This research investigated immunogenetic variability and explored how genetics and the unique histories of First Nations may contribute to differential resistance and/or susceptibility to tuberculosis. With the support of First Nations communities, DNA samples were collected from Dene, Saulteaux, Cree and Caucasian cohorts within Manitoba. Single nucleotide polymorphisms (SNPs) in the cytokines promoter region of IL-12 (rs3212227) and in genes encoding the TLR2 (rs5743708)and TLR4 (rs4986790&4986791) were typed using PCR-RFLP analysis. Compared with the Caucasian and Saulteaux populations, the Dene and Cree were found to have a significantly higher frequency of SNPs associated with IL-12 low expression, while variation within TLRs was not statistically significant. The lower production of IL-12 has been associated with a down-regulated Th1 immune response, which is essential for the containment of Mycobacterium tuberculosis. First Nations have unique cultural, political and historical identities and the contemporary immunogenetic profiles are likely a reflection of these histories.

This research investigated immunogenetic variability and explored how genetics and the unique histories of First Nations may contribute to differential resistance and/or susceptibility to tuberculosis. With the support of First Nations communities, DNA samples were collected from Dene, Saulteaux, Cree and Caucasian cohorts within Manitoba. Single nucleotide polymorphisms (SNPs) in the cytokines promoter region of IL-12 (rs3212227) and in genes encoding the TLR2 (rs5743708)and TLR4 (rs4986790&4986791) were typed using PCR-RFLP analysis. Compared with the Caucasian and Saulteaux populations, the Dene and Cree were found to have a significantly higher frequency of SNPs associated with IL-12 low expression, while variation within TLRs was not statistically significant. The lower production of IL-12 has been associated with a down-regulated Th1 immune response, which is essential for the containment of Mycobacterium tuberculosis. First Nations have unique cultural, political and historical identities and the contemporary immunogenetic profiles are likely a reflection of these histories.

Os alelos HLA-DRB1, que codificam uma sequência de aminoácidos (QKRAA/QRRAA/RRRAA) nas posições 70 a 74 da terceira região hipervariável da cadeia &#61538;1 do gene DRB1, denominada epítopo compartilhado (EC), estão associados com maior susceptibilidade e gravidade para artrite reumatóide (AR) em diversas populações. Uma nova classificação proposta por Du Montcel et al tem sido desenvolvida para apurar a associação entre HLA-DRB1 e AR. Este estudo foi desenhado com o objetivo de determinar a frequência dos alelos HLA-DRB1 em pacientes brasileiros com AR, e sua associação com o fator reumatoide (FR), anticorpos antipeptídeos citrulinados (ACPA) e lesão radiográfica articular e óssea. Quatrocentos e doze pacientes com AR e 215 controles foram incluídos. A tipificação HLA-DRB1 foi realizada pela reação em cadeia de polimerase (PCR) usando primers específicos e hibridação com oligonucleotídeos de sequência específica (SSOP). A pesquisa de ACPA foi determinada pela técnica de ELISA e a do FR por nefelometria, a avaliação radiográfica realizada pelo método do índice de Sharp modificado de Van Der Heijde. Para análises estatísticas foram utilizados os testes do qui-quadrado, t de Student e a regressão logística. Nos pacientes com AR alelos HLA-DRB1*04:01, *04:04, *04:05 se associaram com AR (p<0,05), embora o amplo intervalo de confiança, vale a pena ressaltar a associação observada com o alelo DRB1*09:01 e a doença (p<0,05). Alelos HLA-DRB1 EC+ foram observados em 62,8% dos pacientes e em 31,1% do grupo controle (OR 3,62; p <0,001) e estiveram associados com ACPA (OR 2,03; p<0,001). Alelos DRB1 DERAA mostraram efeito protetor para a AR (OR 0,42; p<0,001). A análise da nova classificação de HLA-DRB1 mostra que S2 e S3P se associaram a AR (p<0,05). Alelos S2 e/ou S3P esteve presente em 65% dos pacientes e 32% do grupo controle (OR 3,86; p<0,001) e estiveram associados