Multiple sclerosis: disease modifying therapy and the human leukocyte antigen / Esclerose múltipla: terapêutica modificadora da doença e antígenos leucocitários humanos

ABSTRACT Objective: To investigate the potential relationship between the human leukocyte antigen (HLA) type (class I and II) and the response to several disease-modifying therapies (DMTs) in patients with multiple sclerosis (MS). Methods: We analyzed clinical data of 87 patients with MS at the beginning and end of each type of DMT including the disease duration, Expanded Disability Status Scale and Multiple Sclerosis Severity Score (MSSS). Genotyping of HLA-DRB1, HLA-DPB1, HLA-DQB1, HLA-A, HLA-B and HLA-C alleles were identified using high-resolution techniques. Statistical correlation between the HLA type and response to DMTs was done using the initial and final MSSS. Results: Statistical relationships (p < 0.05) were found for only 15 of 245 alleles tested. There was a reduction in the MSSS for patients treated with corticosteroids (DRB1*15:01, DPB1*04:01, DQB1*02:01 and DQB1*03:01), azathioprine (DRB1*03:01, DPB1*04:01, DQB1*03:02, DQB1*06:02, HLA-C*07:02), interferon β-1a 22 mcg (DRB1*11:04, DQB1*03:01 and DQB1*03:02), interferon β-1a 30 mcg (DPB1*02:01, HLA-C*05:01) and interferon β-1b (DQB1*02:01). Conclusion: These findings suggest a few relationships between the HLA and response to DMTs in the disability for some types of HLA class I and II alleles in a specific subset of MS patients.

RESUMO Objetivo: Investigação da possível relação entre os tipos dos antígenos leucocitários humanos (HLA) classes I e II e a reposta a diversas terapêuticas modificadores da doença na incapacidade (DMT) da esclerose múltipla (MS). Métodos: Foram estudados os dados clínicos de 87 pacientes com MS no início e no final de cada de cada DMT, incluindo o tempo de doença, EDSS e MSSS. Através de técnicas de genotipagem de alta resolução, foram identificados os alelos dos HLA-DRB1, HLA-DPB1, HLA-DQB1, HLA-A, HLA-B e HLA-C. Foram realizados estudos estatísticos entre os tipos de HLA e a resposta às DMT, utilizando os valores iniciais e finais do MSSS. Resultados: Foram encontradas relações estatísticas (p < 0.05) para somente 15 alelos de 245 analisados. Houve redução dos valores do MSSS em pacientes tratados com corticosteroides (DRB1*15:01, DPB1*04:01, DQB1*02:01 e 03:01), azatioprina (DRB1*03:01, DPB1*04:01, DQB1*06:02, DQB1*03:02, HLA-C*07:02), interferon β-1a 22 mcg (DRB1*11:04, DQB1*03:01 e 03:02), interferon β-1a 30 mcg (DPB1*02:01, HLA-C*05:01) e interferon β-1b (DQB1*02:01). Conclusão: Os dados sugerem poucas relações entre os alguns tipos de HLA classe I e II com a resposta às DMT na incapacidade em grupos específicos de pacientes com MS.

Type 1 diabetes susceptibility determined by HLA alleles and CTLA-4 and insulin genes polymorphisms in Brazilians / Suscetibilidade ao diabetes tipo 1 determinada por alelos de HLA e polimorfismos nos genes CTLA-4 e insulina em brasileiros

INTRODUCTION:Type 1A diabetes mellitus (T1ADM) is a multifactorial disease in which genetic and environmental aspects are important to its development. The association of genetic variations with disease has been demonstrated in several studies; however, the role of some gene loci has not yet been fully elucidated. OBJECTIVE:To compare the frequency of HLA alleles and polymorphism in CTLA-4 and insulin genes in Brazilians with T1ADM and individuals without the disease, as well as to identify genetic markers that are able to discriminate between diabetic and non-diabetic individuals. METHODS: The presence of HLA DQB1, DQA1 and DRB1 alleles, as well as the -2221 MspI polymorphism in the insulin gene and 49 A/G in the CTLA-4 gene were identified by the "Time-resolved fluorometer" technique after hybridization with probes labeled with Eu (III) / Sm (III) and Tb (III). RESULTS: The DQB1 *0302 and DQA1 *03 alleles were identified as predisposed to T1ADM, and the DQB1 *0301 allele presented a protective effect against the disease.The DQA1 label proved to be able to differentiate between 71.13 percent of the diabetic and non-diabetic individuals.This value increased to 82.47 percent when the DQB1 label was added. No significant difference in the frequency of polymorphisms in the insulin and CTLA-4 genes was observed between the two groups. CONCLUSIONS: The genetic markers that best characterized and discriminated diabetic and non-diabetic individuals were the HLA DQA1 and DQB1.alleles.

