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Conselho Nacional para o Desenvolvimento Cient?fico e Tecnol?gico (CNPq) ; Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior, Brazil (CAPES ? DS and PDSE) ? Finance Code 001 S?o Paulo State University. Graduate Program in Biosciences. S?o Jos? do Rio Preto, SP, Brazil. Lisboa University. Tropical Medicine and Hygiene Institut. Global Health and Tropical Medicine. Lisboa, Portugal. Federal University of Sergipe. Department of Biology. Aracaj?, SE, Brazil. Minist?rio da Sa?de. Secretaria de Vigil?ncia em Sa?de. Instituto Evandro Chagas. Laborat?rio de Imunogen?tica da Mal?ria Ananindeua, PA, Brasil. Minist?rio da Sa?de. Secretaria de Vigil?ncia em Sa?de. Instituto Evandro Chagas. Laborat?rio de Microscopia Eletr?nica. Ananindeua, PA, Brasil / Universidade Federal do Par?. Bel?m, PA, Brasil. Fluminense Federal University. Center of Microorganisms Investigation. Niter?i, RJ, Brazil. Fluminense Federal University. Center of Microorganisms Investigation. Niter?i, RJ, Brazil. Fluminense Federal University. Center of Microorganisms Investigation. Niter?i, RJ, Brazil. Funda??o Oswaldo Cruz. Oswaldo Cruz Institute. Laboratory of Malaria Research. Rio de Janeiro, RJ, Brazil. S?o Paulo State University. Graduate Program in Biosciences. S?o Jos? do Rio Preto, SP, Brazil. Funda??o Oswaldo Cruz. Oswaldo Cruz Institute. Laboratory of Immunoparasitology. Rio de Janeiro, RJ, Brazil. S?o Paulo State University. Graduate Program in Biosciences. S?o Jos? do Rio Preto, SP, Brazil / Fluminense Federal University. Center of Microorganisms Investigation. Niter?i, RJ, Brazil. BACKGROUND: It is well established that infection by Plasmodium vivax is a result of host-parasite interactions. In the present study, association with the IL1/IL2 cytokine profiles, anticircumsporozoite protein antibody levels and parasitic loads was evaluated in individuals naturally infected with P. vivax in an endemic area of the Brazilian Amazon. METHODS: Molecular diagnosis of P. vivax and variants was performed using the PCR-RFLP method and IL1B -511C>T, IL2 -330T>G and IL2+114T>G polymorphisms were identified using PCR-RFLP and allele-specific PCR. IL-1? and IL-2 cytokine levels were detected by flow cytometry and circumsporozoite protein (CSP) antibodies were measured by ELISA. RESULTS: Three variants of P. vivax CSP were identified and VK247 was found to be the most frequent. However, the prevalence and magnitude of IgG antibodies were higher for the VK210 variant. Furthermore, the antibody response to the CSP variants was not associated with the presence of the variant in the infection. Significant differences were observed between the single nucleotide polymorphism (SNP) -511T>C in the IL1B gene and levels of antibodies to the VK247 and P. vivax-like variants, but there were no associations between SNPs in IL1 and IL2 genes and their plasma products. CONCLUSIONS: Individuals with the rs16944 CC genotype in the IL1? gene have higher antibody levels to the CSP of P. vivax of VK247 and P. vivax-like variants.

