Análise da influência de polimorfismo do gene TLR1 na suscetibilidade a hanseníase per se: um estudo de caso - controle / Analysis of the influence of the TLR1 gene polymorphism in susceptibility to leprosy per se: A case-control

Desde a década de 1960, há evidências da influência da arquitetura genética individual na suscetibilidade à hanseníase. Polimorfismos em genes que codificam citocinas e receptores envolvidos na resposta imune, como o receptor TLR1, capaz de reconhecer o patógeno,podem associar-se ao risco à doença. O objetivo deste trabalho foi analisar a influência do polimorfismo G743A no gene TLR1 com a suscetibilidade à hanseníase em um estudo caso controle na Microrregião de Almenara, Minas Gerais. O cenário envolveu os municípios de Almenara, Felizburgo, Jacinto, Jordânia, Palmópolis e Rubim. A amostra de casos foi selecionada por consulta aos indivíduos diagnosticados com hanseníase registrados no SINAN entre 2001 e 2014. Controles foram selecionados a partir dos contatos domiciliares desses casos, incluídos os que residiam nos municípios selecionados, com idade igual ou superior a sete anos e aceite na coleta de material biológico. Contatos com histórico ou suspeita de hanseníase e parentesco consanguíneo com casos foram excluídos. A coleta dedados envolveu visitas domiciliares com aplicação de questionário estruturado e coleta de sangue, realizadas em 2011 e 2014. A extração do DNA utilizou o kit Qiagen Flexigene e agenotipagem realizada por PCR em tempo real. O software Epi Info foi utilizado para aconstrução do banco de dados, sendo as análises feitas nos softwares SPSS e R com o pacote estatístico SNPassoc. Esta pesquisa foi aprovada pelo Comitê de Ética em Pesquisa com Seres Humanos da Universidade Federal de Minas Gerais. A amostra, composta por 234 casos e233 controles, totalizou 467 indivíduos, com a maioria de adultos do sexo feminino. Apenas entre os casos predominaram indivíduos do sexo masculino e uma maior proporção de jovens. Nas variáveis epidemiológicas, houve um número expressivo de indivíduos vivendo em domicílios de até quatro cômodos e com histórico de helmintoses, principalmente entre os casos da doença. A forma multibacilar foi frequente...

Since the 60s, there is evidence of the genetic architecture influence in susceptibility toleprosy. Polymorphisms in genes encoding cytokines and receptors involved in immuneresponse, such as TLR1 receptor that can recognize the pathogen, may be associated with therisk of disease. The objective of this study was to analyze the influence of the G743Apolymorphism in the TLR1 gene with susceptibility to leprosy in a case-control study in themicro-region of Almenara, Minas Gerais. The scenario involved the cities of Almenara,Felisburgo, Jacinto, Jordânia, Palmópolis and Rubim. The case sample was selected inconsultation with individuals diagnosed with leprosy registered in SINAN between 2001 and2014. Controls were selected from the household contacts of these cases. Including those wholived in the selected cities, age greater than or equal seven years old and who accepted the biological material collection. Contacts with a history or suspected leprosy and consanguinity with cases were excluded. Data collection involved home visits with a structuredquestionnaire and blood collection, carried out in 2011 and 2014. The DNA extraction usedthe Qiagen kit Flexigene and genotyping performed by Real-Time PCR. The Epi Infosoftware was used to build the database and the analysis done in SPSS software and R with the SNPassoc statistical package. This study was approved by the Ethics Committee of the Federal University of Minas Gerais. A sample of 234 cases and 233 controls amounted to 467individuals, most adult females. Only between cases predominated males and a higherproportion of young people. In epidemiological variables, there was a significant number of individuals living in houses with up to 4 rooms and helminths history, especially among the cases. The multibacillary form was common in the case group as well as physical disabilities, leprosy reactions and the absence of BCG...

Análise da influência de fatores genéticos na suscetibilidade à hanseníase na população da microrregião de Almenara, Minas Gerais / Analysis of the influence of genetic factors on the susceptibility to leprosy among the population from the microregion of Almenara, Minas Gerais

A hanseníase é uma doença infectocontagiosa que apresenta um largo espectro de manifestações clínicas. Essa grande variação é determinada pela resposta imunológica do hospedeiro à infecção pelo Mycobacterium leprae, que por sua vez é influenciada pela composição genética do indivíduo. A maioria dos genes e regiões genômicas associadas com a suscetibilidade ou resistência à doença estão relacionadas à produção de citocinas e outras moléculas importantes das vias imunológicas. No entanto, embora esta hipótese seja amplamente aceita, diferentes estudos realizados com populações distintas apresentam resultados muitas vezes discordantes ou controversos. Por esta razão, torna-se necessária a realização de estudos adicionais, com diferentes desenhos e populações, visando replicar e validar os resultados já encontrados. O objetivo deste estudo foi analisar a influência de polimorfismos de base única (SNP) na suscetibilidade à hanseníase na população da microrregião de Almenara, Minas Gerais. Para tal fim, utilizou -se um estudo baseado em famílias e a análise foi realizada por meio do Teste de Desequilíbrio de Transmissão (TDT). Foram analisados polimorfismos dos genes TLR1, NOD2, LTA4H, IFNG e IL10. A amostra populacional foi composta por 125 núcleos familiares de casos de hanseníase residentes nos municípios de Almenara, Felisburgo, Jacinto, Jordânia, Palmópolis e Rubim, totalizando 447 indivíduos. Foram realizadas meta-análises para se estimar as medidas de associação de consenso entre os estudos disponíveis sobre os genes TLR1, IFNG e IL10. A análise do desequilíbrio de transmissão identificou a associação estatisticamente significativa dos SNPs rs4833095 e rs5743618 do gene TLR1 e a hanseníase per se, com os alelos G e T, respectivamente, associados à suscetibilidade à doença. A análise da transmissão desses dois marcadores também indicou que os aplótipos G/T e A/G (rs4833095/rs5743618) estavam associados à suscetibilidade e à...