INTRODUÇÃO: O diabetes melito tipo 1 (T1ADM) é uma doença multifatorial em que os aspectos genéticos e ambientais são importantes para o seu desenvolvimento. A associação das variações genéticas com a doença tem sido demonstrada em vários trabalhos, no entanto, o papel de alguns locos gênicos não foi ainda completamente elucidado. OBJETIVOS: Comparar a frequência de alelos do HLA e polimorfismos nos genes CTLA-4 e insulina em brasileiros com T1ADM e indivíduos sem a doença, além de identificar marcadores gênicos que sejam capazes de discriminar indivíduos diabéticos e não diabéticos. MÉTODOS: A presença dos alelos de HLA DQB1, DQA1 e DRB1, bem como dos polimorfismos -2221 MspI no gene da insulina e 49 A/G no gene CTLA-4, foram identificados por meio da técnica Time-resolved fluorometer, após hibridização com sondas marcadas com Eu (III)/Sm (III) e Tb (III). RESULTADOS: Os alelos DQB1*0302 e DQA1*03 foram identificados como sendo de predisposição ao T1ADM, e o alelo DQB1*0301 mostrou um efeito protetor à doença. Analisando somente o marcador DQA1, este mostrou ser capaz de diferenciar 71,13 por cento dos indivíduos entre diabéticos e não diabéticos, cujo valor aumentou para 82,47 por cento quando adicionado o marcador DQB1. A frequência dos polimorfismos nos genes da insulina e CTLA-4 não mostrou diferença significativa entre os dois grupos estudados. CONCLUSÕES: Os marcadores genéticos que melhor caracterizaram e discriminaram diabéticos e não diabéticos foram os alelos de HLA DQA1 e DQB1.

Estudo comparativo entre reação de Mitsuda e antígenos leucocitários humanos em pacientes hansenianos / Comparative study between the Mitsuda test and the human leukocyte antigens in leprosy patients

Neste estudo, propomos comparar o teste cutâneo de Mitsuda e os alelos HLA-DR2/HLA-DR3 e HLA-DQ1 relacionados com as formas clínicas da hanseníase em 176 pacientes (50 TT, 50 LL e 76 B). Os resultados obtidos não revelaram associação entre reação de Mitsuda e os alelos HLA nas formas clínicas isoladas; no entanto, quando analisados de acordo com a resposta ao teste de Mitsuda, associação significativa foi encontrada entre os pacientes Mitsuda negativos e HLA-DQ1 (p=0,002). Não foi observada associação entre reação de Mitsuda positiva e alelos HLA-DR2/DR3. Concluímos que existe importante participação do alelo HLA-DQ1 na ausência de resposta ao teste de Mitsuda. Sugerimos estudos mais específicos para este alelo.

In this study, we aimed to compare the Mitsuda skin test with the alleles HLA-DR2/HLA-DR3 and HLA-DQ1, in relation to the clinical forms of leprosy in 176 patients (50 TT, 50 LL and 76 B). The results obtained did not reveal any association between the Mitsuda reaction and the HLA alleles in the clinical forms isolated. However, when analyzed according to Mitsuda test response, a significant association was found between patients with negative Mitsuda reaction and HLA-DQ1 (p=0.002). No association was observed between positive Mitsuda reaction and the HLA-DR2/DR3 alleles. We concluded that the allele HLA-DQ1 has an important participation when there is no response to the Mitsuda test. We suggest that more specific studies should be developed on this allele.

