An overview of the immune response and Arginase I on CHIKV immunopathogenesis.

Chikungunya virus (CHIKV) is mosquito-borne alphavirus that has caused epidemics around the world. Many individuals affected by the disease may experience joint pain that persists for months after the acute phase. The pathophysiology of viral arthritis is not completely elucidated. And it is important to emphasize that the effects of the viral infection in each host may depend on host factors that include immune response, as well as factors specific to the virus as tissue tropism. The main pathway for the response against viral infection is through induction of type I interferon (IFN-I), whose function is important to control viral replication. Beside this, T cell and macrophage mediated immunopathology in CHIKV infections has been reported. It has been demonstrated that some association with the Arginase I and macrophages type II are involved in the infection profile along with myeloid-derived suppressor cells (MDSC) that are responsible for T cell suppression. Therefore, in this review, will be discuss an overview on CHIKV immunopathogenesis and the importance of Arginase I.

An association between chronic life stressors prior to diagnosis of breast cancer.

The clinical course of breast cancer (BC) and survival depend on a wide range of risk factors. From the psychosomatic point of view, BC is one of the most studied type of cancer but there is no evidence available for this relation. Therefore, in the present study we evaluate the impact of chronic life stressors in BC patients. A total of 100 BC patients were invited to participate in an interview, when information about social parameters and emotional changes in the period prior to diagnosis were collected. The emotional changes were evaluated by the Holmes and Rahe's Stress Scale, which analyzes the difficulty required for a person to readjust to society after significant changes in their life. Clinicopathological parameters were obtained from the medical records. For all data, the level of significance adopted was p <0.05. It was observed that 55.2 % of the patients have a medium and 13.8 % were at high risk for disease development related to stressful events in the period prior to the BC diagnosis. The highest stress levels were presented by separated, divorced, or widowed patients compared to married (p <0.01) and single (p = 0.037) patients. The high-risk (HR) group had a lower proportion of positivity for estrogen receptor when compared to the low (LR) and moderate risk (MR) groups (p= 0.001). In addition, a binary logistic regression analysis was performed, and we found that the relationship between the estrogen receptor and the HR of chronic stress was independently associated with the histological type of BC and lymph nodes involvement. The relationship of stressful life experiences and BC is not well established, so our study collaborates with the literature to demonstrate the importance of stress as a factor associated with the development of BC.

Frequency of CCR5-Delta32 deletion in human immunodeficiency virus type 1 (HIV-1) in healthy blood donors, HIV-1-exposed seronegative and HIV-1-seropositive individuals of southern Brazilian population.

The frequency of CCR5-Delta32 allele in human immunodeficiency virus type 1 (HIV-1) infection in the southern Brazilian population was determined in a cross-sectional study carried out from October 2001 to June 2004. Genomic DNA was extracted from peripheral blood cells of 134 healthy blood donors, 145 HIV-1-exposed seronegative individuals, 152 HIV-1-seropositive asymptomatic individuals, and 478 HIV-1-seropositive individuals with AIDS. A fragment with 225 base-pairs of the CCR5 gene was amplified by polymerase chain reaction. The CCR5-Delta32 homozygous deletion was observed in 2 (1.5%) blood donors and in 1 (0.7%) individual HIV-1-exposed seronegative, and was absent among all the HIV-1-seropositive individuals (Fisher's exact test, p=0.0242). The frequency of the homozygous CCR5-Delta32 deletion in the HIV-1-exposed did not differ when compared with that observed in the HIV-1 seronegative blood donors (Fisher's exact test, p=0.6093; OR: 2.18, 95% CI: 0.11-129.6). The wild-type genotype CCR5/CCR5 frequency was higher among the HIV-1-seropositive with AIDS compared to HIV-1 seropositive asymptomatic individuals (Chi-square test, p=0.0263; OR: 2.02, 95% CI: 1.03-3.97). The absence of the homozygous deletion of CCR5-Delta32 among HIV-1-seropositive individuals underscored that this genotype is an important genetic factor associated with the decreased susceptibility to HIV-1 infection. The higher frequency of heterozygosity for the CCR5-Delta32 and the CCR5-Delta32 allele in HIV-1 seropositive asymptomatic compared to HIV-seropositive with AIDS individuals also underscored that this deletion could be associated with the delay of the HIV-1 disease progression in this population. However, the low frequency of CCR5-Delta32 homozygosity observed among HIV-1-exposed seronegative individuals shows that the allele could not explain, by itself, the natural resistance to HIV-1 infection and different mechanisms of protection against HIV-1 infection that must be involved in this population.

