Abstract Background Anti-desmoglein (Dsg)1 is produced in pemphigus foliaceus (PF), affecting exclusively the skin. Pemphigus vulgaris (PV) shows the production of anti-Dsg3 in the mucosal form, and anti-Dsg1 and 3 in the mucocutaneous form. Anti-Dsg3 autoantibodies have been rarely reported in PF. Objectives To determine the factors associated with the production and pathogenicity of anti-Dsg3 in PF. Methods Comparative analytical study of three patients groups: 16 PF-anti-Dsg3+, and 42 PF-anti-Dsg3(-) and 22 PV treatment-naïve cases. Serum was used in the anti-Dsg1 and 3 ELISA, and in immunoblotting (IB) with human epidermis extract. The expression of Dsg1 and 3 in paraffin sections was analyzed by immunohistochemistry (IHC). HLA-DRB1 alleles were compiled from a database. Results In the PF-anti-Dsg3+ group: age range similar to that of the PV group (p > 0.9999); predominance of the generalized form of PF (p = 0.002); anti-Dsg3 titers lower than those of PV (p < 0.0001); IB confirmed Dsg3 identification in one (8.33%) of 12 patients; IHC showed exclusive cytoplasmic internalization of Dsg1; HLA-DRB1 alleles of susceptibility to PF, with the absence of alleles associated with PV, in the five typed patients. Study limitations Most of the patients in the PF-anti-Dsg3+ group were undergoing treatment. Conclusion The presence of anti-Dsg3 antibodies in PF was related to older age (comparable to that of PV) and the generalized form of PF. The non-pathogenicity of anti-Dsg3 antibodies in PF can be attributed to the low serum anti-Dsg3 titers, the lack of Dsg3 internalization as detected by IHC, and the absence of PV-associated HLA-DRB1 alleles. Antidesmoglein Anti desmoglein Dsg 1 (Dsg) , (PF) skin (PV antiDsg3 antiDsg anti anti-Dsg antiDsg1 AntiDsg3 AntiDsg Anti-Dsg groups PFantiDsg3+, PFantiDsg3 PFantiDsg Dsg3+, 4 PF-anti-Dsg3(- 2 treatmentnaïve treatment naïve cases ELISA (IB extract IHC. . (IHC) HLADRB1 HLADRB HLA DRB1 DRB HLA-DRB database PFantiDsg3+ Dsg3+ PF-anti-Dsg3 p 0.9999 09999 0 9999 0.9999) 0.002 0002 002 0.002) 0.0001 00001 0001 0.0001) 8.33% 833 8 33 (8.33% comparable nonpathogenicity non PVassociated (Dsg (PF PF-anti-Dsg3( (IHC PF-anti-Dsg 0.999 0999 999 0.00 000 00 0.000 0000 8.33 83 (8.33 0.99 099 99 0.0 8.3 (8.3 0.9 09 9 0. 8. (8. (8 (

ABSTRACT Introduction: Epidemiologic studies on pediatric acute lymphoblastic leukemias (ALL) have been conducted to evaluate the possible risk factors including genetic, infectious and environmental factors with the objective of idenfying the etiology. Mannose-bind-ing lectin 2 (MBL2) plays an important role in first-line immune defense. HLA DRB1 alleles play a role in presentation of peptides to T cells and in activation of the adaptive immune response. Objective: In our study, we aimed to investigate both the MBL2 gene variant and HLA-DRB1 alleles in pediatric ALL patients. Materials: In this study, 86 high-risk ALL patients and 100 controls were included. Polymerase Chain Reaction (PCR)-Restriction Fragment Length Polymorphism (PCR-RFLP) and PCR-sequence specific primer (SSP) methods were used for detection of polymorphism of the MBL2 and HLA-DRB1 alleles, respectively. Results: The frequency of the MBL2 AB genotype was lower in female ALL patients, compared to male ALL patients (p = 0.034). An association was found between the MBL2 BB genotype and DRB1*07 and among patients with the MBL2 BB genotype; those who also carried the DRB1*07 and *04 alleles were significantly higher than those without the DRB1*07 and *04 alleles. (p = 0.048, p = 0.022, respectively). Conclusion: This is the first study suggesting that the MBL2 BB genotype in association with the DRB1*07 or co-inheritance of the HLA-DRB1*04 and HLA DRB1*07 may have an impact on the etiopathogenesis of the disease. Introduction (ALL genetic etiology Mannosebinding Mannose bind ing MBL (MBL2 firstline line defense DRB response Objective HLADRB1 HLADRB HLA-DRB Materials 8 highrisk high 10 included PCRRestriction PCR Restriction PCRRFLP RFLP (PCR-RFLP PCRsequence sequence SSP (SSP respectively Results 0.034. 0034 0.034 . 0 034 0.034) DRB107 07 DRB1*0 04 *0 0048 048 0.048 0022 022 0.022 respectively) Conclusion coinheritance co inheritance HLADRB1*04 HLADRB104 DRB1*04 HLA-DRB1*0 disease (MBL 1 003 0.03 03 DRB10 DRB1* * 004 0.04 002 02 0.02 HLADRB1*0 HLADRB10 DRB104 HLA-DRB1* 00 0.0 HLADRB1* 0.