a ACPA (OR.2,11; p=0,001). Alelos S3D, S1, X mostraram efeito protetor para a AR. Os resultados obtidos neste estudo demonstram que pacientes brasileiros com AR de etnia majoritariamente mestiça, alelos HLA-DRB1 avaliados segundo a hipótese do EC e a classificação proposta por Du Montcel estiveram associados à suscetibilidade à doença e à presença de ACPA. / HLA-DRB1 alleles that encode an amino acid sequence at positions 70-74 of the third hypervariable region of the B chain of the DRB1 gene, called shared epitope (SE), are associated with increased susceptibility and severity to rheumatoid arthritis (RA) in different populations. A new classification proposed by Du Montcel et al has been developed to determine the association between HLA-DRB1 and RA. This study was designer to determine the frequency of HLA-DRB1 alleles in Brazilian patients with RA, and its association with rheumatoid factor (RF), citrullinated peptide antibodies (ACPA) and radiographic joint damage and bone. Four hundred and twelve patients with RA and 215 controls were included. The HLA-DRB1 typing was performed by polymerase chain reaction (PCR) using specific primers and hybridization with sequence specific oligonucleotides (SSOP). The survey of ACPA was determined by ELISA and the RF by nephelometry, the radiographic evaluation by index method modified Sharp Van Der Heijde. For statistical analysis we used the chi-square, Student and logistic regression. In patients with rheumatoid arthritis HLA-DRB1*04:01, *04:04, *04:05 are associated with RA (p<0,05), although the wide confidence interval, it is worth noting the association observed with the DRB1*09:01 allele and the disease (p<0,05). HLA-DRB1 SE+ were observed in 62.8% of patients and in 31.1% of the control group (OR 3.62, p<0,001) and were associated with ACPA (OR 2.03, p<0,001). DERRA alleles showed a protective effect against RA (OR 0,42, p<0,001). The analysis of the new classification of HLA-DRB1 shows that S2 and S3P were associated with RA (p<0,05). Alleles S2 and/or S3P was present in 65% and 32% of patients in the control group (OR 3,86, p<0,001) and were associated with ACPA (OR 2.11, p=0,001). S3D alleles, S1, X showed a protective effect against RA. The results of this study demonstrate that Brazilian patients with RA from mostly mixed ethnicity, HLA-DRB1 evaluated under the hypothesis of the SE and the classification proposed by Du Montcel et al were associated with disease susceptibility and the presence of ACPA.

Os alelos HLA-DRB1, que codificam uma sequência de aminoácidos (QKRAA/QRRAA/RRRAA) nas posições 70 a 74 da terceira região hipervariável da cadeia &#61538;1 do gene DRB1, denominada epítopo compartilhado (EC), estão associados com maior susceptibilidade e gravidade para artrite reumatóide (AR) em diversas populações. Uma nova classificação proposta por Du Montcel et al tem sido desenvolvida para apurar a associação entre HLA-DRB1 e AR. Este estudo foi desenhado com o objetivo de determinar a frequência dos alelos HLA-DRB1 em pacientes brasileiros com AR, e sua associação com o fator reumatoide (FR), anticorpos antipeptídeos citrulinados (ACPA) e lesão radiográfica articular e óssea. Quatrocentos e doze pacientes com AR e 215 controles foram incluídos. A tipificação HLA-DRB1 foi realizada pela reação em cadeia de polimerase (PCR) usando primers específicos e hibridação com oligonucleotídeos de sequência específica (SSOP). A pesquisa de ACPA foi determinada pela técnica de ELISA e a do FR por nefelometria, a avaliação radiográfica realizada pelo método do índice de Sharp modificado de Van Der Heijde. Para análises estatísticas foram utilizados os testes do qui-quadrado, t de Student e a regressão logística. Nos pacientes com AR alelos HLA-DRB1*04:01, *04:04, *04:05 se associaram com AR (p<0,05), embora o amplo intervalo de confiança, vale a pena ressaltar a associação observada com o alelo DRB1*09:01 e a doença (p<0,05). Alelos HLA-DRB1 EC+ foram observados em 62,8% dos pacientes e em 31,1% do grupo controle (OR 3,62; p <0,001) e estiveram associados com ACPA (OR 2,03; p<0,001). Alelos DRB1 DERAA mostraram efeito protetor para a AR (OR 0,42; p<0,001). A análise da nova classificação de HLA-DRB1 mostra que S2 e S3P se associaram a AR (p<0,05). Alelos S2 e/ou S3P esteve presente em 65% dos pacientes e 32% do grupo controle (OR 3,86; p<0,001) e estiveram associados a ACPA (OR.2,11; p=0,001). Alelos S3D, S1, X mostraram efeito protetor para a AR. Os resultados obtidos neste estudo demonstram que pacientes brasileiros com AR de etnia majoritariamente mestiça, alelos HLA-DRB1 avaliados segundo a hipótese do EC e a classificação proposta por Du Montcel estiveram associados à suscetibilidade à doença e à presença de ACPA. / HLA-DRB1 alleles that encode an amino acid sequence at positions 70-74 of the third hypervariable region of the B chain of the DRB1 gene, called shared epitope (SE), are associated with increased susceptibility and severity to rheumatoid arthritis (RA) in different populations. A new classification proposed by Du Montcel et al has been developed to determine the association between HLA-DRB1 and RA. This study was designer to determine the frequency of HLA-DRB1 alleles in Brazilian patients with RA, and its association with rheumatoid factor (RF), citrullinated peptide antibodies (ACPA) and radiographic joint damage and bone. Four hundred and twelve patients with RA and 215 controls were included. The HLA-DRB1 typing was performed by polymerase chain reaction (PCR) using specific primers and hybridization with sequence specific oligonucleotides (SSOP). The survey of ACPA was determined by ELISA and the RF by nephelometry, the radiographic evaluation by index method modified Sharp Van Der Heijde. For statistical analysis we used the chi-square, Student and logistic regression. In patients with rheumatoid arthritis HLA-DRB1*04:01, *04:04, *04:05 are associated with RA (p<0,05), although the wide confidence interval, it is worth noting the association observed with the DRB1*09:01 allele and the disease (p<0,05). HLA-DRB1 SE+ were observed in 62.8% of patients and in 31.1% of the control group (OR 3.62, p<0,001) and were associated with ACPA (OR 2.03, p<0,001). DERRA alleles showed a protective effect against RA (OR 0,42, p<0,001). The analysis of the new classification of HLA-DRB1 shows that S2 and S3P were associated with RA (p<0,05). Alleles S2 and/or S3P was present in 65% and 32% of patients in the control group (OR 3,86, p<0,001) and were associated with ACPA (OR 2.11, p=0,001). S3D alleles, S1, X showed a protective effect against RA. The results of this study demonstrate that Brazilian patients with RA from mostly mixed ethnicity, HLA-DRB1 evaluated under the hypothesis of the SE and the classification proposed by Du Montcel et al were associated with disease susceptibility and the presence of ACPA.

Camundongos AIRmax são resistentes e AIRmin susceptíveis à carcinogênese de pele por repetidas doses de DMBA. Apenas os AIRmin desenvolvem reação de hipersensibilidade de contacto (CHS) inicial seguida de tumores de pele e pulmão. O receptor aril hidrocarboneto (AHR) é importante no metabolismo do DMBA. Após ligação ao agonista este fator de transcrição aumenta a expressão de enzimas CYP450 necessários à sua metabolização. Nos AIRmin ocorreu um aumento do mRNA de IL1<font face=\"symbol\">b, TNF<font face=\"symbol\">a, IL6, TGF<font face=\"symbol\">b1 e CYP1B1 na pele às 48h após as doses de DMBA. Nos AIRmax não houve alteração. O aumento de expressão de citocinas e de P450 em AIRmin é coerente com a indução de CHS por DMBA dependente da ativação do AHR. Todos os AIRmax são homozigotos para o alelo Ahrd que confere resistência a CHS e carcinogênese enquanto os AIRmin portam o alelo Ahrb1 que confere susceptibilidade. Esta segregação alélica sugere a participação do Ahr como marcador ou gene que regula a carcinogênese e inflamação. Esta última hipótese foi confirmada pela análise de linkage dos genótipos Ahr parentais com o grau da inflamação em população F2 (AIRmax x AIRmin). Fatores genéticos ligados ao AHR e reações imunes específicas contribuem para a