Investigation of MHC gamma block C4A and C4B polymorphisms in unrelated hematopoietic stem cell transplantation

ABSTRACT Background: Immunological life-threatening complications frequently occur in post-hematopoietic stem cell transplantation (HSCT), despite matching recipient and donor (R/D) pairs for classical human leukocyte antigens (HLA). Studies have shown that R/D non-HLA disparities within the major histocompatibility complex (MHC) are associated with adverse effects post-HSCT. Methods: We investigated the impact of mismatches of single-nucleotide polymorphisms (SNPs) in C4A/C4B genes, for showing the highest diversity in the MHC gamma block, on 238 patients who underwent HLA 10/10 unrelated donor (URD) HSCT. The endpoints were acute graft-versus-host disease (aGVHD), chronic graft-versus-host disease (cGVHD) and mortality. One hundred and twenty-nine R/D pairs had 23 C4-SNPs typed by PCR-SSP (Gamma-Type™v.1.0), and 109 R/D pairs had these 23 SNPs identified by next-generation sequencing (NGS) using the Illumina platform. Results: The percentage of patients who received HSC from HLA 10/10 donors with 1-7 mismatches was 42.9%. The R/D pairs were considered C4 mismatched when bearing at least one disparity. These mismatches were not found to be risk factors for aGVHD, cGVHD or mortality after unrelated HSCT when SNPs were analyzed together (matched or mm ≥ 1), independently or according to the percentage of incompatibilities (full match for 23 SNPs; 1-3 mm and >3 mm). An exception was the association between 1-3 mismatches at the composite of SNPs C13193/T14952/T19588 with the development of aGVHD (P = 0.012) and with grades III-IV of this disease (P = 0.004). Conclusion: Our data are not consistent with the hypothesis that disparities in C4A/C4B SNPs increase the risks of post-HSCT adverse effects for the endpoints investigated in this study.

HLA-alleles class I and II associated with genetic susceptibility to neuromyelitis optica in Brazilian patients / Alelos HLA classes I e II associados à suscetibilidade genética a neuromielite óptica em pacientes brasileiros

ABSTRACT Objective: To study the genetic susceptibility to neuromyelitis optica (NMO) as well as the relationship between HLA genotypes and susceptibility to the disease in the southern Brazilian population. Methods: We analyzed patients with NMO, who met criteria for Wingerchuk's diagnosis of NMO, with detected serum anti-AQP4-IgG antibody. The HLA genotyping was performed by high-resolution techniques (Sanger sequencing) in patients and controls. The HLA genotypes were statistically compared with a paired control population. Results: The HLA genotyping revealed the diversity of the southern Brazilian population whose HLA profile resembled European and Asian populations. Some alleles had statistical correlations with a positive association (increased susceptibility) with NMO, particularly the HLA-DRB1*04:05 and *16:02. Conclusions: In our study, the HLA genotype was different to that previously reported for other Brazilian populations. Although our study had a small cohort, HLA genotypes were associated with increased susceptibility to NMO for HLA-DRB1*04:05 and *16:02. The alleles of HLA class I HLA-A*02:08 and *30:09, HLA-B*08:04 and *35:04 showed an association before the Bonferroni correction.

RESUMO Objetivo: Estudar a suscetibilidade genética a neuromielite óptica (NMO) assim como sua relação com o genótipo HLA na população do sul do Brasil. Métodos: Nós analisamos pacientes com NMO que preenchiam os critérios diagnósticos de Wingerchuk para NMO, com presença do anticorpo anti-AQP4-IgG no soro. O genótipo HLA foi realizado usando técnicas de alta resolução (sequenciamento de Sanger) em pacientes e controles. Genótipos HLA foram estatisticamente comparados com uma população controle pareada. Resultados: Genotipagem HLA revelou a diversidade da população sul brasileira cujo perfil HLA lembra as populações europeia e asiática. Alguns alelos tiveram correlação estatística com associação positiva (suscetibilidade aumentada) com NMO, particularmente o HLA-DRB1*04:05 e *16:02. Conclusões: Em nosso estudo, o genótipo HLA foi diferente do previamente relatado em outras populações brasileiras. Embora o número de pacientes tenha sido pequeno, HLA específicos foram associados com suscetibilidade aumentada a NMO para HLA-DRB1*04:05, *16:02. Os alelos HLA classe I HLA*02:08 e *30:09, HLA-B*08:04 e *35:04 tiveram associação antes da correção de Bonferroni.

