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.

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.

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.

HLA alleles in pre-menopausal breast cancer patients from western India.

BACKGROUND & OBJECTIVES: Cytotoxic function of Natural Killer (NK) cells is regulated by the products of HLA class I genes. Associations between HLA alleles and risk for cancers have been suggested earlier. Several reports further emphasize the need to examine influence of HLA genotypes on risk for malignant disorders. Therefore, we undertook this study to assess the possibility of association of HLA-class I alleles in pre-menopausal breast cancer patients. METHODS: Eighty one pre-menopausal breast cancer patients and 160, age and ethnicity matched healthy women from western India were studied. Genotyping for HLA class I alleles and HLA-B*40 alleles (high resolution) was performed using genotyping kits from Genovision Inc., USA. RESULTS: Nearly two-fold higher frequency of HLA - B*40 (16%) was observed in patients compared to controls (O.R. = 2.2; 95% C.I.-1.15-4.34; P<0.02). High resolution typing for HLA-B*40 alleles revealed predominance of HLA-B*4006 allele in both the study groups. Two other important observations relate to lower frequency of HLA - B*08 in patients and homozygosity at HLA-Cw locus in significantly higher proportion of patients. INTERPRETATION & CONCLUSION: The nature of peptides presented by HLA-B*4006 may have implications for higher frequency of HLA-B*40 in breast cancer patients. Higher frequency of homozygosity at HLA-Cw alleles in patients suggests a role for killer immunoglobulin-like receptors (KIRs) in NK cell mediated immune surveillance. Results of this study provide directions to further analyse role of immunogenetic mechanisms governing innate and adaptive immune responses contributing to modulation of risk for breast cancer.

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.

Research report: Frequencies of mica gene polymorphism: a comparison between Indonesians on Bacan Island and suburban Japanese.

MHC class I chain related gene A (MICA) is located near the HLA-B gene on the short arm of human chromosome 6. In the transmembrane (TM) of region of MICA, there is a trinucleotide repeat (GCT/AGC) microsatellite polymorphism in exon 5. Five alleles with 4, 5, 6 and 9 repetitions or 5 repetitions with 1 additional nucleotide insertion (GGCT) are identified and they were named A4, A5, A5.1, A6, and A9 respectively. We report the allele frequencies of 127 Indonesians on Bacan Island and 250 Japanese in the Kanto area. From the genotyping result, the frequency among Indonesians was as follows: A4 15.4%, A5 26.0%, A5.1 16.5%, A6 5.5%, and A9 36.6%. The frequency among Japanese was as follows: A4 20.6%, A5 28.1%, A5.1 10.8%, A6 27.2%, and A9 13.2%. Allele 9 is significantly increased and allele 6 significantly decreased in Indonesians compared with Japanese subjects. The results suggested that MICA microsatellite polymorphism are quite different in each race. Among Indonesians, the frequency of MICA-A9 allele, which was reported to be negatively associated with Behçet's disease, was significantly higher, whereas the MICA-A6 allele frequency, which was reported to be positively associated with Behçet's disease, was significantly lower among Japanese.

A comparative study on mouse MHC class I sequences detected in Schistosoma japonicum recovered from BALB/c (H-2d) and C57BL/6 (H-2b) mice.

The mouse major histocompatibility complex (MHC) class I sequence was detected in all the 8-week-old Schistosoma japonicum recovered from BALB/c (H-2d) and C57BL/6 (H-2b) mice by in situ polymerase chain reaction (in situ PCR). The signals of the mouse class I MHC sequence were observed in the nuclei of the mesenchymal and reproductive cells of 8-week-old S. japonicum. Furthermore, the class I MHC sequence was detected in each DNA extracted from S. japonicum cercariae maintained in BALB/c and C57BL/6 mice by nested PCR. To prove both horizontal and vertical transmission of this sequence in schistosomes, we have used cercariae obtained from parasites maintained in BALB/c mice to infect C57BL/6 and BALB/c mice, and vice versa. The MHC sequences from adult worms were compared to the cercarial MHC and host MHC sequences. Nucleotide sequence comparisons between adult worm DNA, host (H-2d and H-2b mice) DNA and cercarial DNA used for the infection suggested that the sequence of mouse class I MHC was incorporated into schistosome adults and inherited throughout their life-cycle.

Los factores genéticos determinantes de la resistencia a la infección por VIH y del control de la progresión al SIDA: Implicaciones sobre la patogénesis y las estrategias terapéuticas para la erradicación del VIH. Una revisión

Esta revisión describe y discute los factores genéticos que al menos en parte, determinan la resistencia a la infección y que controlan el curso progresivo de la enfermedad en las personas infectadas por el virus de la inmunodeficiencia humana. Los factores genéticos podrían explicar la no progresión o la progresión lenta de la enfermedad, de una proporción de individuos infectados por VIH denominados no progresores a largo plazo. En general, este grupo permanece sin síntomas durante más de 10 años, mantiene estable sus niveles circulantes de cT CD4+ y habitualmente tiene baja carga viral. No obstante que los fenómenos de la no progresión y de la progresión rápida son aún incomprendidos, es probable que ciertos alelos de clase I y clase II del complejo principal de histocompatibilidad se asocien con un riesgo menor o mayor para desarrollar el síndrome de inmunodeficiencia adquirida...

