HLA-DQA1*04: 01 is related to a higher multiple sclerosis lesion load on T2/Flair MRI sequences / O HLA-DQA1*04: 01 está relacionado com uma alta carga lesional na ressonância magnética em T2/Flair nos pacientes com esclerose múltipla

ABSTRACT Background: The genetic predisposition to multiple sclerosis (MS) is associated with HLA alleles, especially HLA-DRB1*15:01. Objective: To identify associations between findings in magnetic resonance imaging (MRI) and genetic features in a Brazilian cohort of patients with MS. Methods: We retrospectively studied data from 95 consecutive patients with MS. Two independent observers who were blinded to the clinical data identified black holes and enhanced lesions on T1 MRI sequences, and counted and measured contrast-enhanced lesions on T2 and Flair (fluid attenuation inversion recovery) sequences. Cases were classified according to lesion size, number, and volume. The HLA-DRB1, HLA-DQB1, and HLA-DQA1 alleles, and the rs4774, rs3087456, rs6897932, rs731236, and rs1033182 single nucleotide polymorphisms were identified by polymerase chain reaction amplification with sequence-specific primers using the One Lambda Inc. Kit, Canoga Park, CA, USA. Results: Patients with the HLA-DQA1*04:01 allele had lesion load (adjusted for age, sex, and MS duration) above median compared with patients with other HLA-DQA1 alleles (p=0.02). There were no differences among all the other HLA alleles and single nucleotide polymorphisms and lesion load. Conclusions: The correlation of the HLA-DQA1*04:01 allele with a higher lesion load on T2/Flair MRI sequences suggests that the presence of this allele is associated with the risk of greater MS severity.

RESUMO Antecedentes: A predisposição genética para a esclerose múltipla (EM) está associada a alelos HLA, principalmente o HLA-DRB1*15:01. Objetivo: Identificar associações entre lesões na ressonância magnética e características genéticas em uma coorte brasileira de pacientes com EM. Métodos: Estudamos retrospectivamente os dados de 95 pacientes consecutivos com EM. Dois observadores independentes que desconheciam os dados clínicos identificaram "black holes" e lesões realçadas pelo contraste nas sequências de ressonância magnética T1 e contaram e mediram as lesões nas sequências T2 e FLAIR (fluid attenuated inversion recovery). Os casos foram classificados de acordo com tamanho, número e volume da lesão. Os alelos HLA-DRB1, HLA-DQB1 e HLA-DQA1 e os polimorfismos de nucleotídeo único rs4774, rs3087456, rs6897932, rs731236 e rs1033182 foram identificados por amplificação de reação em cadeia da polimerase com iniciadores específicos de sequência usando o kit One Lambda Inc., Canoga Park, CA, EUA. Resultados: Os pacientes com alelo HLA-DQA1*04:01 apresentaram carga de lesão (ajustada para idade, sexo e duração da EM) acima da mediana em comparação com outros pacientes com demais alelos HLA-DQA1 (p=0,02). Não houve diferenças entre todos os outros alelos HLA e polimorfismos de nucleotídeo único e carga lesional. Conclusões: A correlação do alelo HLA-DQA1*04:01 com maior carga de lesão nas sequências de RM em T2 sugere que a presença desse alelo pode estar associada ao risco de maior gravidade da EM.

Identification of blood-derived candidate gene markers and a new 7-gene diagnostic model for multiple sclerosis