Polimorfismos de un solo nucleótido representativos para los alelos clásicos del antígeno leucocitario humano en familias antioqueñas con diabetes mellitus tipo 1 / Classical HLA alleles tag SNP in families from Antioquia with type 1 diabetes mellitus

Resumen Introducción. La región del antígeno leucocitario humano (Human Leukocyte Antigen, HLA) se ha asociado claramente con enfermedades autoinmunitarias, como la diabetes mellitus de tipo 1. Los polimorfismos representativos de un solo nucleótido (tag Single Nucleotide Polymorphism, tag SNP) constituyen una forma alternativa de evaluar los alelos clásicos del HLA. En la población europea se ha reportado un grupo de tag SNP para múltiples alelos clásicos relacionados con la predisposición o la resistencia frente a dicha enfermedad. Objetivo. Validar la metodología basada en los tag SNP enfocada en la inferencia de alelos HLA clásicos, y evaluar su asociación con la diabetes mellitus de tipo 1 en una muestra de familias antioqueñas. Materiales y métodos. Se estudió una muestra de 200 familias antioqueñas con uno a dos hijos afectados por diabetes mellitus de tipo 1. Se genotipificaron 13 SNP mediante el ARMS-PCR (Amplification Refractory Mutation System-Polymerase Chain Reaction) con cuatro iniciadores, o mediante la PCR-RFLP (PCR-Restriction Fragment Length Polymorphism). Además, se evaluó la validez de los tag SNP de 1.000 genomas reportados en europeos en una muestra de 60 individuos de la población colombiana de Medellín. Se hicieron las pruebas de desequilibrio de la transmisión, de desequilibrio de ligamiento y de equilibrio de Hardy-Weinberg. Resultados. En la población de estudio no se encontró suficiente desequilibrio de ligamiento entre los SNP y los alelos clásicos evaluados, por lo cual no fue posible inferir los alelos clásicos del HLA para el conjunto de familias con diabetes mellitus de tipo 1. El estudio de asociación evidenció que esta región aporta factores tanto de riesgo como de protección para el desarrollo de la enfermedad. Los tag SNP apropiados para la muestra de estudio se determinaron usando los SNP ubicados en la región HLA en la base de datos del 1000 Genomes Project en la mencionada población. Conclusiones. Los patrones de desequilibrio de ligamiento en la población estudiada fueron diferentes a los reportados para la población europea. A pesar de esto, se encontró evidencia clara sobre el papel de la región HLA en el riesgo de padecer diabetes mellitus de tipo 1 en la población de estudio.

abstract Introduction: The HLA region strongly associates with autoimmune diseases, such as type 1 diabetes. An alternative way to test classical HLA alleles is by using tag SNP. A set of tag SNP for several classical HLA alleles has been reported as associated with susceptibility or resistance to this disease in Europeans. Objective: We aimed at validating the methodology based on tag SNP focused on the inference of classical HLA alleles, and at evaluating their association with type 1 diabetes mellitus in a sample of 200 families from Antioquia. Materials and methods: We studied a sample of 200 families from Antioquia. Each family had one or two children with T1D. We genotyped 13 SNPs using tetra-primer ARMS-PCR or PCRRFLP. In addition, we tested the validity of the tag SNP reported for Europeans in 60 individuals from a population of Colombians living in Medellín (CLM) from the 1000 Genomes Project database. Statistical analyses included the Hardy-Weinberg equilibrium, the transmission disequilibrium and the linkage disequilibrium tests. Results: The linkage disequilibrium was low in reported tag SNP and classical HLA alleles in this CLM population. Association analyses revealed both risk and protection factors to develop type 1 diabetes mellitus. Appropriate tag SNPs for the CLM population were determined by using the genotype information available in the 1000 Genome Project database. Conclusions: Although linkage disequilibrium patterns in this CLM population were different from those reported in Europeans, we did find strong evidence of the role of HLA in the development of type 1 diabetes mellitus in the study population.

