, when adding its allelic state in a linear model. Accordingly, in silico analysis predicted that this SNP lays in a nonconserved position for CMYB binding. Therefore, no functional effect could be predicted for this variant.Institute of Biotechnology and Biomedicine of the Azores - “High Prevalence Diseases in the Azores Islands” M2.1.2/I/026/2008,Fundação para a Ciência e a Tecnologia (FCT) - “Transcriptional variation of the ATXN3 gene as modulator of the clinical heterogeneity in Machado–Joseph disease (MJD)Secretaria Regional da Ciência, Tecnologia e Equipamentos - M3.1.3/F/004/2009CNP

Alguns dados sobre a Fauna entomológica da ilha das Flores - Açores

IV Expedição Científica do Departamento de Biologia - Flores 1989Com este trabalho, realizado em Julho de 1989 nas Flores - a ilha mais ocidental do Arquipélago dos Açores -, acrescentaram-se onze espécies de Lepidópteros à lista referenciada para aquela ilha, pertencendo uma à família Lycaenidae (Lampides boeticus L.), oito a familia Noctuidae (Agrotis ipsilon HFN., Brotolomia meticulosa L., Chrysodeixis chalcites ESPER., Heliothis armigera HBN., Noctua atlantica WARREN, Noctua pronuba L., Peridroma saucia HBN., Sesamia nonagrioides LEF.), uma à família Nymphalidae (Vanessa atalanta L.) e uma a família Pyralidae (Glyphodes unionalis HBN.). Entre os demais insectos, foram identificadas cerca de duas dezenas e meia de espécies, distribuídas pelas Ordens Dermaptera, Orthoptera, Dictyoptera, Heteroptera, Homoptera, Coleoptera, Neuroptera, Diptera, Hymenoptera e Collembola. Salienta-se ainda a importância, do ponto de vista agronómico, das pragas Mythimna unipuncta (HAWORTH) e Xestia c-nigrun L. naquela ilha.RÉSUMÉ: Avec ce travail, réalisé en Juillet 1989 a Flores - l'île plus occidental de l'archipel des Açores, onze espèces de Lépidoptères ont été ajoutées à la liste des espèces connus pour cette île, dont une appartient a la famille Lycaenidae (Lampides boelicus L.), huit à la famille Noctuidae (Agrotis ipsilon HFN., Brotolomia meticulosa L. Chrysodeicis chalcites ESPER., Heliothis armigera HBN., Noctua atlantica WARREN, Noctua pronuba L., Peridroma saucia HBN., Sesamia nonagrioides LEF.), une à la famille Nymphalidae (Vanessa atalanta L.) et une à la famille Pyralidae (Glyphodes unionalis HBN.). Parmi les autres insects ont été identifiés environ deux dizaines et demie d'espèces, lesquelles sont réparties par les Ordres Dermaptera, Orthoptera, Dictyoptera, Heteroptera, Homoptera, Coleoptera, Neuroptera, Diptera, Hymenoptera et Collembola. On remarque I'importance, du point de vue agronomique, des ravageurs Mythimna unipuncra (HAWORTH) et Xestia c-nigrum L. dans cette île

Characterization of Dengue Virus Type 2: New Insights on the 2010 Brazilian Epidemic

Dengue viruses (DENV) serotypes 1, 2, and 3 have been causing yearly outbreaks in Brazil. In this study, we report the re-introduction of DENV2 in the coast of São Paulo State. Partial envelope viral genes were sequenced from eighteen patients with dengue fever during the 2010 epidemic. Phylogenetic analysis showed this strain belongs to the American/Asian genotype and was closely related to the virus that circulated in Rio de Janeiro in 2007 and 2008. The phylogeny also showed no clustering by clinical presentation, suggesting that the disease severity could not be explained by distinct variants or genotypes. The time of the most recent common ancestor of American/Asian genotype and the São Paulo and Rio de Janeiro (SP/RJ) monophyletic cluster was estimated to be around 40 and 10 years, respectively. Since this virus was first identified in Brazil in 2007, we suggest that it was already circulating in the country before causing the first documented outbreak. This is the first description of the 2010 outbreak in the State of São Paulo, Brazil, and should contribute to efforts to control and monitor the spread of DENVs in endemic areas