Leprosy is an infectious disease that presents a large spectrum of clinical manifestations. This variation is correlated to the level of the host immune response to the Mycobacterium leprae, which in turn is influenced by the individual genetic background. The majority of genes and genomic regions associated with susceptibility/resistance to leprosy are related to the production of cytokines and other important molecules in the immunological pathways. However, although this hypothesis is widely accepted, different studies with distinct populations have often discordant or controversial results. For this reason, it is necessary to perform additional studies, with different designs and populations, aiming to replicate and validate the results already found. The objective of this study was to analyze the influence of single nucleotide polymorph isms (SNP) on the susceptibility to leprosy among the population from the microregion of Almenara, Minas Gerais. For this purpose, it was conducted a family based study and the analysis was performed using the Transmission Disequilibrium Test (TDT). Genetic polymorphisms of TLR1, NOD2, LTA4H, IFNG and IL10 genes were analyzed. The sample was composed of 125 nuclear families of leprosy cases from the cities of Almenara, Felisburgo, Jacinto, Jordania, Palmopolis and Rubim, with a total of 447 individuals. Meta-analysis were carried out to define consensus association estimates for the available studies about TLR1, IFNG and IL10 genes. The analysis of transmission disequilibrium identified a statistically significant association between the TLR1 rs4833095 and rs5743618 SNPs and the leprosy per se, and the G and T alleles, respectively, were associated to the disease susceptibility. The analysis of the transmission of these markers also indicated that the G/T and A/G haplotypes (rs4833095/rs5743618) were associat ed to susceptibility and resistance to leprosy, respectively. No significant...

Principales aspectos inmunológicos en familias con casos secundarios de lepra en el área de salud Frank País García / Main immunological aspects in families with secondary cases of leprosy in Frank País García health area

Se realizó un estudio descriptivo y transversal de 32 familias con casos secundarios de lepra (entre los cuales predominaron los pacientes menores de 15 años, como evidencia de la transmisión activa de la enfermedad) y contactos de primer orden, pertenecientes al área de salud Frank País García de Santiago de Cuba, desde enero del 2007 hasta marzo del 2008, a fin de caracterizarles según elementos inmunológicos y epidemiológicos. El número de eosinófilos puede ser utilizado como marcador para pronosticar la evolución de los pacientes y contactos; asimismo, la neutrofilia y la eosinofilia por una parte y la leucopenia, la linfopenia y las alteraciones en la calidad de los clones linfocitarios T, por la otra, pudieran considerarse en función de marcadores de efecto: los primeros como indicativos de respuesta ante el Mycobacterium leprae y los segundos como expresión del daño inmunológico existente

A descriptive and cross-sectional study of 32 families with secondary cases of leprosy was carried out (among them prevailed the patients younger than 15 years, as evidence of the active transmission of the disease) and first contacts belonging to Frank País García health area in Santiago de Cuba, from January, 2007 to March, 2008, to characterize them according to the immunological and epidemiological elements. The number of eosinophils may be used as a marker to predict the clinical course of the patients and contacts; the neutrophilia, the eosinophilia on the one hand and the leukopenia, lymphocytopenia and disorders in the quality of the lymphocitary clones T, on the other hand, could be considered as effect markers: the former as indicative of response before the Mycobacterium leprae and the latter as expression of the existing immunological damage

Immunological unresponsiveness in leprosy and its relevance to immunoregulation in man.

The varied forms of leprosy form a clinical and immunological spectrum which offers extraordinary possibilities for insight into immunoregulatory mechanisms in man. At one pole, tuberculoid leprosy, patients develop high levels of cell-mediated immunity which ultimately results in killing of bacilli in the tissues, albeit often with damage to nerves. At the lepromatous pole, patients exhibit selective immunological unresponsiveness to antigens of Mycobacterium leprae. Even though all currently known protein species of Mycobacterium leprae and BCG are cross-reactive, lepromatous patients unreactive to Mycobacterium leprae antigens frequently respond strongly to tuberculin. In vitro experiments suggest the existence of lepromin-induced suppressor activity, mediated by both monocytes and Τ cells. The Τ suppressor cells have the T8 phenotype of which 50% express the activation markers, Ia and FcR. The one unique species of antigen of the leprosy bacillus is a phenolic glycolipid, and it appears that the Ts cells largely recognize the terminal trisaccharide of this unique antigen. Depletion of Ts cells restores in vitro reactivity of lymphocytes to lepromin in a portion of lepromatous patients, and addition of IL-2 containing supernatants partially restores responsiveness to Mycobacterium leprae antigens. Vaccination of lepromatous patients with a mixture of Mycobacterium leprae and live BCG restores cell-mediated immunity in the majority of lepromatous patients, and concomitantly reduces the in vitro suppressor activity and number of activated T8 cells. These experiments suggest the existence of stage-of-disease related suppressor cells in leprosy which appear to block the responsiveness of TH capable of responding to either specific or cross-reactive mycobacterial antigens. The mode of action of these Ts appears to be the inhibition of production of IL-2 and other lymphokines. Successful immunotherapeutic vaccination appears to overcome this block in the majority of patients.