PPARγ induces growth inhibition and apoptosis through upregulation of insulin-like growth factor-binding protein-3 in gastric cancer cells

Peroxisome proliferator activator receptor-gamma (PPARγ) is a ligand-activated transcriptional factor involved in the carcinogenesis of various cancers. Insulin-like growth factor-binding protein-3 (IGFBP-3) is a tumor suppressor gene that has anti-apoptotic activity. The purpose of this study was to investigate the anticancer mechanism of PPARγ with respect to IGFBP-3. PPARγ was overexpressed in SNU-668 gastric cancer cells using an adenovirus gene transfer system. The cells in which PPARγ was overexpressed exhibited growth inhibition, induction of apoptosis, and a significant increase in IGFBP-3 expression. We investigated the underlying molecular mechanisms of PPARγ in SNU-668 cells using an IGFBP-3 promoter/luciferase reporter system. Luciferase activity was increased up to 15-fold in PPARγ transfected cells, suggesting that PPARγ may directly interact with IGFBP-3 promoter to induce its expression. Deletion analysis of the IGFBP-3 promoter showed that luciferase activity was markedly reduced in cells without putative p53-binding sites (-Δ1755, -Δ1795). This suggests that the critical PPARγ-response region is located within the p53-binding region of the IGFBP-3 promoter. We further demonstrated an increase in PPARγ-induced luciferase activity even in cells treated with siRNA to silence p53 expression. Taken together, these data suggest that PPARγ exhibits its anticancer effect by increasing IGFBP-3 expression, and that IGFBP-3 is a significant tumor suppressor.

Skeletal muscle major histocompatibility complex class I and II expression differences in adult and juvenile dermatomyositis

OBJECTIVE: To analyze major histocompatibility complex expression in the muscle fibers of juvenile and adult dermatomyositis. METHOD: In total, 28 untreated adult dermatomyositis patients, 28 juvenile dermatomyositis patients (Bohan and Peter's criteria) and a control group consisting of four dystrophic and five Pompe's disease patients were analyzed. Routine histological and immunohistochemical (major histocompatibility complex I and II, StreptoABComplex/HRP, Dakopatts) analyses were performed on serial frozen muscle sections. Inflammatory cells, fiber damage, perifascicular atrophy and increased connective tissue were analyzed relative to the expression of major histocompatibility complexes I and II, which were assessed as negatively or positively stained fibers in 10 fields (200X). RESULTS: The mean ages at disease onset were 42.0±15.9 and 7.3±3.4 years in adult and juvenile dermatomyositis, respectively, and the symptom durations before muscle biopsy were similar in both groups. No significant differences were observed regarding gender, ethnicity and frequency of organ involvement, except for higher creatine kinase and lactate dehydrogenase levels in adult dermatomyositis (p<0.050). Moreover, a significantly higher frequency of major histocompatibility complex I (96.4% vs. 50.0%, p<0.001) compared with major histocompatibility complex II expression (14.3% vs. 53.6%, p=0.004) was observed in juvenile dermatomyositis. Fiber damage (p=0.006) and increased connective tissue (p<0.001) were significantly higher in adult dermatomyositis compared with the presence of perifascicular atrophy (p<0.001). The results of the histochemical and histological data did not correlate with the demographic data or with the clinical and laboratory features. CONCLUSION: The overexpression of major histocompatibility complex I was an important finding for the diagnosis of both groups, particularly for juvenile dermatomyositis, whereas there was lower levels of expression of major histocompatibility complex II than major histocompatibility complex I. This finding was particularly apparent in juvenile dermatomyositis.