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.

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.

ABSTRACT: Background: Vogt-Koyanagi-Harada (VKH) syndrome is a severe disease with autoimmune etiology. It manifests with bilateral panuveitis and can affect the nervous and auditory system, as well as the skin. The influence of genetic factors on the expression of VKH has been evidenced in multiple studies. It has a poor visual prognosis if diagnosis and treatment are delayed. Having biomarkers of genetic susceptibility could be of great help. The aim of this study is to describe the clinical spectrum and determine genetic biomarkers of susceptibility in VKH disease. Methodology: Case-control study of genetic susceptibility for VKH. Clinical data was registered and HLA DRB1 genotyping of cases and controls was performed. Results: 21 patients with VKH were included for the clinical registry, 16 of these were enrolled for HLA-DRB1 genotyping. Thirty two healthy controls were included. Most patients were female (81%,) average age 35 years, the clinical forms were: Probable VKH 10 (47.6%) and Incomplete VKH 10 (47.6%), Complete VKH 1 case (4.7%). Genotyping: alleles of the HLA DRB1*02 group were present in 5 of the 16 patients (31%) (p0.004) and absent in the controls, no relationship with specific alleles was found. The most frequent allele was HLA DRB1*01:02 present in 4 (25%)of cases and absent in controls. Conclusion: Most of the patients were young female adults. Probable and Incomplete forms were more common. Genetic association of VKH disease with alleles of the DRB1*02 group was found in this Paraguayan cohort. No statistically significant relationship was found with any specific allele, probably because the sample was small. The most frequent allele HLA DRB1*01:02 could be a candidate genetic biomarker in this population.

RESUMEN: Introducción: La enfermedad de Vogt-Koyanagi-Harada (VKH) es de etiología autoinmune y severa, se manifiesta con panuveítis bilateral y puede afectar sistema neuroauditivo y piel. La influencia de los factores genéticos en la expresión de VKH, ha quedado en evidencia en múltiples estudios. Posee mal pronóstico visual si se realiza el diagnóstico y el tratamiento en forma tardía, contar con biomarcadores genéticos susceptibilidad podrían ser de gran ayuda. El objetivo de este estudio es describir el espectro clínico y determinar biomarcadores genéticos de susceptibilidad en la enfermedad de VKH. Metodología: Estudio de casos y controles, de susceptibilidad genética para VKH. Se procedió al registro clínico de los pacientes y genotipado HLA DRB1 a casos y controles. Resultados: se incluyeron 21 pacientes con VKH para el registro clínico, de éstos se enrolaron 16 para el genotipado HLA-DRB1, los controles sanos incluidos fueron 32. Sexo fe menino 81%, edad promedio 35 años, las formas clínicas fueron VKH Probable 10(47,6%) y VKH incompleto 10(47,6%), VKH Completo 1 caso (4,7%) Genotipado: los alelos del grupo HLA DRB1*02 estaban presentes 5 de los 16 pacientes (31%) (p 0,004) y ausente en los controles, no se encontró relación con alelos específicos. El alelo más frecuente fue HLA DRB1*01:02 presente en 4 (25) % de casos y ausente en los controles. Conclusión: La mayoría de los pacientes fueron adultos jóvenes, predominancia del sexo femenino, las formas clínicas VKH Probables e Incompleta fueron más comunes. Se ha encontrado en esta cohorte paraguaya asociación genética de la enfermedad de VKH con alelos del grupo DRB1*02, no se halló relación estadísticamente significativa con ningún alelo específico, probablemente esto se debió a que la muestra fue pequeña. El alelo más frecuente HLA DRB1*01:02 podría ser un candidato a biomarcador genético en esta población.