Diabetes melito do tipo 1A na primeira infância de gêmeos dizigóticos: associação entre fatores genéticos e ambientais / Early infancy onset of type 1A diabetes mellitus in dizygotic twins: association with genetic and environmental factors

O Diabetes Mellitus tipo 1A diagnosticado antes do 1° ano de vida é uma condição rara, podendo haver uma associação entre fatores genéticos e ambientais (infecção) que explique tal precocidade. Foi descrita a presença do genoma do Citomegalovírus (CMV) nos linfócitos, em cerca de 15 por cento de novos casos de DM1. Relatamos os casos de desenvolvimento do diabetes em gêmeos dizigóticos do sexo masculino, nos primeiros 9 meses de idade com identidade nos alelos HLA (DR3/DR4) e história de infecção pelo CMV em ambos, comprovada por IgG+ e PCR urinária. Apenas o 2° gemelar apresentava o anticorpo anti-GAD positivo (9,6 UI/mL). Apesar de tratar-se de gêmeos dizigóticos, cuja taxa de concordância para diabetes, na literatura, é de 3,8 por cento, assumem risco equivalente a monozigóticos (de 40 por cento) por apresentarem HLA de alto risco para o diabetes. Acreditamos que tanto a concordância temporal como o início precoce do diabetes são decorrentes da associação entre infecção por CMV e forte suscetibilidade genética.

The onset of type 1A diabetes before the first year of age is a rare condition and is probably due to an interaction between genetic and environmental factors (infection), which, together, may explain such an early event. Studies say that about 15 percent of newly diagnosed type 1 diabetic patients had human Cytomegalovirus (CMV) specific viral genome in their lymphocytes. We report two cases of dizygotic twins with type 1 diabetes onset in their first 9 months of age, with genetic homogeneity (for HLA DR3/DR4 alleles), a history of CMV infection (positive IgG and urinary PCR) and positive antibody anti-GAD (9.6 UI/ml), present only in the second twin. Although they were dizygotic twins, which concordance rate is 3.8 percent, they assume the equivalent risk as monozygotic (40 percent) as they have similar high risk genotype (HLA) for type 1 diabetes. We believe that both time concordance and also the early onset of diabetes are due to an association between infection and the high genetic liability.

HLA antigen distribution in Jain population from Mumbai, Maharashtra, India.

BACKGROUND & OBJECTIVES: The Indian population is well known for its genetic diversity. Among the numerous endogamous communities, the Jain community from Mumbai is very restricted by custom, marriage and occupation. We present here the HLA antigen distribution of individuals belonging to this endogamous community. METHODS: A total of 161 healthy individuals of the Jain community working or studying in a hospital at Mumbai were selected randomly during 1985-1988. HLA class I and class II antigens were identified by using the standard National Institutes of Health (NIH) microlymphocytotoxicity assay. RESULTS: The phenotypic frequencies of HLA A1, A2, A9, A11, A24, B5, B35, B40, Cw4, DR2, DR3, DR4, DR5 and DR7 were increased while frequencies of HLA A10, A19, A26, A32, B7, B14, B16, B21, B22, B27, B37, Cw2, DR1 and DR9 were decreased when compared with other populations from, Maharashtra. The phenotype frequencies of HLA A26, A28, A30, B18, B40, B56, Cw3, Cw4, DR3, DR4 and DR5 were increased while the frequencies of HLA B7, B15, B16, B22, B37, Cw2, Cw6, DR1 and DR9 were decreased when compared with frequencies in other Indian populations. Two locus haplotype analyses revealed that A9-B5, B35-Cw4, DR2-DQ1 and DR7-DQ2 were significant haplotypes among the positive linkage disequilibrium haplotypes. Whereas A9-B35, B35-Cw1 and DR1-DQ2 were significant haplotypes among the negative linkage disequilibrium haplotypes. INTERPRETATION & CONCLUSION: The study revealed that the Jain population of Mumbai cannot be considered as a single panmictic population with reference to genetic characteristics, this may have a clinical relevance in unrelated donor selection for allogenic bone marrow transplantation in India.