Frecuencia de alelos HLA de clase I y II en una cohorte de pacientes con espondiloartritis provenientes del noroccidente colombiano / Frequency of HLA alleles class I and II in a cohort of northwestern Colombian patients with spondyloarthritis

Introducción. Las espondiloartritis son enfermedades reumatológicas crónicas que afectan el esqueleto axial y las articulaciones periféricas, con varias manifestaciones extraarticulares. La asociación con el HLA-B27 sigue siendo uno de los vínculos más fuertes conocidos entre estas entidades y el complejo mayor de histocompatibilidad; sin embargo, la distribución mundial del HLA-B27 varía considerablemente y se han descrito asociaciones con genes no HLA-B27. Objetivo. Conocer la frecuencia de alelos HLA de clase I y II en pacientes con espondiloartritis provenientes del noroccidente colombiano y su frecuencia en las manifestaciones clínicas y radiológicas específicas. Materiales y métodos. Se condujo un estudio descriptivo, observacional, de corte transversal, retrospectivo y prospectivo entre 2005 y 2008 de 56 pacientes colombianos con espondiloartritis. Se identificaron los alelos correspondientes a los loci HLA de clase I y II (HLA-B, HLADQB1 y HLADRB). Se analizó su frecuencia con las manifestaciones clínicas axiales, periféricas, extraarticulares y radiológicas. Resultados. Se encontró una baja frecuencia de HLA-B27 en la población total (50 %), aunque fue el alelo más frecuente, junto con HLA-DRB4*01 (35,7 %) y HLA-DQB1*0501 (28,6 %), en todos los pacientes en general y en cada una de las manifestaciones clínicas y radiológicas. Se resalta la alta frecuencia de HLA-B27 y HLA-DRB4*01 (64,3 %) en pacientes con dactilitis, hallazgo novedoso sin previa descripción. Conclusión. Los alelos HLA-B27, HLA-DRB4*01 y HLA-DQB1*0501 fueron frecuentes en los diferentes subtipos de espondiloartritis y en las manifestaciones clínicas axiales, periféricas y extraarticulares específicas, además de la sacroiliítis radiológica.

Introduction. Spondyloarthritis is a chronic rheumatic disease that affect the axial skeleton and peripheral joints, along with several extra-articular manifestations. The association with HLA-B27 remains one of the strongest known links between these entities and the major histocompatibility complex. However, the global distribution of HLA-B27 varies considerably and furthermore, associations with non-HLA-B27 genes have been described. Objective. The frequency of HLA class I and II was determined in a population of patients with spondyloarthritis with respect to detection in the clinical setting and by radiology. Materials and methods. A descriptive, observational, cross-sectional, retrospective and prospective study was conducted in 56 patients from northwestern Colombia. Each was diagnosed with spondyloarthritis between 2005 and 2008. In each case, alleles were identified for the loci HLA class I and II (HLA-B; HLADQB1 and HLADRB). The frequency of these alleles in the axial, peripheral, extraarticular and radiological manifestations. Results.The frequency of HLA-B27 was 50% overall, and it was the most frequent allele. The two other alleles were HLA.DRB4*01 at 35.7% and HLA-DQB1*0501 at 28.6%, as detected in each of the clinical and radiological manifestations. A high frequency of HLA-B27 and HLA-DRB4*01 (64.3%) was noted in patients with dactylitis. Conclusion. The alleles HLA-B27, HLA-DRB4*01 and HLA-DQB1*0501 were common in the different subtypes of spondyloarthritis and were frequent in the specific clinical axial, peripheral and extraarticular clinical manifestations, as well as radiological sacroiliitis.