Abstract INTRODUCTION: Tuberculosis (TB) is the leading cause of death worldwide caused by a single infectious disease agent. Brazil, Russia, India, China, and South Africa (BRICS) account for more than half of the world’s TB cases. Bacillus Calmette-Guérin (BCG) remains the only vaccine available despite its variable efficacy. Promising antigen-based vaccines have been proposed as prophylactic and/or immunotherapeutic approaches to boost BCG vaccination. Relevant antigens must interact with the range of human leukocyte antigen (HLA) molecules present in target populations; yet this information is currently not available. METHODS: MEDLINE and EMBASE were systematically searched for articles published during 2013-2020 to measure the allelic frequencies of HLA-DRB1 in the BRICS. RESULTS: In total, 67 articles involving 3,207,861 healthy individuals were included in the meta-analysis. HLA-DRB1 alleles *03, *04, *07, *11, *13, and *15 were consistently identified at high frequencies across the BRICS, with a combined estimated frequency varying from 52% to 80%. HLA-DRB1 alleles *01, *08, *09, *10, *12, and *14 were found to be relevant in only one or two BRICS populations. CONCLUSIONS: By combining these alleles, it is possible to ensure at least 80% coverage throughout the BRICS populations.

RESUMEN La investigación en Inmunogenética brinda información acerca de marcadores genéticos asociados con enfermedades autoinmunes, como el Lupus Eritematoso Sistémico (LES), se puede observar entonces ciertos factores de riesgo o protección hacia la enfermedad en una población determinada. OBJETIVO: Determinar la asociación genética entre los polimorfismos del Complejo Principal de Histocompatibilidad (CPH) representados por los loci HLA-DRB1 y HLA-DQB1 con la susceptibilidad a LES. METODOLOGÍA: Se trabajó con 85 pacientes lúpicos y 85 pacientes sin la enfermedad; se obtuvo DNA humano a partir de sangre periférica, se realizó un PCR-SSP de baja y alta resolución para tipificar molecularmente a los loci HLA-DRB1 y HLA-DQB1. Se determinó las frecuencias alélicas, las cuales fueron asociadas con ambas muestras mediante el uso del Odds Ratio, a un nivel de significancia del 5 %. RESULTADOS: Los resultados del PCR-SSP de baja resolución muestran que ningún alelo HLA tiene un rol predisponente, se observó que el alelo HLA-DRB1*04 presenta un rol protector OR=0,49 (p=0,03). Los resultados por PCR-SSP de alta resolución muestran que los alelos HLA-DRB1*03:01 (OR=18,3; p=0,007), DRB1*04:04 (OR=4,2; p=0,009), DRB1*09:01 (OR=18,3; p=0,007), HLA-DQB1*03:03 (OR=18,8; p=0,006) y DQB1*02:01 (OR=21,2; p=0,003) son factores de riesgo. Se evidenció que los alelos HLA-DRB1*08:02 (OR=0,42; p=0,003) y HLA-DQB1*04:02 (OR=0,50; p=0,02) son de carácter protector. CONCLUSIONES: Los alelos que representan riesgo de padecer LES en la muestra estudiada son HLA-DRB1*03:01, 04:04, 09:01 y HLA-DQB1*03:03, 02:01. Los alelos que tiene un carácter protector a la enfermedad son HLA-DRB1*08:02 y HLA-DQB1*04:02.