Association study of CCR5 delta 32 polymorphism among the HLA-DRB1 Caucasian population in Northern Paraná, Brazil.

Chemokines are important determinants of early inflammatory response. The CC chemokine receptor 5 (CCR5) delta 32 variant results in a nonfunctional form of the chemokine receptor and has been implicated in a variety of immune-mediated diseases. In the present study, polymerase chain reaction (PCR) for genomic deoxyribonucleic acid (DNA) samples, using specific CCR5 oligonucleotide primers surrounding the breakpoint deletion, detected a 225-basepair (bp) product from the normal CCR5 allele and a 193-bp product from the 32 bp deletion allele. Human leukocyte antigen (HLA) class II (DRB1) typing was performed by PCR-sequence-specific primer (PCR-SSP). The aim of this study was to evaluate the association of HLA-DRB1 and CCR5 genetic polymorphisms. To evaluate the frequency distributions of CCR5 delta 32 polymorphisms in a Brazilian population and their association with allelic distribution of HLA genes, DRB1; a total of 120 Caucasian individuals from northern Paraná, Brazil, were tested. The CCR5/CCR5 genotype was found in 108 individuals (90%) and only one carried the CCR5 delta 32 allele homozygous genotype (0.0238), while 12 (10%) carried the CCR5 delta 32 allele heterozygous genotype. The observed frequency for the CCR5 delta 32 allele was 0.05 in the population studied. The results revealed a CCR5 delta 32 allele occurrence with HLA-DRB1(*)01 and DRB1(*)04 (P<0.05). It is possible that HLA-DRB1(*)01 and DRB1(*)04 alleles could be associated with the delta 32-bp deletion of CCR5.

CCR5-Delta32 genetic polymorphism associated with benign clinical course and magnetic resonance imaging findings in Brazilian patients with multiple sclerosis.

The CCR5 chemokine receptor has been implicated in the pathogenesis of multiple sclerosis (MS). This research was carried out to investigate the association between the CCR5-Delta32 deletion in 124 patients with MS from Southern Brazil. Ninety-eight (79.0%) patients presented with relapsing-remitting MS (RR-MS), 17 (13.7%) secondary progressive MS (SP-MS), 8 (6.5%) primary progressive MS (PP-MS) and one (0.8%) clinically isolated syndrome (CIS). The control group consisted of 127 healthy blood donors from the same geographic region. The disease severity was assessed clinically using the Expanded Disability Status Scale (EDSS). Genomic DNA was extracted from peripheral blood cells and the genetic polymorphism was evaluated by polymerase chain reaction. Of the MS patients, 85 (68.5%) were females (p=0.0093). The CCR5-Delta32 frequency among the controls was 5.5%, and did not differ from that observed among the MS patients (4.8%) (p=0.7337). The mean (+/-SD) age at disease onset among the carriers and non-carriers of the CCR5-Delta32 allele was 31.7 (+/-11.1) and 36.6 (+/-12.0) years, respectively (p=0.1312). The duration (+/-SD) of the disease was 11.2 (+/-12.9) and 7.7 (+/- 5.6) years among the CCR5-Delta32 heterozygous, and CCR5 wild type, respectively (p=0.396). The mean (+/-SD) EDSS among the MS patients carriers and non-carriers of the CCR5-Delta32 allele was 2.4+/-1.2 and 2.67+/-2.2, respectively (p=0.9796). The MRI findings in MS patients with the CCR5-Delta32 genotype exhibited lower positive gadolinium enhancing-imaging (p=0.0013) and lower brain atrophy (p=0.1333) than MS patients with the CCR5 wild-type genotype. Despite that the differences were not significant, the results suggested that the disease onset and progression to disability may be prolonged in MS carriers of CCR5-Delta32, and CCR5-Delta32 could be considered a favorable prognostic biomarker of MS. Further studies comprising larger numbers of individuals carrying non-wild-type haplotypes are needed to determine CCR5-Delta32 involvement in the specific process of MS pathology and pathogenesis.