Molecular characterization of MHC-DRB cDNA in water buffalo (Bubalus bubalis)

In the present study, water buffalo MHC (Bubu)-DRB cDNA was cloned and characterized. The 1022 base long-amplified cDNA product encompassed a single open reading frame of 801 bases that coded for 266 amino acids. The Bubu-DRB sequence showed maximum homology with the BoLA-DRB3*0101 allele of cattle. A total of seven amino acid residues were found to be unique for the Bubu-DRB sequence. The majority of amino acid substitutions was observed in the β1 domain. Residues associated with important functions were mostly conserved. Water buffalo DRB was phylogenetically closer to goat DRB*A.

Estudo de HLA classes I e II em trinta pacientes equatorianos com artrite reumatoide em comparação com alelos de indivíduos sadios e afetados com outras doenças reumáticas / Study of class I and II HLA alleles in 30 ecuadorian patients with rheumatoid arthritis compared with alleles from healthy and affected subjects with other rheumatic diseases

INTRODUÇÃO: A artrite reumatoide (AR) é uma doença inflamatória crônica sistêmica autoimune que provém de uma desordem incapacitante. Até hoje, a etiologia da AR é desconhecida. No entanto, já se cogitou a existência de indivíduos geneticamente passíveis de tê-la. Muitos estudos já foram realizados em todo o mundo, como, por exemplo, na Polônia, Argentina, Chile, México, Brasil, Colômbia, entre outros países, com relação à influência entre os alelos HLA-DR e a doença, mas não no Equador. OBJETIVO: O principal objetivo deste estudo foi determinar a participação dos alelos de HLA classes I e II em pacientes com AR. PACIENTES E MÉTODOS: Esta pesquisa foi desenvolvida em 30 pacientes adultos com AR, previamente diagnosticados de acordo com os critérios de classificação do Colégio Norte-Americano de Reumatologia (ACR, 1987) e 28 controles. Para a tipificação de HLA classes I e II, adotou-se a técnica PCR-SSP, e as significâncias estatísticas foram avaliadas pelo teste de Qui-Quadrado. RESULTADOS: O HLA-DR4 está presente em 76,7 por cento dos pacientes, com uma frequência alélica de 45 por cento, enquanto apenas 21 por cento dos sujeitos controle o apresentaram. O teste de Qui-Quadrado confirma que as variáveis HLA-DR4 e RA estão altamente vinculadas (X² = 11,38, P = 0,00074). CONCLUSÃO: Há frequência maior de HLA-DR4 e HLA-DR14. Os resultados encontrados são similares aos encontrados em outros estudos. Porém, seria desejável aumentar o tamanho da amostra para encontrar um maior número de perfis genéticos e de alelos envolvidos.

INTRODUCTION: Rheumatoid arthritis (RA) is a chronic systemic inflammatory autoimmune disease that originates from a disabling disorder. To date, the etiology of RA is unknown. However, the existence of genetically susceptible individuals was considered. Many studies have been performed worldwide, for example, in Poland, Argentina, Chile, Mexico, Brazil, and Colombia, among others, regarding the influence between HLA-DR alleles and disease, but not in Ecuador. OBJECTIVE: The aim of this study was to determine the involvement of Class I and II HLA alleles in patients with RA. PATIENTS AND METHODS: This study was conducted in 30 adult patients with RA previously diagnosed, according to the classification criteria of the American College of Rheumatology (ACR, 1987) and 28 controls. For Class I and II HLA typing, we adopted the PCR-SSP, and statistical significances were evaluated by Chi-Square. RESULTS: HLA-DR4 is present in 76.7 percent of patients, with an allele frequency of 45 percent, while only 21 percent of control subjects presented it. The chi-square confirms that HLA-DR4 and RA variables are highly bound (X2 = 11.38, P = 0.00074). CONCLUSION: There is increased frequency of HLA-DR4 and HLA-DR14. The results are similar to those found in other studies. But it would be desirable to increase the sample size in order to find a greater number of genetic profiles and alleles involved.