BACKGROUND: Multiple sclerosis (MS) is a central nervous system disease with a high disability rate. Modern molecular biology techniques have identified a number of key genes and diagnostic markers to MS, but the etiology and pathogenesis of MS remain unknown. RESULTS: In this study, the integration of three peripheral blood mononuclear cell (PBMC) microarray datasets and one peripheral blood T cells microarray dataset allowed comprehensive network and pathway analyses of the biological functions of MS-related genes. Differential expression analysis identified 78 significantly aberrantly expressed genes in MS, and further functional enrichment analysis showed that these genes were associated with innate immune response-activating signal transduction (p = 0.0017), neutrophil mediated immunity (p = 0.002), positive regulation of innate immune response (p = 0.004), IL-17 signaling pathway (p < 0.035) and other immune-related signaling pathways. In addition, a network of MS-specific protein-protein interactions (PPI) was constructed based on differential genes. Subsequent analysis of network topology properties identified the up-regulated CXCR4, ITGAM, ACTB, RHOA, RPS27A, UBA52, and RPL8 genes as the hub genes of the network, and they were also potential biomarkers of MS through Rap1 signaling pathway or leukocyte transendothelial migration. RT-qPCR results demonstrated that CXCR4 was obviously up-regulated, while ACTB, RHOA, and ITGAM were down-regulated in MS patient PBMC in comparison with normal samples. Finally, support vector machine was employed to establish a diagnostic model of MS with a high prediction performance in internal and external datasets (mean AUC = 0.97) and in different chip platform datasets (AUC = (0.93). CONCLUSION: This study provides new understanding for the etiology/pathogenesis of MS, facilitating an early identification and prediction of MS.

Doença de Addison e esclerose múltipla: relato de caso / Addison's disease and multiple sclerosis: case report

A doença de Addison é uma endocrinopatia rara, de etiologia autoimune. É caracterizada por défice na secreção de glicocorticoides e mineralocorticoides. A esclerose múltipla consiste em patologia neurológica, de origem autoimune, que resulta na desmielinização da bainha de mielina. O objetivo deste relato foi demonstrar a associação rara entre essas duas patologias e suas possíveis relações imunológicas. A paciente analisada é do sexo feminino, 41 anos, portadora de esclerose múltipla, que posteriormente foi diagnosticada com insuficiência adrenal primária. (AU)

Addison's disease is a rare endocrinopathy of autoimmune etiology. It is characterized by a secretion's deficit of glucocorticoids and mineralocorticoids. Multiple sclerosis is a neurological pathology of autoimmune origin, which results in demyelination of the myelin sheath. The purpose of this report is to demonstrate the uncommon association between these two pathologies and their possible immunological relationships. The analyzed patient is a woman, 41 years old, with multiple sclerosis, who was later diagnosed with primary adrenal insufficiency. (AU)

Polymorphisms in the CIITA -168A/G (rs3087456) and CIITA +1614G/C (rs4774) may influence severity in multiple sclerosis patients / Os polimorfismos no gene CIITA - 168A/G (rs3087456) e CIITA +1614G/C (rs4774) podem influenciar a gravidade em pacientes com esclerose múltipla

ABSTRACT It is currently unknown how genetic factors may influence the clinical course of multiple sclerosis (MS). Objective: We examined the impact of CIITA polymorphisms −168A/G (rs3087456) and +1614G/C (rs4774) on the risk of disability progression, severity and on responses to first-line immunomodulator treatments. Methods: Genomic DNA was extracted from blood samples. We used ABI3730xl and GeneMapper v.4.0 software to identify genotype variations. All patients were followed up and clinically reassessed at three-month intervals. Disability progression was measured by the Expanded Disability Status Scale and disease severity by the Multiple Sclerosis Spasticity Scale (MSSS). Results: We included 37 men and 80 women. We found no evidence regarding the influence of the single nucleotide polymorphisms studied in the Expanded Disability Status Scale or therapeutic response of the evaluated drugs. We performed a logistic regression analysis with the MSSS and found that a less severe MS course was associated with wild type CIITA −168AA and CIITA +1614GG, as the chance of the patient progressing to MSSS2 and MSSS3 decreased in 61% and 75% with CIITA −168AA and 66% and 75% with CIITA +1614GG, respectively (p < 0.0001). Although less significant, the CIITA +1614 GC also pointed to a less severe MS course and the chance of the patient progressing to MSSS3 decreased 79% (p = 0.015). We also observed that the CIITA −168GG genotype was more frequent in MSSS2 and MSSS3 and had 40% lower odds ratio to becoming more severe MS. Conclusion: These data suggest that CIITA −168AA, CIITA +1614GG and CIITA +1614 GC polymorphisms may be associated with a better MS clinical course. This knowledge may be useful for a better understanding of MS and its therapeutic management.