ABSTRACT Immunogenetics research provides information on genetic markers associated with autoimmune diseases such as systemic lupus erythematosus (SLE), you can then observe certain risk factors or protection to the disease in a given population. To determine the genetic association between polymorphisms ofthe Major Histocompatibility Complex loci represented by the HLA-DRB1 and HLA-DQB1 with susceptibility to SLE. METHODOLOGY: We worked with 85 lupus patients and 85 patients without the disease; Human DNA was obtained from peripheral blood, PCR-SSP low and high resolution molecularly performed to establish the loci HLA-DRB1 and HLA-DQB1. Allele frequencies, which were associated with both samples using the Odds Ratio at a level of significance of 5% were determined. RESULTS: Results of PCR-SSP low-resolution HLA show that no predisposing allele plays a role, we observed that HLA-DRB1*04 allele has a protective role OR=0.49 (p=0.03). The PCR-SSP results of high resolution show that the HLA-DRB1*03:01 alleles (OR=18.3; p=0.007), DRB1*04:04 (OR=4.2; p=0.009), DRB1*09:01 (OR=18.3; p=0.007), HLA-DQB1*03:03 (OR=18.8; p=0.006) and DQB1 *02:01 (OR=21.2; p=0.003) are risk factors. We demonstrated that HLA-DRB1 *08:02 alleles (OR=0.42; p=0.003) and HLA-DQB 1*04:02 (OR=0.50; p=0.02) are ofa protective nature. CONCLUSIONS: The alleles representing LES risk in the study sample are HLA-DRB1*03:01, *04:04, *09:01 and HLA-DQB1*03:03, *02:01. The alleles having a protective character to the disease are HLA-DRB 1 *08:02 and HLA-DQB1 *04:02.

<sec><title>OBJETIVO:</title><p> Investigar a associação dos alelos HLA-A, -B e -DRB1 com a ocorrência de Aborto Espontâneo Recorrente.</p></sec><sec><title>MÉTODOS:</title><p> Estudo caso-controle com 200 mulheres com idade entre 18 e 35 anos, sendo a amostra de conveniência com 100 mulheres que tiveram aborto espontâneo recorrente idiopático e 100 mulheres sem aborto e com dois ou mais filhos. A obtenção do DNA Genômico foi de sangue periférico, sendo a extração realizada a partir de 500l do Buffy-Coat conservado a -20°C. A Tipificação HLA foi feita pelo método PCR-SSOP (<italic>Polymerase Chain Reaction - Specific Sequence of Oligonucleotides Probes</italic>, One Lambda^(r), CA, EUA). As regiões do DNA amplificado foram o exon 2 e 3 para os <italic>loci</italic>A e B e apenas o exon 3 para o <italic>locus</italic> DRB1. Para determinação da genotipagem HLA-A, HLA-B e HLA-DRB1, utilizou-se o programa HLA FUSION^TM(One Lambda, Canoga Park, CA, United States, 3.0 version). Na análise estatística, utilizaram-se frequências absolutas e porcentagens, e cálculo de média e desvio padrão. As variáveis qualitativas foram comparadas utilizando-se o teste χ², com correção de Yates, ou Teste Exato de Fisher. Para as comparações e significância (p<0,05), foi calculado <italic>Odds Ratio</italic> com IC95%.</p></sec><sec><title>RESULTADOS:</title><p> O alelo A*34 apresentou frequência significativamente maior no grupo caso em relação ao controle (4,0<italic> versus</italic>0,5%; p<0,05). Os alelos A*24 (6,0<italic> versus</italic>12,5%; p<0,05) e B*35 (8,0<italic> versus</italic>20,5%; p<0,05) foram significativamente menos frequentes no grupo caso. Entre os alelos de classe II, o DRB1*03 apresentou frequência ligeiramente maior no grupo caso (11,0<italic> versus</italic>5,5%; p=0,056).</p></sec><sec><title>CONCLUSÕES:</title><p> Foi demonstrado que o alelo HLA-A*34 é fator de risco para o abortamento espontâneo recorrente, enquanto os alelos HLA-A*24 e HLA-B*35 estão associados à proteção, e nenhum alelo do <italic>locus</italic> DRB1 apresentou associação com AER.</p></sec>