Made available in DSpace on 2018-11-26T15:28:15Z (GMT). No. of bitstreams: 0 Previous issue date: 2015-11-01 Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Co-stimulatory molecules are essential in the orchestration of immune response and polymorphisms in their genes are associated with various diseases. However, in the case of variable allele frequencies among continental populations, this variation can lead to biases in genetic studies conducted in admixed populations such as those from Brazil. The aim of this study was to evaluate the influence of genomic ancestry on distributions of co-stimulatory genes polymorphisms in an admixed Brazilian population. A total of 273 individuals from the north of Brazil participated in this study. Nine single nucleotide polymorphisms in 7 genes (CD28, CTLA4, ICOS, CD86, CD40, CD40L and BLYS) were determined by polymerase chain reaction-restriction fragment length polymorphism. We also investigated 48 insertion/deletion ancestry markers to characterize individual African, European and Amerindian ancestry proportions in the samples. The analysis showed that the main contribution was European (43.9%) but also a significant contribution of African (31.6%) and Amerindian (24.5%) ancestry. ICOS, CD40L and CD86 polymorphisms were associated with genomic ancestry. However there were no significant differences in the proportions of ancestry for the other SNPs and haplotypes studied. Our findings reinforce the need to apply AIMs in genetic association studies involving these polymorphisms in the Brazilian population. (c) 2015 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved. Univ Estadual Paulista, Inst Biociencias Letras & Ciencias Exatas, Sao Jose Do Rio Preto, Brazil Fac Med Sao Jose do Rio Preto, Ctr Invest Microrganismos, Sao Jose Do Rio Preto, Brazil Fed Univ Para, Inst Ciencias Biol, BR-66059 Belem, Para, Brazil Univ Fed Sergipe, Dept Biol, Aracaju, Brazil Fed Univ Para, Lab Genet Humana & Med, BR-66059 Belem, Para, Brazil Secretaria Vigilancia Saude, Inst Evandro Chagas, Lab Pesquisas Basicas Malaria, Ananindeua, Brazil Univ Estadual Paulista, Inst Biociencias Letras & Ciencias Exatas, Sao Jose Do Rio Preto, Brazil CNPq: 471605/2011-5

Background Plasmodium vivax is the most prevalent malaria species in Brazil. The parasite-host coevolutionary process can be viewed as an 'arms race', in which adaptive genetic changes in one are eventually matched by alterations in the other. Methods Following the candidate gene approach we analyzed the CD40, CD40L and BLYS genes that participate in B-cell co-stimulation, for associations with P. vivax malaria. The study sample included 97 patients and 103 controls. We extracted DNA using the extraction and purification commercial kit and identified the following SNPs: -1C > T in the CD40 gene, -726T > C in the CD40L gene and the -871C > T in the BLyS gene using PCR-RFLP. We analyzed the genotype and allele frequencies by direct counting. We also compared the observed with the expected genotype frequencies using the Hardy-Weinberg equilibrium. Results The allele and genotype frequencies for these SNPs did not differ statistically between patient and control groups. Gene-gene interactions were not observed between the CD40 and BLYS and between the CD40L and BLYS genes. Overall, the genes were in Hardy-Weinberg equilibrium. Significant differences were not observed among the frequencies of antibody responses against P. vivax sporozoite and erythrocytic antigens and the CD40 and BLYS genotypes. Conclusions The results of this study show that, although the investigated CD40, CD40L and BLYS alleles differ functionally, this variation does not alter the functionality of the molecules in a way that would interfere in susceptibility to the disease. The variants of these genes may influence the clinical course rather than simply increase or decrease susceptibility.