RESUMO Atualmente não se sabe como os fatores genéticos podem influenciar o curso clínico da esclerose múltipla (EM). Objetivo: Examinamos o impacto dos polimorfismos CIITA −168A/G (rs3087456) e CIITA +1614G/C (rs4774) no risco de progressão da incapacidade, gravidade e resposta aos tratamentos imunomoduladores de primeira linha. Métodos: O DNA genômico foi extraído de amostras de sangue. Utilizamos o software ABI3730xl e GeneMapper v.4.0 (Applied Biosystems) para identificar variações genotípicas. Todos os pacientes foram acompanhados e reavaliados clinicamente em intervalos de três meses. A progressão da incapacidade foi medida pela EDSS e a gravidade da doença pelo MSSS. Resultados: Incluímos 37 homens e 80 mulheres. Não encontramos evidências sobre a influência dos SNPs estudados no EDSS e na resposta terapêutica aos fármacos avaliados. Realizamos uma análise de regressão logística com o MSSS e observamos uma evolução menos grave da EM associada aos tipos selvagens CIITA −168AA e CIITA +1614GG, pois a chance do paciente atingir MSSS2 e MSSS3 diminuiu em 61%/75%, e 66/75% respectivamente (p < 0,0001). Embora menos significativo, o CIITA +1614GC também foi relacionado com evolução menos grave da EM e a chance do paciente atingir o MSSS3 diminuiu 79% (p = 0,015). Nós também observamos que o genótipo CIITA −168GG foi mais frequente no MSSS2 e MSSS3 e teve uma razão de chance 40% menor para atingir forma mais grave da EM. Conclusão: Estes dados sugerem que os polimorfismos CIITA −168AA, CIITA +1614GG e CIITA +1614GC podem estar associados a um melhor curso clínico da EM. Este conhecimento pode ser útil para uma melhor compreensão da EM e o seu manejo terapêutico.

Associação entre esclerose múltipla e alelos HLA-DRB1 em uma população miscigenada de Salvador, Ba, Brasil / Association between multiple sclerosis and HLA-DRB1 alleles in an admixed population of Salvador, Ba, Brazil

Introdução: a esclerose múltipla é uma doença que afeta preferencialmente o sistema nervoso central de mulheres jovens, causandolhes graus variáveis de incapacidades física e cognitiva. Etiologicamente associa fatores ambientais, biológicos, sócio-econômicos e genéticos, como por exemplo genes do MHC classe II, especialmente os alelos HLA-DRB1*. Objetivo: determinar a frequência dos alelos HLA DRB1* em portadores de esclerose múltipla atendidos no centro de referência do C.H.U.P.E.S, UFBA, no período de outubro de 2014 a abril de 2015 e associá-las a variáveis clínico-demográficas. Metodologia: estudo do tipo caso-controle, aprovado pelo comitê de ética da Faculdade de medicina da Universidade Federal da Bahia (CAAE: 3517134.0.0000.5577), que envolveu uma amostra de conveniência composta por 97 indivíduos, cujos dados clínico-demográficos foram coletados através de questionário desenvolvido para a pesquisa. A genotipagem dos alelos HLA-DRB1* foi realizada através da técnica HLA-DR SSO GenotypingTest. Resultados: a análise quantitativa revelou perfil genotípico do tipo HLA-DRB1*15 (20,5%), em mulheres (83,0%), das raças/etnias negra ou parda (75,0%), com faixa etária entre 30 e 39 anos (28,0%). Houve predomínio da forma clínica surtoremissiva da doença (76,0%), dentre os doentes com idade mais avançada (55,0%), sem permanência de sequela clínica (70,0%) e que usavam algum tipo de Interferon (58,0%). A análise qualitativa indicou maiores frequências, na forma progressiva de esclerose múltipla dos grupos alélicos HLA-DRB1*12 (22,0%), e dos alelos HLA-DRB1*13 (12,6%)e HLA-DRB1*15 (22,0%) naqueles indivíduos com a forma surtoremissiva. Negros e pardos demonstraram maior prevalência do alelo HLA-DRB1*15 (24,0%), enquanto que nos brancos houve maior prevalência do alelo HLA-DRB1*07 (20,0%). Conclusão: forte associação entre as frequências alélicas, esclerose múltipla e as variáveis raça/etnia e forma clínica da doença.