The effect of stromal cell-derived factor 1 (SDF1/CXCL12) genetic polymorphism on HIV-1 disease progression.

The human immunodeficiency virus type 1 (HIV-1) epidemic is increasing in Brazil, and little information has been reported about the genetic host factors related to HIV-1 infection in the Brazilian population. A polymorphism in the conserved 3' untranslated region of the stromal cell-derived factor 1 (SDF1/CXCL12) gene has been related either to resistance to HIV-1 infection and delayed progression to AIDS or to rapid disease progression and death. A longitudinal study was conducted to evaluate the association of the SDF1 polymorphism and the progression of HIV-1 infection in 161 asymptomatic patients infected with HIV-1 (ASYMPT) and 617 patients with AIDS (SYMPT) from Londrina and the surrounding region, southern Brazil. The endpoints used were the development of AIDS, death, and the slopes of the CD4+ T cell counts and HIV-1 RNA plasma levels. Among the 161 ASYMPT patients, all of the 7 patients (4.3%) homozygous for the mutation remained asymptomatic (p=0.1906); 6 of them had not initiated antiretroviral therapy. Among the 617 patients with AIDS, 40 (6.5%) progressed to death. Of these, 33/388 (8.5%) did not have the SDF1-3'A allele, 6/196 (3.1%) were heterozygous and 1/33 (3.0%) was homozygous for the SDF1-3'A allele (p=0.029). The SDF1 genotypes were not associated with the surrogate markers of HIV-1 disease progression such as the CD4+ T cell decline and plasma HIV-1 RNA levels. The results observed in this study support the hypothesis that the mutation of SDF1-3'A could have a possible late-stage protective effect on HIV-1 disease progression in the Brazilian population.

Genetic polymorphisms in glutathione-S-transferases are associated with anxiety and mood disorders in nicotine dependence.

BACKGROUND: Nicotine dependence is associated with an increased risk of mood and anxiety disorders and suicide. The primary hypothesis of this study was to identify whether the polymorphisms of two glutathione-S-transferase enzymes (GSTM1 and GSTT1 genes) predict an increased risk of mood and anxiety disorders in smokers with nicotine dependence. MATERIALS AND METHODS: Smokers were recruited at the Centre of Treatment for Smokers. The instruments were a sociodemographic questionnaire, Fagerström Test for Nicotine Dependence, diagnoses of mood disorder and nicotine dependence according to DSM-IV (SCID-IV), and the Alcohol, Smoking and Substance Involvement Screening Test. Anxiety disorder was assessed based on the treatment report. Laboratory assessment included glutathione-S-transferases M1 (GSTM1) and T1 (GSTT1), which were detected by a multiplex-PCR protocol. RESULTS: Compared with individuals who had both GSTM1 and GSTT1 genes, a higher frequency of at least one deletion of the GSTM1 and GSTT1 genes was identified in anxious smokers [odds ratio (OR)=2.21, 95% confidence interval (CI)=1.05-4.65, P=0.034], but there was no association with bipolar and unipolar depression (P=0.943). Compared with nonanxious smokers, anxious smokers had a greater risk for mood disorders (OR=4.67; 95% CI=2.24-9.92, P<0.001), lung disease (OR=6.78, 95% CI=1.95-23.58, P<0.003), and suicide attempts (OR=17.01, 95% CI=2.23-129.91, P<0.006). CONCLUSION: This study suggests that at least one deletion of the GSTM1 and GSTT1 genes represents a risk factor for anxious smokers. These two genes may modify the capacity for the detoxification potential against oxidative stress.