Made available in DSpace on 2018-11-26T16:48:24Z (GMT). No. of bitstreams: 0 Previous issue date: 2016-07-19 Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Para State Research Support Foundation (Fundacao de Amparo a Pesquisa do Estado do Para) CAPPES Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Background: The immune response against Plasmodium vivax immunogenic epitopes is regulated by pro-and anti-inflammatory cytokines that determine antibody levels and class switching. Cytokine gene polymorphisms may be responsible for changes in the humoral immune response against malaria. The aim of this study was to evaluate whether polymorphisms in the TNFA, IFNG and IL10 genes would alter the levels of anti-PvAMA1, PvDBP and -PvMSP-1(19) IgG antibodies in patients with vivax malaria. Methods: Samples from 90 vivax malaria-infected and 51 uninfected subjects from an endemic area of the Brazilian Amazon were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) to identify polymorphisms of the genes TNFA (-1031T > C, -308G > A, -238G > A), IFNG (+874T > A) and IL10 (-819C > T, -592C > A). The levels of total IgG against PvAMA1, PvDBP and -PvMSP-1(19) were determined using an enzyme-linked immunosorbent assay (ELISA). Associations between the polymorphisms and the antibody response were assessed by means of logistic regression models. Results: No significant differences were found in the levels of IgG antibodies against the PvAMA-1, PvDBP or PvMSP-1(19) proteins in relation to the studied polymorphisms. Conclusions: Although no associations were found among the evaluated genotypes and alleles and anti-merozoite IgG class P. vivax antibody levels, this study helps elucidate the immunogenic profile involved in the humoral immune response in malaria. Sao Jose Rio Preto Med Sch, Dept Dermatol Infect & Parasit Dis, Sao Jose Do Rio Preto, SP, Brazil Sao Paulo State Univ, Dept Biol, Sao Jose Do Rio Preto, SP, Brazil Univ Fed Sergipe, Dept Biol, Lab Mol Genet & Biotechnol, Sao Cristovao, SE, Brazil Univ Fed Para, UFPA, Inst Biol Sci, Lab Microbiol & Immunol, Belem, Para, Brazil Univ Estadual Campinas, Lab Trop Dis, Dept Genet Evolut & Bioagents, Campinas, SP, Brazil Evandro Chagas Inst, Sect Parasitol, Lab Basic Res Malaria, Belem, PA, Brazil Sao Paulo State Univ, Dept Biol, Sao Jose Do Rio Preto, SP, Brazil CNPq: 472135/2012

S?o Paulo State University. Department of Biology. S?o Jos? do Rio Preto, SP, Brazil / S?o Jos? do Rio Preto Medical School. Department of Skin. Infectious and Parasitic Diseases. S?o Jos? do Rio Preto, SP, Brazil. S?o Jos? do Rio Preto Medical School. Department of Skin. Infectious and Parasitic Diseases. S?o Jos? do Rio Preto, SP, Brazil. S?o Jos? do Rio Preto Medical School. Department of Skin. Infectious and Parasitic Diseases. S?o Jos? do Rio Preto, SP, Brazil / S?o Paulo State University. Department of Biology. S?o Jos? do Rio Preto, SP, Brazil. Federal University of Sergipe. Department of Biology. S?o Crist?v?o, SE, Brazil. Oswaldo Cruz Foundation. Le?nidas and Maria Deane Institute. Manaus, AM, Brazil. Minist?rio da Sa?de. Secretaria de Vigil?ncia em Sa?de. Instituto Evandro Chagas. Laborat?rio de Pesquisa B?sica de Mal?ria. Bel?m, PA, Brasil. Minist?rio da Sa?de. Secretaria de Vigil?ncia em Sa?de. Instituto Evandro Chagas. Laborat?rio de Pesquisa B?sica de Mal?ria. Bel?m, PA, Brasil. Oswaldo Cruz Foundation. Le?nidas and Maria Deane Institute. Manaus, AM, Brazil. S?o Paulo State University. Department of Biology. S?o Jos? do Rio Preto, SP, Brazil / S?o Jos? do Rio Preto Medical School. Department of Skin. Infectious and Parasitic Diseases. S?o Jos? do Rio Preto, SP, Brazil / Minist?rio da Sa?de. Secretaria de Vigil?ncia em Sa?de. Instituto Evandro Chagas. Laborat?rio de Pesquisa B?sica de Mal?ria. Bel?m, PA, Brasil. Background: Humoral immune responses against proteins of asexual blood-stage malaria parasites have been associated with clinical immunity. However, variations in the antibody-driven responses may be associated with a genetic component of the human host. The objective of the present study was to evaluate the influence of co-stimulatory molecule gene polymorphisms of the immune system on the magnitude of the humoral immune response against a Plasmodium vivax vaccine candidate antigen. Methods: Polymorphisms in the CD28, CTLA4, ICOS, CD40, CD86 and BLYS genes of 178 subjects infected with P. vivax in an endemic area of the Brazilian Amazon were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The levels of IgM, total IgG and IgG subclasses specific for ICB2-5, i.e., the N-terminal portion of P. vivax merozoite surface protein 1 (PvMSP-1), were determined by enzyme-linked immuno assay. The associations between the polymorphisms and the antibody response were assessed by means of logistic regression models. Results: After correcting for multiple testing, the IgG1 levels were significantly higher in individuals recessive for the single nucleotide polymorphism rs3116496 in CD28 (p = 0.00004). Furthermore, the interaction between CD28 rs35593994 and BLYS rs9514828 had an influence on the IgM levels (p = 0.0009). Conclusions: The results of the present study support the hypothesis that polymorphisms in the genes of co-stimulatory components of the immune system can contribute to a natural antibody-driven response against P. vivax antigens.