Is there a relationship between narcolepsy, multiple sclerosis and HLA-DQB1* 06: 02? / Existe relação entre narcolepsia, esclerose múltipla e HLA-DQB1* 06: 02?

ABSTRACT We studied multiple sclerosis (MS) patients with the HLA-DQB1*06:02 allele and compared them with MS patients who did not carry the HLA-DQB1*06:02 allele. We analyzed clinical and neurophysiological criteria for narcolepsy in six MS patients with HLA-DQB1*06:02, compared with 12 MS patients who were HLA-DQB1*06:02 non-carriers. Only two patients with HLA-DQB1*06:02 allele scored higher than 10 on the Epworth Sleepiness Scale. Polysomnography recording parameters and the multiple sleep latency test showed an absence of narcolepsy in the study group. Our study suggested no significant correlation between narcolepsy, MS and HLA-DQB1*06:02. The HLA-DQB1*06:02 allele alone was not sufficient to cause MS patients to develop narcolepsy.

RESUMO Pacientes com esclerose múltipla (EM) portadores do alelo HLA-DQB1*06:02 foram estudados e comparados com pacientes com EM mas que não são portadores do alelo HLA-DQB1*06:02. Os critérios clínicos e neurofisiológicos para narcolepsia foram analisados em pacientes com EM sendo 6 pacientes com o HLA-DQB1*06:02 comparados a 12 pacientes sem o HLA-DQB1*06:02. Somente 2 pacientes com EM e HLA-DQB1*06:02 tiveram escore maior que 10 na escala “Epworth Sleepiness Scale”. Os parâmetros da polissonografia e o teste de múltiplas latências do sono mostraram ausência de narcolepsia no grupo estudo. Nosso estudo não sugere correlações significantes entre narcolepsia, EM e HLA-DQB1*06:02. Somente o HLA-DQB1*06:02 não foi suficiente para desenvolver narcolepsia em pacientes com EM.

The immunogenetics of multiple sclerosis. The frequency of HLA-alleles class 1 and 2 is lower in Southern Brazil than in the European population / Imunogenética na esclerose múltipla. A frequência dos alelos HLA classe 1 e 2 no sul do Brasil são menores que da população Europeia

ABSTRACT Objective To study the HLA of class 1and 2 in a multiple sclerosis (MS) population to verify the susceptibility for the disease in the Southern Brazil. Methods We analyzed patients with MS and controls, by direct sequencing of the genes related to HLA DRB1, DQB1, DPB1, A, B and C alleles with high resolution techniques. Results We found a lower frequency of all HLA alleles class 1 and 2 in MS and controls comparing to the European population. Several alleles had statistical correlation, but after Bonferroni correction, the only allele with significance was the HLA-DQB1*02:03, which has a positive association with MS. Conclusions Our data have different frequency of HLA-alleles than the previous published papers in the Southeast Brazil and European population, possible due to several ethnic backgrounds.

RESUMO Objetivo Estudo do HLA classes 1 e 2 em pacientes com esclerose múltipla (EM) a fim de verificar a susceptibilidade para a doença em uma população do Sul do Brasil. Métodos Foram analisados por sequenciamento direto de alta resolução os genes relacionados com os HLA DRB1, DQB1, DPB1, A, B e C em casos de EM comparados com uma população controle normal. Resultados Foi encontrado uma frequência menor dos alelos dos HLA classe 1 e 2 nos casos de EM e controles quando comparado com a população Europeia. Diversos alelos mostraram correlação estatística, mas depois da correção de Bonferroni, somente o alelo do HLA-DQB1*02:03 foi positivo para a EM. Conclusões Encontramos frequência diferente dos alelos do HLA relatados previamente nos Sudeste do Brasil e Europeus, possivelmente devido a origem étnica diferente da população estuda.