MHC class I loci of the Bar-Headed goose (Anser indicus)

MHC class I proteins mediate functions in anti-pathogen defense. MHC diversity has already been investigated by many studies in model avian species, but here we chose the bar-headed goose, a worldwide migrant bird, as a non-model avian species. Sequences from exons encoding the peptide-binding region (PBR) of MHC class I molecules were isolated from liver genomic DNA, to investigate variation in these genes. These are the first MHC class I partial sequences of the bar-headed goose to be reported. A preliminary analysis suggests the presence of at least four MHC class I genes, which share great similarity with those of the goose and duck. A phylogenetic analysis of bar-headed goose, goose and duck MHC class I sequences using the NJ method supports the idea that they all cluster within the anseriforms clade.

Frequência dos alelos HLA de Classe I e classe II em indivíduos com contratura de Dupuytren no Estado de São Paulo / Frequency of HLA Class I and Class II subjects with Dupuytren's contracture in the State of Sao Paulo

A contratura de Dupuytren é uma doença do tecido conectivo, resultante de um desequilíbrio fibroproliferativo, em que se formam nódulos e cordões fibrosos na fáscia palmar. Com a evolução da doença os cordões se retraem longitudinalmente em direção aos dedos causando a contratura digital que determina o aspecto característico da doença, levando ao diagnóstico diferencial com hanseníase. Sua incidência é maior na raça branca de origem européia, atingindo principalmente adultos do sexo masculino com idade superior a 50 anos. Muitos fatores de risco têm sido associados à contratura de Dupuytren, como fumo, álcool, trauma local, epilepsia e Diabetes mellitos, entre outros. Embora de etiologia desconhecida, é bem aceito o papel hereditário desta patologia. Estudos com marcadores genéticos, sugerem a associação do HLA-DR3 e autoanticorpo para o colágeno na contratura de Dupuytren. Recentemente foi demonstrada associação genética significativa entre HLA-DRB1*15 e risco de desenvolver a doença em pacientes do Norte Europeu. Assim, o presente estudo teve por objetivo, identificar a Freqüência dos alelos HLA de classe I e classe II em pacientes com a contratura de Dupuytren, atendidos no Instituto Lauro de Souza Lima. Ao mesmo tempo, investigar a presença de algum alelo que pudesse sugerir associação com fator de risco para o desenvolvimento da doença nessa população. Trata-se de um estudo inédito não havendo até o momento, estudo associando HLA e doença de Dupuytren na população brasileira. Para isso foram estudados 25 pacientes com diagnóstico da contratura de Dupuytren, com média etária de 54,24 anos e 443 controles saudaveis de mesma etnia e regiao geográfica. Foi possível observar a predominância do sexo masculino (68%) em relação ao feminino e a manifestação mais tardia no grupo das mulheres, concordadndo com dados da literatura. Foi também constatado alto índice de atividades manuais de moderada a pesada no grupo estudado e a descendência européia na totalidade...

Estudo dos polimorfismos do HLA e microssatélites na infecção pelo HIV-1/AIDS / Study of HLA and microsatellite markers polymorphisms in the HIV-1 disease