diferente susceptibilidade das linhagens à carcinogênese. / AIRmax mice are resistant and AIRmin susceptible to skin carcinogenesis by repeated DMBA doses. AIRmin mice developed initial contact hypersensitivity reaction (CHS) and late skin and lung tumors. The aryl hydrocarbon receptor (AHR) plays important roles in DMBA metabolism. Upon binding to agonist this transcription factor induces the expression of CYP P450 enzymes. Up regulated levels of IL1<font face=\"symbol\">b, TNF<font face=\"symbol\">a, IL6, TGF<font face=\"symbol\">b1 and CYP1B1 mRNAs were found in the skin of AIRmin at 48h after DMBA. In AIRmax the levels were similar to controls. The cytokine and P450 mRNA up regulation in AIRmin is coherent with CHS elicitation by DMBA dependent on AHR activation. All AIRmax were found homozygous for the Ahrd allele, which confers resistance to CHS and carcinogenesis, whereas all AIRmin are homozygous for the Ahrb1 allele, related to susceptibility. The allelic segregation in the lines suggests that Ahr is a marker or a gene involved in carcinogenesis and in inflammatory response control. This last hypothesis was confirmed by linkage analysis of Ahr parental genotypes with acute inflammation degree in F2 (AIRmax x AIRmin) population. The results point to genetic and molecular factors underlying the differential susceptibility of AIRmax and AIRmin mice to carcinogenesis.

Camundongos AIRmax são resistentes e AIRmin susceptíveis à carcinogênese de pele por repetidas doses de DMBA. Apenas os AIRmin desenvolvem reação de hipersensibilidade de contacto (CHS) inicial seguida de tumores de pele e pulmão. O receptor aril hidrocarboneto (AHR) é importante no metabolismo do DMBA. Após ligação ao agonista este fator de transcrição aumenta a expressão de enzimas CYP450 necessários à sua metabolização. Nos AIRmin ocorreu um aumento do mRNA de IL1<font face=\"symbol\">b, TNF<font face=\"symbol\">a, IL6, TGF<font face=\"symbol\">b1 e CYP1B1 na pele às 48h após as doses de DMBA. Nos AIRmax não houve alteração. O aumento de expressão de citocinas e de P450 em AIRmin é coerente com a indução de CHS por DMBA dependente da ativação do AHR. Todos os AIRmax são homozigotos para o alelo Ahrd que confere resistência a CHS e carcinogênese enquanto os AIRmin portam o alelo Ahrb1 que confere susceptibilidade. Esta segregação alélica sugere a participação do Ahr como marcador ou gene que regula a carcinogênese e inflamação. Esta última hipótese foi confirmada pela análise de linkage dos genótipos Ahr parentais com o grau da inflamação em população F2 (AIRmax x AIRmin). Fatores genéticos ligados ao AHR e reações imunes específicas contribuem para a diferente susceptibilidade das linhagens à carcinogênese. / AIRmax mice are resistant and AIRmin susceptible to skin carcinogenesis by repeated DMBA doses. AIRmin mice developed initial contact hypersensitivity reaction (CHS) and late skin and lung tumors. The aryl hydrocarbon receptor (AHR) plays important roles in DMBA metabolism. Upon binding to agonist this transcription factor induces the expression of CYP P450 enzymes. Up regulated levels of IL1<font face=\"symbol\">b, TNF<font face=\"symbol\">a, IL6, TGF<font face=\"symbol\">b1 and CYP1B1 mRNAs were found in the skin of AIRmin at 48h after DMBA. In AIRmax the levels were similar to controls. The cytokine and P450 mRNA up regulation in AIRmin is coherent with CHS elicitation by DMBA dependent on AHR activation. All AIRmax were found homozygous for the Ahrd allele, which confers resistance to CHS and carcinogenesis, whereas all AIRmin are homozygous for the Ahrb1 allele, related to susceptibility. The allelic segregation in the lines suggests that Ahr is a marker or a gene involved in carcinogenesis and in inflammatory response control. This last hypothesis was confirmed by linkage analysis of Ahr parental genotypes with acute inflammation degree in F2 (AIRmax x AIRmin) population. The results point to genetic and molecular factors underlying the differential susceptibility of AIRmax and AIRmin mice to carcinogenesis.

No description available.