The CIITA genetic polymorphism rs4774*C in combination with the HLA-DRB1*15:01 allele as a putative susceptibility factor to multiple sclerosis in Brazilian females / O polimorfismo rs4774*C no gene CIITA em conjunção com o alelo HLA-DRB1*15:01 é um possível fator de susceptibilidade a esclerose múltipla em mulheres brasileiras

The objective of this study was to investigate the association between the HLA alleles at the DQA1, DQB1 and DRB1 loci, the CIITA genetic polymorphisms -168A/G and +1614G/C, and susceptibility to multiple sclerosis (MS) in a sample from Rio de Janeiro State, Brazil. Furthermore, we wished to determine whether any of these associations might be more significant in women compared with men. DNA samples from 52 relapsing-remitting MS (RRMS) patients and 126 healthy controls matched for sex and age were analyzed. We identified a significant HLA-DRB1*15:01-MS association that was female-specific (Odds Ratio (OR) = 4.78; p = 0.001). Furthermore, we observed that the +1614G/C mutation in combination with the HLA-DRB1*15:01 allele increased susceptibility to MS in females (OR = 4.55; p = 0.01). Together, these findings highlight the polygenic nature of MS.

O objetivo deste estudo foi investigar a associação entre alelos HLA, loci DQA1, DQB1 e DRB1, polimorfismos -168A/G e +1614G/C no gene CIITA, e suscetibilidade à esclerose múltipla (EM) em uma amostra de Rio de Janeiro, Brasil. Além disso, buscou-se determinar se alguma dessas associações pode ser gênero-dependente. Foram analisadas amostras de DNA de 52 pacientes com EM reincidente-remitente (EMRR) e 126 controles saudáveis ​​pareados por sexo e idade. Foi identificada associação significativa HLA-DRB1*15:01-EMRR, que foi específica para o gênero feminino (Odds Ratio (OR) = 4,78, p = 0,001). Além disso, observou-se que o polimorfismo +1614 G/C, em combinação com o alelo HLA-DRB1*15:01 provoca o aumento da susceptibilidade à EM em pacientes do sexo feminino (OR = 4,55, p = 0,01). Juntos, estes resultados destacam a natureza poligênica da EM.

Novel mutations identified in EIF2B5 gene in Kashmiri patients as susceptibility factor for multiple sclerosis.

White matter disease refers to a set of diseases that affect the white matter of the brain and all of which have different consequences on brain function. Most of the studies have shown that it results from the defects during protein synthesis, with the gene defects in EIF2B1–5, encoding the five subunits of eukaryotic translation initiation factor 2B (eIF2B) α, β, γ, δ and ε, respectively. eIF2B plays a crucial role in protein translation and its regulation under different conditions. The previous studies have shown that mutations in five subunits of eIF2B cause white matter disease of the brain and thus EIF2B is the main culprit in development of white matter disease. In this study, the mutational screening of EIF2B5 gene encoding eIF2Bε was performed for the first time in 12 Kashmiri patients, each having a unique white matter disease condition. We found two novel missense mutations in EIF2B5: c.580A>G, p.Thr194Ala and c.611C>T, p.Ala204Val among the patients with demyelinating disease (multiple sclerosis), but no mutation was found in other patients. In conclusion our study suggests involvement of the EIF2B5 gene in MS development, thus suggesting p.Thr194Ala to be a susceptibility factor for the development of multiple sclerosis.

Investigation of cytocrom c oxidase gene subunits expression on the Multiple sclerosis.