Genetics of the immune responses and disease susceptibility

The identification of factors causing complex diseases contributes to the understanding of their pathophysiology and provides new diagnostic methods and potentially new prevention and treatment strategies. Polymorphic genes functioning in innate and acquired immune mechanisms participate in interindividual and interpopulational differences of susceptibility to many diseases of complex etiology and pathogenesis. Numerous studies have related especially the HLA genes to pathologic autoimmunity, and to the pathogenesis of infectious diseases and cancer. In recent years, the search for additional susceptibility genes has been facilitated by the resources and information generated by genome mapping and diversity analysis. Genes involved in immunity are being identified at an accelerating rate, and the investigation of implications of their variability regarding disease pathogenesis is beginning. Studies of Brazilian populations have especially contributed to recognition of genes modulating susceptibility to infections and their clinical outcome. Since genetic polymorphism differs between populations, the heterogeneity of the Brazilian populations, if properly explored, will add valuable information to the understanding of causes of complex diseases. Conversely, disease studies contribute to knowledge of the evolution and functional implications of genetic polymorphism.

Haplotipos HLA en familias chilenas con diabetes tipo 1 / HLA haplotypes in families with type 1 diabetes

Background: Inherited susceptibility to type 1 diabetes is partially determined by HLA genes. HLA-DQA1 and DQB1 alleles have been chosen as the most sensitive susceptibility markers. Family studies are a good method to establish specific relationship between type 1 diabetes and specific haplotypes as risk markers for the disease. Aim: To analyse the role of class II HLA molecules and the distribution of haplotypes in the genetic predisposition to type 1 diabetes in Chilean families. Material and methods: Twelve family groups constituted by 58 individuals were studied. Fourteen children (10 male) less than 15 years old with diabetes and their family members were included. The allele and haplotype frequency of the population was determined in 74 unrelated healthy children. Results: Risk haplotypes such as HLA-DR3/DQB1*0201/DQA1*0501 and HLA-DQB10302/DQA1*0501 were more common among diabetic patients and comparable to the haplotypes described in other Caucasian populations. Meanwhile, protective haplotypes found in relatives without diabetes, such as HLA-DR2/DQB1*0301/DQA1*0301 and HLA-DR8/DQB1*0402/DQA1*0301, were absent in children with diabetes. Conclusions: The general pattern of neutral or protective haplotypes, found with higher frequency in non diabetic individuals, indicates that their presence could confer protection against the disease, with a higher effect over those haplotypes associated to the disease

Frecuencia de antígenos eritrocitarios del sistema Rh-Hr en los cónyuges de mujeres Rh negativo / Antigenic profile of Rh-Hr erythrocytes system in the couple of the Rh negative women

Con el objetivo de establecer el perfil antigénico del sistema eritrocitario Rh-Hr, se estudiaron a 177 cónyugues de mujeres Rh negativo. En 15 casos (8.5 por ciento), fueron Rh negativo y 162 casos (91.5 por ciento) fueron Rh positivo. Con respecto a la cigocidad probable al antígeno D, en 100 casos (56.5 por ciento) son homocigotos , en 62 casos (35 por ciento), son hetoocigostos y 15 cónyuges (8.5 por ciento) Rh negativo. El fenotipo probable, de acuerdo a la frecuencia porcentual de casos, fueron DCCee (R1/r) en 48 cónyuges (27.1 por ciento), DCCee (R1/R1), con 46 casos (26 por ciento), DCcEe (R1/R2) en 36 casos (20.3 por ciento), DccEe (R2/r) con 14 casos (7.9 por ciento), DccEE (R2/R2) en 13 casos (7.3 por ciento), DCCEe (R1/RZ) y Dccee (Ro/r) con 2 casos cada uno (1.1 por ciento) y DCcEE (R2/RZ) con un sólo caso (0.5 por ciento). En los cónyuges Rh negativo, la más frecuente con 14 casos (7.9 por ciento) fue el fenotipo dcce (r/r y con el fenotipo dccEe (r"/r), se encontró sólo un caso (0.56 por ciento). La frecuencia génica de la población r/r (Rh negativo), mostró diferencia significativa (p < 0.025) con respecto a la frecuencia esperada de los sujetos Rh negativos en la población del Valle de México.

Sistemas ABO e RH, destacando-se a pesquisa do antígeno Du em Salvador, Bahia / ABO and RH blood groups, with special reference to Du antigen in Salvador - Bahia

Foi realizada a determinaçäo dos sistemas sangüíneos ABO e Rh(D) em 1.121 pessoas em Salvador-BA. Os resultados encontrados para os sistemas ABO e Rh foram semelhantes aos encontrados por outros autores brasileiros. O resultado do antígeno Du para Salvador foi de 0,1%