HFE gene mutations in coronary atherothrombotic disease

Although iron can catalyze the production of free radicals involved in LDL lipid peroxidation, the contribution of iron overload to atherosclerosis remains controversial. The description of two mutations in the HFE gene (Cys282Tyr and His63Asp) related to hereditary hemochromatosis provides an opportunity to address the question of the association between iron overload and atherosclerosis. We investigated the prevalence of HFE mutations in 160 survivors of myocardial infarction with angiographically demonstrated severe coronary atherosclerotic disease, and in 160 age-, gender- and race-matched healthy control subjects. PCR amplification of genomic DNA followed by RsaI and BclI restriction enzyme digestion was used to determine the genotypes. The frequency of the mutant Cys282Tyr allele was identical among patients and controls (0.022; carrier frequency, 4.4 per cent), whereas the mutant His63Asp allele had a frequency of 0.143 (carrier frequency, 27.5 per cent) in controls and of 0.134 (carrier frequency, 24.5 per cent) in patients. Compound heterozygotes were found in 2 of 160 (1.2 per cent) controls and in 1 of 160 (0.6 per cent) patients. The finding of a similar prevalence of Cys282Tyr and His63Asp mutations in the HFE gene among controls and patients with coronary atherothrombotic disease, indirectly questions the possibility of an association between hereditary hemochromatosis and atherosclerosis.

Complejo de histocompatibilidad / Histocompatibility complex

El compleho principal de histocompatibilidda (MHC) es un complejo génico altamente polimórfico que controla la expresión de moléculas que desempeñan un rol fundamental en las interacciones celulares que se producen durante la respuesta inmune y en el procesamiento y presentación de antígenos a los linfocitos T. Los genes de clase I del MHC controlan la expresión de los clásicos antígenos de histocompatibilidad y que en realidad funcionan como moléculas de presentación de fragmentos antigénicos a los linfocitos TCD8+ (linfocitos T citotóxicos). Los genes de clase II corresponden a los antiguos genes de respuesta inmune (genes Ir) y codifican la expresión de moléculas de presentación de fragmentos peptídicos a linfocitos TCD4+ (linfocitos T helper). Los genes de clase II codifican la expresión de los factores de complemento C4, Bf y C2. El complejo incluye, además, genes que codifican la expresión de subunidades del proteasoma (LMP2 y LMP7), transportadores peptídicos (TAP1 y TAP2), factor de necrosis tumoral (TNFa y TBFb) y proteínas de shock térmico (hsp70)

Los mecanismos moleculares de susceptibilidad y de protección dependientes del MHC en la diabetes tipo I en mexicanos / Molecular susceptibility and protection mechanisms dependent of MHC in type I diabetes in Mexicans

Los genes clase II del MHC juegan un papel central en la destrucción autoinmune de las células b del páncreas, en la DMDI. Se investigó el patrón genético de la DMDI en mexicanos. Los hallazgos serológicos del HLA mostraron una asociación muy significativa con los antígenos DR3, DR4, DQ2 y DQ8 y un efecto protector de DR11, DR15, DQ5, DQ6 y DQ7. Con estos datos, se analizaron los alelos DRB1, B3, B4, DQA1, DQB1,DPA1 y DPB1 a nivel del DNA por PCR, hibridando con sondas alelo-específicas. El 92.7 por ciento de los pacientes portan alelos DQA1 que tienen ARG en la posición 52 de la cadena DQa y el 78,2 por ciento son ASP57- en la cadena DQ~. El RR para los homocigotos es de 32.8 y 5.6 respectivamente. El haplotipo principalmente involucrado es DRB1*0405, DQA1*0301, DQB1*0302. Se concluye que las cadenas DQa y DQ forman un sitio relevante para el reconocimiento del péptido "diabetogénico" que induce la respuesta autoinmune destructiva. Las posiciones 57 y 74 del gen DRB1 contribuyen importantemente a la expresión y a la severidad de la DMDI en mestizos y en otros grupos étnicos, pero no en caucasoides o negros

¿Existe un gen específico en la fibrosis intersticial familiar? / Is there a specific gen for familiar interstitial fibrosis?

La fibrosis interstical pulmonar difusa es una enfermedads poco frecuente que ha tenido un incremento substancial en los últimos años, sin embargo, existe una forma familiar con características autosómaticas dominantes sin que hasta el momento se haya encontrado un gen específico en su transmisión. El objeto del presente trabajo es el reportar en análisis de tres generaciones en donde existieron características comunes e identificándose sistemas genéticos especificos. Se trató de una familia integrada por tres generaciones, dos de las cuales resultaron con datos clínicos radiológicos, funcionales y anatomopatológicos de fibrosis interstical difusa, los antígenos de histocompartibles clase I y II compartieron alelos parecidos (A28, Bw26, Cw3, DR4 y DQ3) en los pacientes analizados, el estudio genético denterminó un carácter autosómico dominante con penetrancia variable de lo que se concluye que lis alotipos axpresados en el sistema HLA juega un papel determinante en el desarrollo de la enfermedad.