INTRODUCTION: Multiple sclerosis (MS) is an autoimmune inflamatory disease, which affects the (Central Nervous System) and leads to the destruction of myelin and atrophy of the axons. Genetic factors, in addition to environmental ones, seem to play a role in MS. Numerous studies have reported mitochondrial defects including a reduction in cytochrome c oxidase (COX) complex function related to the reduction of mitochondrial genes expression in the cortex tissue of patients with MS have been reported. MATERIALS AND METHODS: This study aimed to assess COX5B and COX2 genes expression in MS patients and compare it with normal subjects. We determine expression levels of genes COX5B and COX2, and also gene reference ß-actine using real–time polymerase chain reaction (RT-PCR) method. Data were obtained and obtained and standardized with the gene reference and were analyzed using independent sample t-test with SPSS and Excel programs. RESULT AND DISCUSSION: The resultshowed COX5B gene expression reduced significant in MS patients compared to normal subjects (P < −0.05) whereas, there was no significant difference in the COX2 gene expression between normal subjects and patients. Thus, it can be claimed that down-regulation of mitochondrial electron transport chain genes supported the hypothesis that hypoxia-like tissue injury in MS may be due to mitochondrial genes, different expression impairment.

Association of interleukin-4 polymorphisms with multiple sclerosis in southeastern Iranian patients

Immune system-related factors are important in the pathogenesis of multiple sclerosis [MS]. Interleukin 4 [IL-4] as a helper T cell [2TH] cytokine is involved in the regulation of immune responses. Hence, this study was designed to explore the association between MS and polymorphisms in the -590 region of IL-4. A descriptive study at Rafsanjan University of Medical Sciences, Rafsnajan from September 2009 to August 2010. Blood samples were collected from 100 MS patients and 150 healthy controls on EDTA precoated tubes. DNA was extracted and analyzed for IL-4 polymorphisms using restricted fragment length polymorphism in patients and controls. Demographic data were also collected by a questionnaire that was designed specifically for this study. We observed a significant difference in the C/C, T/C, and T/T genotypes of the -590 region of IL-4 between patients with MS and healthy controls [P<.001]. We conclude that functional polymorphisms of IL-4 possibly play a crucial role in the pathogenesis of MS

MICB gene expression on peripheral blood mononuclear cells and susceptibility to multiple sclerosis in north of Iran

Multiple sclerosis [MS] is an autoimmune multifactorial degenerative disease with detrimental affliction on central nervous system. MHC class I chain- related geneA,B [MICA and MICB] are nonclassical human leukocyte antigens that can affect on some diseases and also on transplantation. The purpose of this study was to evaluate the MICA and MICB MRNA expression in multiple sclerosis patients. In this study, we evaluated MICA and MICB MRNA expression in the peripheral blood mononuclear cells by reverse transcryptase-polymerase chain reaction [RT-PCR] in MS patients and normal controls. The results of this study showed that 32.6% of patients with progressive clinical outcome over expressed MICB genes in comparison with controls [p=0.002]. It is concluded that the high expression of MICB gene in MS patients is an important criterion of MS disease that it may be due to the interaction between MICB and its receptor on CD8+T or NK cells

Is tumor necrosis factor - 376a promoter polymorphism associated with susceptibility to multiple sclerosis? / ¿El polimorfismo-376A del promotor del gen del factor de necrosis tumoral se asocia con una mayor susceptibilidad a padecer esclerosis múltiple?

A single nucleotide polymorphism (SNP) at position -376 of the tumor necrosis factor α gene (TNFA) has been associated with susceptibility to multiple sclerosis (MS) in Spain. However, no association was found in populations from the USA and The Netherlands. Here we investigate the association between the TNFA - 376A SNP and MS susceptibility in Argentinean patients with MS. The A/G genotype was found in 4.4% of patients (n=90) and in 4.8% of healthy individuals (n=84; p=0.92; odds ratio=0.93; confidence interval: 0.23- 3.84). Thus, no significant differences in genotype and allele frequencies were found between healthy individuals and patients with MS in Argentina.

Un polimorfismo de nucleótido único (SNP, por sus iniciales en inglés) en la posición -376 del gen codificante del factor de necrosis tumoral α (TNFA) ha sido asociado en España con un mayor riesgo a padecer esclerosis múltiple (EM). Sin embargo, esta asociación no fue encontrada en estudios hechos en poblaciones provenientes de los EE.UU. y Holanda. Aquí investigamos la asociación entre el SNP TNFA -376A y el desarrollo de EM en una población de pacientes argentinos con EM. El genotipo A/G fue encontrado en 4.4% de los pacientes (n=90) y en 4.8% de los controles sanos (n=84; p=0.92; odds ratio=0.93; intervalo de confianza: 0.23-3.84). En consecuencia, no encontramos diferencias en las frecuencias alélicas y genotípicas entre los sujetos enfermos y los controles sanos en Argentina.

