Lack of association of the KIR and HLA class I ligands with ZIKV infection in south and southeast of Brazil.

BACKGROUND: Zika virus (ZIKV) is an emerging arbovirus associated with foetal malformations and neurological complications. The infection is usually associated with mild symptoms. The comparison between the allelic frequency of polymorphic genes in symptomatic infected individuals in the population can clarify the pathogenic mechanisms of ZIKV. During ZIKV infection, cytokines are produced and natural killer (NK) cells are recruited, whose activation depends on signaling pathways activated by specific receptors, such as killer cell immunoglobulin-like receptors (KIR). These molecules interact with human leukocyte antigen (HLA) class I ligands and are encoded by polymorphic genes. OBJECTIVES: This study aimed to evaluate the frequency of allelic variants of the genes encoding the KIR receptors and their HLA class I ligands in 139 symptomatic ZIKV-patients and 170 controls negative for the virus, and to evaluate the role of these variants for ZIKV susceptibility. METHODS: KIR and HLA class I genes were genotyped using the polymerase chain reaction-sequence specific oligonucleotide (PCR-SSO) technique. FINDINGS: No significant differences in the frequency distribution of KIRs and KIR-HLA in patients compared to controls were observed. MAIN CONCLUSIONS: KIR and its HLA ligands might play a minor role in ZIKV infection in the south and southeast Brazilian individuals.

Lack of association of the KIR and HLA class I ligands with ZIKV infection in south and southeast of Brazil

BACKGROUND Zika virus (ZIKV) is an emerging arbovirus associated with foetal malformations and neurological complications. The infection is usually associated with mild symptoms. The comparison between the allelic frequency of polymorphic genes in symptomatic infected individuals in the population can clarify the pathogenic mechanisms of ZIKV. During ZIKV infection, cytokines are produced and natural killer (NK) cells are recruited, whose activation depends on signaling pathways activated by specific receptors, such as killer cell immunoglobulin-like receptors (KIR). These molecules interact with human leukocyte antigen (HLA) class I ligands and are encoded by polymorphic genes. OBJECTIVES This study aimed to evaluate the frequency of allelic variants of the genes encoding the KIR receptors and their HLA class I ligands in 139 symptomatic ZIKV-patients and 170 controls negative for the virus, and to evaluate the role of these variants for ZIKV susceptibility. METHODS KIR and HLA class I genes were genotyped using the polymerase chain reaction-sequence specific oligonucleotide (PCR-SSO) technique. FINDINGS No significant differences in the frequency distribution of KIRs and KIR-HLA in patients compared to controls were observed. MAIN CONCLUSIONS KIR and its HLA ligands might play a minor role in ZIKV infection in the south and southeast Brazilian individuals.

The impact of KIR/HLA genes on the risk of developing multibacillary leprosy.

BACKGROUND: Killer-cell immunoglobulin-like receptors (KIRs) are a group of regulatory molecules able to activate or inhibit natural killer cells upon interaction with human leukocyte antigen (HLA) class I molecules. Combinations of KIR and HLA may contribute to the occurrence of different immunological and clinical responses to infectious diseases. Leprosy is a chronic neglected disease, both disabling and disfiguring, caused mainly by Mycobacterium leprae. In this case-control study, we examined the influence of KIRs and HLA ligands on the development of multibacillary leprosy. METHODOLOGY/PRINCIPAL FINDINGS: Genotyping of KIR and HLA genes was performed in 264 multibacillary leprosy patients and 518 healthy unrelated controls (238 healthy household contacts and 280 healthy subjects). These are unprecedented results in which KIR2DL2/KIR2DL2/C1/C2 and KIR2DL3/2DL3/C1/C1 indicated a risk for developing lepromatous and borderline leprosy, respectively. Concerning to 3DL2/A3/A11+, our study demonstrated that independent of control group (contacts or healthy subjects), this KIR receptor and its ligand act as a risk factor for the borderline clinical form. CONCLUSIONS/SIGNIFICANCE: Our finding suggests that synergetic associations of activating and inhibitory KIR genes may alter the balance between these receptors and thus interfere in the progression of multibacillary leprosy.

Association of TNF, IL12, and IL23 gene polymorphisms and psoriatic arthritis: meta-analysis.