Fatores genéticos do hospedeiro podem promover resistência à infecção pelo HIV-1 e o retardo no curso da doença. O polimorfismo do HLA é considerado determinante na infecção do HIV-1 e AIDS. Os genes HLA, localizados na região de classe I do MHC, ganham destaque nos estudos de associação como fortes candidatos à patogenia da AIDS. A informação do perfil polimórfico do HLA nas diferentes populações contribui significativamente para o melhor entendimento do curso natural da infecção pelo HIV-1 e, conseqüentemente, na elaboração de vacinas e medicamentos para o tratamento da AIDS. Objetivo: Identificar variações genéticas no MHC e verificar associações com a patogenia da AIDS em indivíduos infectados pelo HIV-1 na população de Salvador, BA. Material e Métodos: Trata-se de um estudo de Coorte e estudo Transversal de comparação de freqüência gênica. Os marcadores do MHC (microssatélites D6S105 (classe I). DRACA (classe II) e TNF-delta, (classe III) e os genes HLA-A, -B e -C) foram genotipados por dois métodos distintos, ambos precedidos por PCR. Após a PCR, os produtos amplificados dos microssatélites foram separados por eletroforese em capilar e os alelos foram denominados de acordo co o tamanho dos fragmentos amplificados. A tipagem do HLA foi feita pelo método SSO. Após a amplificação dos éxons 2 e 3 para os loci HLA-A, -B e -C foi feita a hibridização com sondas que possuem as seqüências de nucleotídeos iguais aos éxons amplificados. Os resultados foram interpretados através de um software que estabeleceu a genotipagem do HLA. As análises estatísticas foram feitas através do Teste exato de Fischer e Mann-Whitney para comparação das variáveis categóricas e contínuas, respectivamente. Resultados: O presente estudo não demonstrou associação entre os polimorfismos do MHC e a progressão para AIDS. Nossos dados sugerem associação do microssatélite TNF-delta com resistência à infecção pelo HIV-1 e modulação da carga viral plasmática e contagem...

Compromiso neuronal en esclerosis multiple / Neuronal injury in multiple sclerosis

La esclerosis múltiple (EM) ha sido considerada clásicamente como una enfermedad desmielinzante. Si bien el compromiso neurodegenerativo fue previamente descripto, sólo recientemente ha sido enfatizado. Por estudiosos recientes se ha identificado la degeneración axonal como el mayor determinante de discapacidad neurológica irreversible en pacientes con EM. El daño axonal se inicia tempranamente y permanece silente durante años, la discapacidad neurológica se desarrolla cuando se alcanza cierto umbral de pérdida axonal y los mecanismos de compensación se agotan. Se han propuesto tres hipótesis para explicar el daño axonal: 1) El daño es causado por un proceso inflamatorio, 2) Existe una excesiva acumulación de Ca2+ intra-axonal, 3) Los axones desmienlinizados evolucionan a un proceso degenerativo producto de la falta de soporte trófico provisto por la mielina o células formadoras de mielina. Si bien la EM fue tradicionalmente considerada como una enfermedad de la sustancia blanca, el proceso de desmielinización tambiém ocurre en la corteza cerebral

The concept of multiple sclerosis (MS) as a demyelinating disease is deeply ingrained. Although the existence of a neurodegenerative component has always been apparent, it has only recently become emphasized. Thus, in recent years several studies have identified axonal degeneration as the major determinant of irreversible neurological disability in patients with MS. Axonal injury begins at disease onset and remains clinically silent for many years; irreversible neurological disability develops when a threshold of axonal loss is reached and CNS compensatory mechanisms are exhausted. The precise mechanisms of axonal loss are poorly understood, and three hypotheses have been proposed: 1) The damage is caused by an inflammatory process, 2) There is an excessive accumulation of intra-axonal Ca2+, 3) Demyelinated axons undergo degeneration due to lack of trophic support by myelin, or myelin forming cells. Although MS has traditionally been regarded as a disease of white matter, demyelination can also occur in the cerebral cortex. Cortical lesions exhibit neuronal injury represented by dendritic and axonal transection as well as neuronal apoptosis. Because conventional nuclear magnetic resonance (NMR) is limited in its ability to provide specific information about axonal pathology in MS, new techniques such as, diffusion-weighted MRI, proton magnetic resonance spectroscopy, functional MRI, as well as novel techniques designed to measure atrophy have been developed to monitor MS evolution. Recognition that MS is in part a neurodegenerative disease should trigger critical rethinking on the pathogenic mechanisms of this disease and provides new targets for a rational treatment

Typing class I HLA-A gene using a nested PCR-RFLP procedure

In order to detect several new HLA-A class I alleles that have been described since 1998, the original PCR-RFLP method developed to identify the 78 alleles recognized at that time at high resolution level was adapted by us for low and medium resolution levels using a nested PCR-RFLP approach. The results obtained from blood samples of 23 subjects using both the PCR-RFLP method and a commercial kit (MicroSSP1A®, One Lambda Inc.) showed an agreement higher than 95 percent. The PCR-RFLP adapted method was effective in low and medium resolution histocompatibility evaluations.