Study of polymorphisms in the interleukin-4 and IL-4 receptor genes in a population of Brazilian patients with multiple sclerosis

This study aimed to investigate in a population of Brazilian patients with multiple sclerosis (MS) single-nucleotide polymorphisms (SNP) in the promoter region of IL4 (*33C-T) and receptor IL4R (*Q551R A-G) genes proposed to interfere with disease progression. No significant differences were observed in either of the SNPs investigated between healthy controls (n=135) and MS patients (n=129). However, the IL4+33 TT genotype was significantly (p=0.039) higher in African descendants MS (AF-MS= 9.09 percent) than in Caucasian MS (CA-MS= 1.35 percent). It was also observed a significant (p=0.016) increase for the IL4R* Q551R CC genotype in AF-MS compared to those of Caucasian ethnicity (AF-MS= 21.62 percent; CA-MS= 4.35 percent). These results suggest that IL4+33 and IL4R*Q551 polymorphisms may have a disease-promoting role of TH2 mediators in African MS descendants. Additionally neither IL4 nor IL4R genes are susceptibility factors for Brazilian MS but may be able to modify ethnicity-dependent disease risk and penetrance of susceptibility factors.

Este é um estudo inédito realizado numa população brasileira de pacientes portadores de esclerose múltipla (EM) visando determinar uma possível associação na expressão de polimorfismo (SNP) nos genes da citocina reguladora IL4 (*33C-T) e do seu respectivo receptor IL4R (*Q551R A-G) capazes de modificar a evolução da doença. Não foi observada diferença significativa em ambos SNPs analisados entre o grupo controle de indivíduos saudáveis (n=135) e os pacientes com EM (n=129). Contudo, o genotipo IL4+33 TT apresentava percentual mais elevado (9,09 por cento) nos pacientes EM com descendência africana (AF-EM) do que nos descendentes caucasianos (CA-EM=1,35 por cento) sendo esta diferença significativa (p=0,039). Também foi observado um aumento significativo (p=0,016) para o genotipo IL4R* Q551R CC nos pacientes AF-EM (21,62 por cento) comparando-se com CA-EM (4,35 por cento). Estes resultados indicam que polimorfismos nos genes da citocina IL4 (*33C-T) e respectivo receptor IL4R (*Q551R A-G) influenciam na produção de citocinas do tipo TH2 e evolução da doença nos pacientes EM com descendência africana. Embora polimorfismo nos genes IL4 (*33C-T) e respectivo receptor IL4R (*Q551R A-G) não sejam fatores indutores de susceptibilidade para EM podem modificar o risco e evolução da EM numa população com alto grau de miscigenação étnica.

HLA profile and clinical presentation of multiple sclerosis in Iran

Multipie sclerosis [MS] is a demyelinating disease of the central nervous system, with unknown etiology in which both genetic and environmental factors are thought to be involved. The HLA system provides a set of genetic markers which lend themselves to systematic study. The disease also has variable clinical manifestations, ranging from a relapsing-remitting course to a chronic progressive disease. In this article we review HLA profile and clinical presentation of the disease from current available data in Iran

Molecular Analysis of HLA Class ll-Associated Susceptibility to Neuroinflammatory Diseases in Korean Children