<sec><title>PURPOSE:</title><p> To investigate the association of the HLA-A, -B and -DRB1 alleles with the occurrence of Recurrent Spontaneous Abortion.</p></sec><sec><title>METHODS:</title><p> A case-control study of 200 women aged 18 to 35 years, consisting of a convenience sample of 100 women who had idiopathic recurrent spontaneous abortion and 100 women without abortion and with two or more children. Peripheral blood genomic DNA was extracted from 500l of Buffy Coat stored at -20°C. HLA typing was performed by the PCR-SSOP method (Polymerase Chain Reaction - Specific Sequence of Oligonucleotides Probes, One Lambda^(r), CA, USA). The regions of the amplified DNA were exon 2 and 3 for the A and B <italic>loci</italic> and only exon 3 for the DRB1 <italic>locus</italic>. The HLA FUSION^TM program (One Lambda, Canoga Park, CA, USA, version 3.0) was used for HLA-A, HLA-B and HLA-DRB1 genotyping. Absolute frequencies and percentages and calculation of mean and standard deviation were used for standard statistical analysis. The qualitative variables were compared by the χ² test with Yates correction or by Fisher's exact test. The odds ratio with the 95%CI was used for the comparisons, with the level of significance set at p<0.05.</p></sec><sec><title>RESULTS:</title><p> The frequency of the A*34 allele was significantly higher in the case group compared to control (4.0<italic> versus</italic>0.5%; p<0.05). Alleles A*24 (6.0<italic> versus</italic>12.5%; p<0.05) and B*35 (8.0<italic> versus</italic>20.5%; p<0.05) were significantly less frequent in the case group. Among the class II alleles, DRB1*03 showed a slightly higher frequency in the case group (11.0<italic> versus</italic>5.5%, p = 0.056).</p></sec><sec><title>CONCLUSIONS:</title><p> It was shown that the HLA-A*34 allele is a risk factor for recurrent spontaneous abortion, while the HLA-A*24 and HLA-B*35 alleles are associated with protection, and no allele of the DRB1 <italic>locus</italic> was associated with RSA.</p></sec>

Objetivo: Utilizar modelos de inteligencia computacional para la clasificación e identificación de endofenotipos (relación entre fenotipo y marcadores genéticos) en pacientes con artritis reumatoide y controles sanos, a partir de información genética, principalmente el HLA DRB1 (antígeno leucocitario humano) y la teoría del epítope compartido. Esto hace referencia a la asociación entre la artritis reumatoide y el HLA DRB1, principalmente los alelos que contienen un motivo común de aminoácidos de las secuencias QKRAA, QRRAA o RRRAA en las posiciones 70 a 74 de la cadena del DRB1, los cuales confieren una susceptibilidad particular de la enfermedad a los individuos. Métodos: Desarrollamos modelos computacionales para clasificación, utilizando técnicas de inteligencia computacional como son las redes neuronales, redes bayesianas y métodos como k-means. Como datos de entrada se utilizaron variables como: factor reumatoide, anticuerpos contra péptido citrulinado, proteína C reactiva, número de articulaciones inflamadas y dolorosas, rigidez matinal, edad, género, antecedentes de comorbilidades y la información del alelo HLA DRB1. Se utilizaron técnicas de bioinformática para la búsqueda de secuencias de aminoácidos relacionadas con la severidad de la enfermedad. Resultados: Se obtuvieron resultados importantes para el diagnóstico de la enfermedad, así como también para su categorización y como potencial aplicación en la medicina personalizada de los individuos afectados por esta enfermedad. Se diseñaron modelos computacionales para clasificación, dentro de los cuales la red neuronal utilizando 5 variables obtuvo una sensibilidad del 92,3% con una especificidad del 86,66% y la red bayesiana logró una sensibilidad del 92,3% y una especificidad del 93,33%. La red neuronal utilizando 11 variables obtuvo una sensibilidad del 84,61% y una especificidad del 93,33% mientras que la red bayesiana consiguió una sensibilidad del 92,3% con una especificidad del 93,33%. Un método de agrupamiento tipo k-means fue utilizado para dividir en 2 grupos la totalidad de pacientes y controles. Además, se logró separar 2 grupos entre los pacientes para definir su severidad. Finalmente, se consiguió obtener un árbol de distancia entre secuencias de aminoácidos de los distintos alelos HLADRB1,lo cual permite visualizar grupos con cercanía genética y lograr determinar que posiblemente existen más grupos fuera de los propuestos en las distintas teorías. Conclusión: Los métodos utilizados permiten una mejor estratificación de la enfermedad en relación con la predicción de fenotipos y posibles desenlaces de la enfermedad, así como para la potencial prevención primaria de la enfermedad.