BACKGROUND: Psoriatic arthritis (PsA) is a chronic skin and joint condition that considerably affects patient quality of life. Several studies have demonstrated different associations of genetic polymorphisms in the pathogenic process of PsA. Therefore, we conducted a meta-analysis to estimate the effect of polymorphisms in the cytokines TNF, IL12B, IL23A, and IL23R on PsA risk. METHODS: We screened 1,097 abstracts and identified 14 relevant studies published between January 2007 and December 2017. A systematic search was conducted in PubMed, Web of Knowledge and Scopus databases. Meta-analyses were performed for the comparisons of alleles and multiple genetic models. RESULTS: Among the cytokines studied, we found 17 polymorphisms that were the most investigated. The association to PsA was observed in the presence of polymorphisms: TNF-238 G > A (rs361525), -308 G > A (rs1800629), and -857 C > T (rs1799724); IL12B C > G (rs6887695) and A > C (rs3212227); IL23A A > G (rs2066808) and IL23R G > A (rs11209026). CONCLUSION: Our findings suggest that these variant cytokine genes may strongly influence the immunological response of PsA.

Genetic Polymorphisms of IL17 and Chagas Disease in the South and Southeast of Brazil.

The aim of this study was to investigate possible associations between genetic polymorphisms of IL17A G197A (rs2275913) and IL17F T7488C (rs763780) with Chagas Disease (CD) and/or the severity of left ventricular systolic dysfunction (LVSD) in patients with chronic Chagas cardiomyopathy (CCC). The study with 260 patients and 150 controls was conducted in the South and Southeast regions of Brazil. The genotyping was performed by PCR-RFLP. The A allele and A/A genotype of IL17A were significantly increased in patients and their subgroups (patients with CCC; patients with CCC and LVSD; and patients with CCC and severe LVSD) when compared to the control group. The analysis according to the gender showed that the A/A genotype of IL17A was more frequent in female with LVSD and mild to moderate LVSD and also in male patients with LVSD. The frequency of IL17F T/C genotype was higher in male patients with CCC and severe LVSD and in female with mild to moderate LVSD. The results suggest the possible involvement of the polymorphisms of IL17A and IL17F in the susceptibility to chronic Chagas disease and in development and progression of cardiomyopathy.

n-Octyl gallate as inhibitor of pyruvate carboxylation and lactate gluconeogenesis.

The alkyl gallates are found in several natural and industrial products. In the latter products, these compounds are added mainly for preventing oxidation. In the present work, the potencies of methyl gallate, n-propyl gallate, n-pentyl gallate, and n-octyl gallate as inhibitors of pyruvate carboxylation and lactate gluconeogenesis were evaluated. Experiments were done with isolated mitochondria and the isolated perfused rat liver. The potency of the gallic acid esters as inhibitors of pyruvate carboxylation in isolated mitochondria obeyed the following decreasing sequence: n-octyl gallate > n-pentyl gallate > n-propyl gallate > methyl gallate. A similar sequence of decreasing potency for lactate gluconeogenesis inhibition in the perfused liver was found in terms of the portal venous concentration. Both actions correlate with the lipophilicity of the compounds. The effects are harmful at high concentrations. At appropriate concentrations, however, octyl gallate should act therapeutically because its inhibitory action on gluconeogenesis will contribute further to its proposed antihyperglycemic effects.

Kinetics of the transformation of n-propyl gallate and structural analogs in the perfused rat liver.

n-Propyl gallate and its analogs are used in foods and other products to prevent oxidation. In the liver the compound exerts several harmful effects, especially gluconeogenesis inhibition. The mode of transport and distribution of n-propyl gallate and its kinetics of biotransformation have not yet been investigated. To fill this gap the transformation, transport and distribution of n-propyl gallate and two analogs were investigated in the rat liver. Isolated perfused rat liver was used. n-Propyl gallate, methyl gallate, n-octyl gallate and transformation products were quantified by high pressure-liquid chromatography coupled to fluorescence detection. The interactions of n-propyl gallate and analogs with the liver presented three main characteristics: (1) the hydrolytic release of gallic acid from n-propyl gallate and methyl gallate was very fast compared with the subsequent transformations of the gallic acid moiety; (2) transport of the esters was very fast and flow-limited in contrast to the slow and barrier-limited transport of gallic acid; (3) the apparent distribution volume of n-propyl gallate, but probably also of methyl gallate and n-octyl gallate, greatly exceeded the water space in the liver, contrary to the gallic acid space which is smaller than the water space. It can be concluded that at low portal concentrations (<50µM) the gallic acid esters are 100% extracted during a single passage through the liver, releasing mainly gallic acid into the systemic circulation. For the latter a considerable time is required until complete biotransformation. The exposure of the liver to the esters, however, is quite prolonged due to extensive intracellular binding.