The work was done to study immunogenetic peculiarities of neuroinflammatory diseases among Korean children. A total of 13 children with neuroinflammatory diseases (8 males and 5 females; mean age 4.6+/-2.6 yr) were consecutively recruited. Genomic typing was performed on their HLA DRB/HLA DQB genes using PCR-SSOP/ SSP techniques with gel immunoelectrophoresis. The frequencies of HLA-DR1* 15 in children with acute disseminated encephalomyelitis (ADEM) (31%) and DQB1* 06 in other neuroinflammatory diseases (38%) were significantly increased compared with control subjects. The frequencies of HLA-DRB3*0202 (100%), HLA-DRB1*1302 (67%), HLA-DRB3*0301 (67%), and HLA-DQB1*0301 (67%) were significantly increased in children with multiple sclerosis and the frequencies of HLA-DRB1*1501 (40%) and HLA-DRB5*0101 (40%) were significantly increased in children with ADEM. HLA-DRB1*1401, HLA- DRB3*0202, and HLA-DQB1*0502 were found in children with acute necrotizing encephalopathy. In conclusion, HLA-DR1*15 and DQB1*06 may be involved in susceptibility to inflammation in Korean children. The frequencies of HLA-DRB1*1501, HLA-DRB5*0101, HLA-DRB3*0301, and HLADQB1* 0602 were not as high in Korean children with multiple sclerosis as in western children. However, HLA-DRB3*0202 was seen in all children with multiple sclerosis. Our data may provide further evidence that the immunogenetic background of neuroinflammatory diseases in Korean is distinctly different from the ones in western countries. Further studies are necessary to confirm this finding.

Determinação de autoanticorpos para antígenos da mielina no soro de pacientes HLA - DQB1*0602 com esclerose múltipla / Determination of autoantibody for myelin antigens in the serum of patients HLA - DQB1*0602 with multiple sclerosis

Esclerose múltipla (EM) é doença inflamatória desmielinizante do sistema nervoso central (SNC) de natureza autoimune, mediada por linfócitos Th1. A produção de autoanticorpos séricos para proteína básica da mielina (MBP), proteolipídeo PLP e sequência da glicoproteína de oligodendrócito MOG 92-106, foi determinada em 54 indivíduos saudáveis e 26 pacientes com EM expressando ou não o alelo de suscetibilidade HLA-DQB1*0602. Independentemente da expressão do alelo DQB1*0602, todos os pacientes apresentaram produção marcante (p< 0,0001) de autoanticorpos isotipo IgG para MBP e MOG 92-106, e do isotipo IgA para PLP e MOG 92-106. Os resultados sugerem que outros alelos HLA da classe II exerçam influência na suscetibilidade à EM e no reconhecimento imunológico dos antígenos encefalitogênicos, determinando o padrão de resposta autoimune e contribuindo na manutenção e/ou controle da inflamação no SNC

Esclerosis múltiple: aproximación epidemiológico-genética en habitantes de Antioquia, Colombia. II: desequilibrio de ligamento al HLA DQÓ / Multiple sclerosis: an epidemiologycal approach in Antioquia, Colombia. II: Linkage desequilibrium to HLA, locus DQÓ

La discriminación y cuantificación de los componentes ambientales y genéticos en el desarrollo de esclerosis múltiple (EM) no se ha podido realizar. con la finalidad de acercarnos a la discriminación de dichos componentes, hemos analizado casos afectados de EM a partir de la comunidad paisa de Antioquia, Colombia, zona situada en el trópico; para detectar un posible desequilibrio de ligamiento al HLA, locus DQÓ, aspecto que revelaría la importancia del componente genético en el desarrollo de EM. Un análisis de contingencia entre las distribuciones genotípicas del HLA DQÓ de los casos y controles, usando el remuestreo de Monte Carlo para solucionar el problema del tamaño muestral que es inherente a las poblaciones con baja prevalencia de EM, reveló que existen diferencias significativas entre las dos distribuciones. La tendencia alélica observada fue de un incremento de los alelos 1.1., 1.2 y una disminución de los alelos 3 (con un p significativamente < de 0,05) y 4 en la población afectada. Los mismos resultados han sido descritos en otras poblaciones de origen caucasoide no localizadas en el trópico, lo cual puede indicar que este componente genético descrito en la población caucasoide se ha mantenido en la poblaciòn de enfermos con EM originarios de Antioquia y que continúa siendo importante para el desarrollo de la enfermedad