Objective: To use computational intelligence models for the classification and identification of endophenotype (relationships between phenotype and genetic markers) in patients with rheumatoid arthritis and healthy controls from genetic information, primarily the DRB1 HLA (human leukocyte antigen) and the shared epitope theory. This refers to the association between rheumatoid arthritis and the HLA-DRB1 alleles mainly containing amino acid common motif sequences QKRAA, RRRAA, QRRAA or at positions 70 to 74 DRB1 chain, which have been associated to susceptibility of this disease. Methods: Computational models were developed for classification using computational intelligence techniques, such as neural networks, Bayesian networks, and methods such as k-means. The input data consisted of variables such as: rheumatoid factor, anti-citrullinated protein antibody, C-reactive protein, number of swollen and tender joints, morning stiffness, age, gender, history of comorbidities, and the information on the HLA-DRB1. Bioinfor-matics techniques were used to search for amino acid sequences related to disease severity. Results: Promising results for the diagnosis of the disease were obtained, as well as its categorisation as potential application in personalised medicine for individuals suffering from this disease. Computational models were designed for the classification, in which the neural network using 5 variables obtained a sensitivity of 92.3% with a specificity of 86.66%, and the Bayesian network obtained a sensitivity of 92.3% and a specificity of 93.33%. The neural network using 11 variables had a sensitivity of 84.61% and a specificity of 93.33%, while the Bayesian network obtained a sensitivity of 92.3% with a specificity of 93.33%. K-means clustering method type was used to divide all patients and controls into two groups of data. It also managed to obtain two patient groups to define severity. Finally, a tree distance was obtained between amino acid sequences of the different alleles HLA DRB1, which allows genetic proximity groups to be visualised and to determine and ensure that there are may be more groups outside the proposed different theories. Conclusion: The proposed method can be used to provide better stratification of the disease in relation to the predicted phenotypes, and the potential for primary prevention of this disease.

Objective:To investigate the relationship between the polymorphism of human leukocyte antigen (HLA)-DRB1 and the susceptibility and repellency of drug use combined with HIV infection in Chinese.Methods:A total of 213 unrelated healthy people, 41 HIV-infected drug users, 24 HIV-uninfected drug users, and 64 HIV-infected non-drug users were recruited. Their HLA-DRB1 allele frequencies were analyzed by PCR-SSP and allele distribution was analyzed.Results:Compared with healthy controls, in drug users, the frequencies of HLA-DRB1 *0401-041, *1001 were significantly higher; in HIV-infected patients, the frequencies of HLA-DRB1 *0101-0103, *0401-0411, *1001 were significantly higher, while the frequencies of DRB1 *1501-1502, *1101-1105, *1301-1302, DRB4, DRB5 were significantly lower; in HIV-infected drug users, the frequencies of HLA-DRB1 *0101-0103, *0401-0411, *0801-0806, *1001, *1401/1404/1405 were significantly higher, while the frequencies of DRB1 *1301/1302, 1501-1502, DRB5 were significantly lower.Conclusion:There is close relationship between the polymorphism of HLA-DRB1 alleles and drug use with HIV infection, which plays an important role in elucidating the pathogenesis and providing the basis for therapeutics and prophylaxis of patients with drug use and HIV infection.