S?o Paulo State University. Department of Biology. S?o Jos? do Rio Preto, SP, Brazil. College of Medicine of S?o Jos? do Rio Preto. Department of Dermatologic, Infectious, and Parasitic Diseases. S?o Jos? do Rio Preto, SP, Brazil. S?o Paulo State University. Department of Biology. S?o Jos? do Rio Preto, SP, Brazil. Federal University of Sergipe. Department of Biology. Aracaju, SE, Brazil. Federal University of Par?. Institute of Biological Sciences. Laborat?rio of Microbiology and Immunology. Bel?m, PA, Brazil. Oswaldo Cruz Foundation. Laboratory of Malaria, Ren? Rachou Research Center. Belo Horizonte, MG, Brazil. Oswaldo Cruz Foundation. Laboratory of Malaria, Ren? Rachou Research Center. Belo Horizonte, MG, Brazil. University of S?o Paulo. Faculty of Pharmaceutical Sciences. Department of Clinical and Toxicological Analyses. S?o Paulo, SP, Brazil. Federal University of Par?. Laboratory of Human and Medical Genetics. Bel?m, PA, Brazil. Minist?rio da Sa?de. Secretaria de Vigil?ncia em Sa?de. Instituto Evandro Chagas. Laborat?rio de Pesquisa B?sica em Mal?ria. Ananindeua, PA, Brasil. Minist?rio da Sa?de. Secretaria de Vigil?ncia em Sa?de. Instituto Evandro Chagas. Laborat?rio de Pesquisa B?sica em Mal?ria. Ananindeua, PA, Brasil / S?o Paulo State University. Department of Biology. S?o Jos? do Rio Preto, SP, Brazil. The development of an effective immune response can help decrease mortality from malaria and its clinical symptoms. However, this mechanism is complex and has significant inter-individual variation, most likely owing to the genetic contribution of the human host. Therefore, this study aimed to investigate the influence of polymorphisms in genes involved in the costimulation of B-lymphocytes in the naturally acquired humoral immune response against proteins of the asexual stage of Plasmodium vivax. A total of 319 individuals living in an area of malaria transmission in the Brazilian Amazon were genotyped for four SNPs in the genes CD40, CD40L, BLYS and CD86. In addition, IgG antibodies against P. vivax apical membrane antigen 1 (PvAMA-1), Duffy binding protein (PvDBP) and merozoite surface protein 1 (PvMSP-119) were detected by ELISA. The SNP BLYS -871CT was associated with the frequency of IgG responders to PvAMA-1 and PvMSP-119. The SNP CD40 -1CT was associated with the IgG response against PvDBP, whereas IgG antibody titers against PvMSP-119 were influenced by the polymorphism CD86 +1057GA. These data may help to elucidate the immunological aspects of vivax malaria and consequently assist in the design of malaria vaccines.

Interleukin 2 (IL-2) is a monomeric glycoprotein that is primarily produced by activated CD4+ T cells, CD8+ T cells and dendritic cells. It is characterized as a proinflammatory cytokine that is secreted by Th1 cells. IL-2 plays a central role in the activation of regulatory T cells to produce the cytokines tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ). IL-2 may also enhance the cytolytic activity of natural killer cells, thereby ensuring their significance in the control of the immune response, and effectively participate in the pathogenesis of several pathological conditions, such as cancer and metabolic, infectious, autoimmune and inflammatory diseases. We emphasize the importance of studies of IL-2 and discuss perspectives resulting from our increasing understanding of genetic diversity and its role in the immune response.