Association of tumor necrosis factor ß genetic polymorphism and sepsis susceptibility.

The association of the tumor necrosis factor ß (TNF-ß) Nco1 genetic polymorphism with susceptibility to sepsis was evaluated in 60 consecutive patients diagnosed with sepsis and in 148 healthy blood donors. Genomic DNA was extracted from peripheral blood cells and a 782 base-pair fragment of the TNF-ß gene was amplified by PCR. The PCR products were subjected to Nco1 restriction digestion and analysed by restriction fragment length polymorphism analysis. Tumor necrosis factor α (TNF-α) and the C-reactive protein (CRP) serum levels were also determined by ELISA and nephelometry, respectively. Among the septic patients, the allelic frequencies of TNFB1 and TNFB2 were 0.2833 and 0.7166, respectively, and they differed from those observed in the blood donors (p=0.0282). The TNFB2 allele frequency was higher in the septic patients than in the blood donors [odds ratio=1.65 (CI 95% 1.02-2.69), p=0.0315]. The TNF-α and CRP serum levels and the APACHE II and SOFA clinical scores did not differ in the patients with the TNFB1 or TNFB2 alleles (p>0.05). The results suggest that the TNFB2 allele is associated with susceptibility to sepsis, but it was not found to be associated with the immunological and clinical biomarkers of the disease.

Plasma malondialdehyde levels and CXCR4 expression in peripheral blood cells of breast cancer patients.

INTRODUCTION: Breast cancer is one of the most common neoplasms in women and is a leading cause of cancer related deaths worldwide. Chemokines and their receptors are involved in the control of lymphocyte traffic, a critical component of systemic immunity. CXCR4 mRNA could be involved in the development of variety of diseases. Lipid peroxidation, the result of nonenzymatic autooxidation of polyunsaturated fatty acids, presents numerous harmful effects on biological systems and has been implicated in diseases like cancer. This study examined CXCR4 mRNA expression in peripheral blood cells and malondialdehyde (MDA) in plasma from blood donors and breast cancer patients. MATERIALS AND METHODS: CXCR4 expression in peripheral blood cells from 59 breast cancer patients and 76 healthy blood donors was analyzed by real-time PCR. Plasma MDA was analyzed using high-performance liquid chromatography (HPLC). CONCLUSION: In all stages, MDA levels in total breast cancer patients (1.41 +/- 0.11) were significantly higher (P < 0.01) than those in healthy subjects (0.34 +/- 0.03). No statistically significant difference occurred between CXCR4 expression in peripheral blood cells from breast cancer patients (1.69 +/- 1.05) and the normal healthy control group (1.8 +/- 0.65). However, stage II samples differed statistically (4.3 +/- 1.72) from control, total cancer patients and stages I, III and IV samples.

Expression of noncoding mRNA in human blood cells activated with synthetic peptide of HIV.

T cells activation includes several steps such as translational events, activation of transcription for different genes, expression of surface molecules, secretion of cytokines, effectors functions. Knowledge has been accumulated on various nontranslatable RNA transcripts that are synthesized. In this context, a member of T cell noncoding transcripts (NTT) has been identified. It has been known that this gene is selectively expressed in activated T cells, as a 17-kb transcript. In this study, we investigate cell activation using RT-PCR to detect NTT. We investigated the expression of IFNgamma mRNA, a cytokine produced by activated blood mononuclear cells treated with HLA-A2 restricted synthetic peptide of HIV (p9) by RT-PCR detecting a fragment of 300 bp. This finding demonstrated that human HLA-A2 blood mononuclear cells have been activated in the presence of synthetic peptide of HIV (p9) and can induce expression of mRNA of NTT and IFNgamma which was confirmed by direct sequencing. For the first time, we have demonstrated an endogenous noncoding human RNA molecule, NTT mRNA, suggesting its implication in the cellular immune response.