Objetivos: Identificar biomarcadores de susceptibilidad para AIJ poliarticular y AR de instalación temprana por estudio del polimorfismos de MHC/HLA-DRB1* y PTPN22. Materiales y métodos: Se realizó un estudio de casos y controles con una relación 1:2. Todos los sujetos de investigación y los controles provinieron de una corta anidada perteneciente a un proyecto institucional; 30 pacientes con AIJ y 30 con AR de instalación temprana. Como controles se estudiaron 60 individuos sanos. El ADN se obtuvo por salting out modificado. La tipificación de los alelos MHC/DRB1* se realizó por PCR-SSP y en el polimorfismo (C1858T) del sistema PTPN22 se utilizó PCR-RTq. Resultados: Para AIJ Poliarticular, el alelo DRB1*0404 se asoció con susceptibilidad (OR=10.82; p<0.05), en el grupo con AR de instalación temprana, DRB1*0101 se mostró como marcador de susceptibilidad (OR=4.04; p<0.05). Se destaca que el alelo HLA-DRB1*0701 aparece como marcador protector para ambas patologías (OR=0,15; p<0,05). El polimorfismo del SNP (C1858T) PTPN22 no se asoció con AIJ Poliarticular. En contraste, en AR de instalación temprana, el Alelo CC se asoció con protección p<0.05. En el mismo grupo, CT/TT se mostró como un marcador de susceptibilidad <0.05. El análisis de la secuencia aminoacídica 70QRRAA74 del epítope compartido se asoció con susceptibilidad para ambas entidades (p<0.05) y la secuencia 70DRRGQ74 con protección en ambos grupos de pacientes (p<0.05). Conclusión: Se destaca que en la asociación con la secuencia del epítope compartido, la ubicación del tipo de aminoácido y posición del mismo define probable asociación como marcador molecular de susceptibilidad en ambas entidades. Los polimorfismos compartidos sugieren un origen genético común para ambas entidades.

Objectives: To identify polymorphisms of MHCIHLA-DRB1* and PTPN22 systems as a genetic biomarker of susceptibility to JIA poliarticular and early installation RA. Material and methods; This was a pilot case control study with a relation of 1:2. Patients and control individuals involved in this study were selected from a nested cohort from an institutional previous RAIJIA project. The sample was represented by thirty patients with JIA and 30 diagnosed with early installation RA. Sixty unrelated healthy individuals were involved as a control DNA Isolation was obtained by a modified salting out technique. The oligotyping of the MHCIDRB1* alleles was performed by PCR-SSP and the typing of the PTPN22 polymorphism was done by RT-PCR. Results: The DRB1*0404 allele was associated with susceptibility to JIA(OR=10.82, P<0.05). In the early installation RA group the DRB1*0101 allele was showed as a marker of susceptibility to JIA patients (OR=4.04, P<0.05). It is noteworthy that the HLA-DRB1*0701 appears as a possible protective marker for both diseases (OR=015, p<0.05). The polymorphism of (C1858T)PTPN22 was not associated with poliarticular JIA. In contrast, in the early installation RA group of patients, the CC PTPN22 polymorphism was found to be as a protective marker (p<0.05). On the other hand, the amino acid sequence 70QRRAA74 of the share epitope was a marker for susceptibility to both entities (p<0.05) By contrast, the sequence 70DRRGQ74 of the same epitope was showed as a possible marker for protection on both entities (p<0.05.). Conclusion: The model that was used for searching association between the shared epitope -region 70-74 of the DRB1* alleles and these two entities showed the importance of the location and also the type of amino acid in those positions. The polymorphisms found as molecular markers of susceptibility for both entities suggested a common origin and could suggest its probable roll as a molecular marker of susceptibility.