Made available in DSpace on 2018-11-26T17:13:49Z (GMT). No. of bitstreams: 0 Previous issue date: 2016-01-01 Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Polymorphisms in cytokine genes can alter the production of these proteins and consequently affect the immune response. The trihybrid heterogeneity of the Brazilian population is characterized as a condition for the use of ancestry informative markers. The objective of this study was to evaluate the frequency of -1031T>C, -308G>A and -238G>A TNFA, +874 A>T IFNG and -819C>T, and -592C>A IL10 gene polymorphisms and their association with malaria vivax and genomic ancestry. Samples from 90 vivax malaria-infected individuals and 51 noninfected individuals from northern Brazil were evaluated. Genotyping was carried out by using ASO-PCR or PCR/RFLP. The genomic ancestry of the individuals was classified using 48 insertion/deletion polymorphism biallelic markers. There were no differences in the proportions of African, European, and Native American ancestry between men and women. No significant association was observed for the allele and genotype frequencies of the 6 SNPs between malaria-infected and noninfected individuals. However, there was a trend toward decreasing the frequency of individuals carrying the TNF-308A allele with the increasing proportion of European ancestry. No ethnic-specific SNPs were identified, and there was no allelic or genotype association with susceptibility or resistance to vivax malaria. Understanding the genomic mechanisms by which ancestry influences this association is critical and requires further study. Coll Med Sao Jose do Rio Preto, Dept Dermatol Infect & Parasit Dis, Sao Jose Do Rio Preto, SP, Brazil UNIRP, Univ Ctr Rio Preto, Sao Jose Do Rio Preto, SP, Brazil Univ Estadual Campinas, Dept Genet Evolut & Bioagents, Lab Trop Dis Prof Luiz Jacintho da Silva, Campinas, SP, Brazil Sao Paulo State Univ, Dept Biol, Sao Jose Do Rio Preto, SP, Brazil Fed Univ Para, Lab Human & Med Genet, Belem, PA, Brazil Evandro Chagas Inst, Sect Parasitol, Lab Basic Res Malaria, Belem, PA, Brazil Sao Paulo State Univ, Dept Biol, Sao Jose Do Rio Preto, SP, Brazil CNPq: 472135/2012-0

Background Several studies have recently demonstrated that the immune responses against malaria is governed by different factors, including the genetic components of the host. The IL-4 gene appears to be a strong candidate factor because of its role in the regulation of the Th2 response. The present study investigated the role of IL-4 polymorphisms in the development of IgG antibodies against PvAMA-1 and the IL-4 levels in individuals infected with Plasmodium vivax in a malaria endemic area in the Brazilian Amazon. Methods The study sample included 83 patients who were diagnosed with P. vivax infection using thick smear and confirmed by nested-PCR. The IL-4 −590 C>T and IL-4 −33 C>T polymorphisms were genotyped by PCR–RFLP, and the intron 3 VNTR was genotyped by PCR. A standardised ELISA protocol was used to measure the total IgG against PvAMA-1. The cytokine/chemokine levels were measured using a Milliplex multiplex assay (Millipore). All of the subjects were genotyped with 48 ancestry informative markers to determine the proportions of African, European and Amerindian ancestry using STRUCTURE software. Results Of the 83 patients, 60 (73%) produced IgG antibodies against PvAMA-1. A significant decrease in the percentage of respondents was observed among the primo-infected individuals. No significant differences were observed in the frequencies of genotypes and haplotypes among individuals who were positive or negative for IgG antibodies against PvAMA-1. Furthermore, no significant correlation was observed between the IL-4 polymorphisms, antibody levels, IL-4 levels, and parasitemia. Conclusions This study indicated that the polymorphisms identified in the IL-4 gene are not likely to play a role in the regulation of the antibody response against PvAMA-1 and IL-4 production in vivax malaria.