Asociación HLA clase I y leucemia en pacientes mestizos del estado Zulia, Venezuela

Resumen. La asociación entre los Alelos Leucocitarios Humanos (HLA) clase I (A, B, C) y las Leucemias Linfoides Agudas y Mieloides, se determinó mediante la técnica de Reacción en cadena de la polimerasa con iniciadores de secuencia específica (PCR-SSP) en un grupo de 60 pacientes y 30 controles sanos. Los valores obtenidos se expresaron como frecuencias alélicas y haplotipicas. Se utilizaron como métodos estadísticos la prueba de Chi-cuadrado corregida, test de Fisher, riesgo relativo y la fracción etiológica. Se observó una asociación positiva significativa de los alelos HLA-B*39 (RR = 16,184, p = 0,0237) y HLA C*03 (RR =5,0; p = 0,0127) con las Leucemias Mieloides (aguda y crónica). Así mismo se encontraron asociaciones positivas de los haplotipos de 2 loci: HLA-A*02-C*03 (RR = 6,0; p = 0,0153), A*24-C*03 (RR = 16,184; p = 0,0237), B*40-C*03 (RR = 10,706; p = 0,0021) y un haplotipo de 3 loci: HLA-A*02-B*40-C*03 (RR = 8,11; p = 0,0102) con las Leucemias Mieloides. No se evidenció ningún tipo de asociación con la Leucemia Linfoide Aguda. No se observaron asociaciones negativas con ningún tipo de Leucemia.

Abstract. The Human Leukocyte Allele (HLA) Class I (A, B, C) and Acute Lymphoid Leukemia and Myeloid Leukemia association, was determined by polymerase chain reaction - sequence specific primers (PCR-SSP) in 60 patients and 30 healthy controls. The results were reported as allelic frequencies and haplotype. The Chi-square corrected, Fisher’s Test, Relative risk and etiologic fraction were calculated. A significant positive association was showed between HLA-B*39 (RR = 16.184; p = 0.0237) and HLA C*03 (RR =5.0; p = 0.0127) alleles and Myeloid Leukaemia. Positive associations between haplotypes 2 loci: HLA-A*02-C*03 (RR = 6.0; p = 0.0153), A*24-C*03 (RR = 16.184; p = 0.0237), B*40-C*03 (RR = 10.706; p = 0.0021) and haplotype 3 loci: HLA-A*02-B*40-C*03 (RR = 8.11; p = 0.0102) and Myeloid Leukemia were found. No association was evident in Acute Lymphoid Leukemia. No negative association with Leukemias were observed.

Como entender a associaçäo entre o sistema HLA e as doenças auto-imunes endócrinas / How to understand the association of the HLA system and autoimmune endocrine disorders

A introduçäo de nova nomenclatura para os componentes do complexo principal de histocompatibilidade (Major Histocompatibility Complex - MHC) e a descriçäo de novos métodos moleculares para a tipificaçäo dos alelos do MHC contribuíram, grandemente, para o entendimento e identificaçäo do extenso polimorfismo do sistema. No entanto, para o näo especialista, essas novas aquisições têm dificultado o entendimento do papel do MHC em associaçäo com as doenças. Assim, neste artigo, foram revisados os conceitos atuais acerca dos genes e moléculas do MHC, os métodos de tipificaçäo desses marcadores de histocompatibilidade e a nomenclatura vigente para os componentes do sistema. Esses aspectos säo extremamente importantes para o entendimento do polimorfismo do MHC, dando embasamento para a compreensäo dos mecanismos propostos de associaçäo desses marcadores com as doenças auto-imunes endócrinas como diabetes mellitus do tipo 1, doença de Graves e tireoidite de Hashimoto, doença de Addison, síndrome poliglandular auto-imune e insuficiência ovariana prematura