INTRODUÇÃO: A artrite reumatoide (AR) é uma doença crônica multifatorial complexa. A importância do sistema de antígenos leucocitários humanos (HLA) como fator significativo de risco genético para AR foi estudada no mundo. Embora amplamente distribuídos em diferentes áreas na Síria, faltam estudos sobre o papel dos HLA. OBJETIVO: O objetivo de nosso estudo foi determinar a associação dos alelos HLA-DRB1 com a suscetibilidade a AR e sua gravidade na Síria. PACIENTES E MÉTODOS: Foram genotipados 86 pacientes com AR e 200 controles normais, usando-se reação em cadeia da polimerase com sequência de primer específico (PCR-SSP). Anticorpos anti-CCP foram determinados por ELISA. Fator reumatoide (FR), proteína C-reativa (PCR), velocidade de hemossedimentação (VHS) e o índice de atividade da doença (DAS-28) foram obtidos nos registros médicos e utilizados para avaliar a gravidade clínica dos pacientes. RESULTADOS: Os alelos HLA-DRB1 *01, *04 e *10 mostraram forte associação com suscetibilidade à doença (OR = 2,29, IC 95% = 1,11-4,75, P = 0,022; OR = 3,16, IC 95% = 2,08-4,8, P < 0,0001; e OR = 2,43, IC 95% = 1,07-5,51, P = 0,029, respectivamente), enquanto a frequência dos alelos HLA-DRB1 *11 e *13 foi significativamente mais baixa nos pacientes com AR do que nos controles (OR = 0,49, IC 95% = 0,3-0,8, P = 0,004; OR = 0,32, IC 95% = 0,15-0,69, P = 0,002, respectivamente). Os outros alelos HLA-DRB1 mostraram diferença significativa. A frequência dos anticorpos anti-CCP foi maior em pacientes epítopo compartilhado (EC) positivos do que em pacientes EC-negativos (OR = 5,5, IC 95% = 2-15,1, P = 0,00054). O índice DAS-28 de pacientes com AR não mostrou diferença significativa entre os grupos EC-negativo e EC-positivo. CONCLUSÃO: Nossos resultados indicam que os alelos HLA-DRB1 *01, *04 e *10 estão relacionados com AR, enquanto os alelos HLA-DRB1 *11 e *13 protegem a população síria contra a AR.

INTRODUCTION: Rheumatoid arthritis (RA) is a complex multifactorial chronic disease. The importance of human leukocyte antigen as a major genetic risk factor for RA was studied worldwide. Although it is widely distributed in different Syrian areas, studies of human leukocyte antigen (HLA) alleles' role are absent. OBJECTIVE: The aim of our study was to determine the association of HLA-DRB1 alleles with the susceptibility and severity of RA in Syria. PATIENTS AND METHODS: Eightysix RA patients and 200 healthy controls from Syria were genotyped using polymerase chain reaction with sequencespecific primer (PCR-SSP). Anti-CCP antibodies were measured by ELISA. Rheumatoid factor (RF), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and disease activity score 28 (DAS-28) values were obtained from patients' medical records. DAS-28 was used to assess the clinical severity of the patients. RESULTS: The HLA-DRB1*01, *04, and *10 frequencies showed a strong association with the disease susceptibility (OR = 2.29, 95% CI = 1.11-4.75, P = 0.022; OR = 3.16, 95% CI = 2.0 -4.8, P < 0.0001; OR = 2.43, 95% CI = 1.07-5.51, P = 0.029 respectively), while the frequencies of HLA-DRB1*11, and *13 were signifi cantly lower in RA patients than in controls (OR = 0.49, 95% CI = 0.3-0.8, P = 0.004; OR = 0.32, 95% CI = 0.15-0.69, P = 0.002, respectively). The other HLA-DRB1 alleles showed no signifi cant difference. The frequency of anti-CCP antibodies was higher in shared epitope (SE) positive patients compared with SE-negative patients (OR = 5.5, 95% CI = 2-15.1, P = 0.00054). DAS-28 of RA patients didn't show signifi cant difference between the SE negative and the SE positive groups. CONCLUSION: Our results indicate that HLA-DRB1*01, *04, and *10 alleles are related with RA, while HLA-DRB1*11 and *13 protect against RA in the Syrian population.

Epidemiological studies have demonstrated that the variability of the clinical response to infection caused by Mycobacterium leprae is associated with host genetic factors. The present study investigated the frequency of human leukocyte antigen (HLA) class II (DRB1) alleles in patients with leprosy from São Luís, Maranhão, Brazil. A case-control study was performed in 85 individuals with leprosy and 85 healthy subjects. All samples were analysed via polymerase chain reaction-sequence specific oligonucleotide probes. The HLA-DRB1*16 allele showed a higher frequency in the group with leprosy [(9.41% vs. 4.12%) odds ratio (OR) = 2.41 95% confidence interval (CI) (0.96-6.08) p = 0.05], whereas the HLA-DRB1*11 allele was less frequent in the group with leprosy [(6.47% vs. 11.76%) OR = 0.51 95% CI (0.23-1.12) p = 0.09]. The frequency of HLA-DRB1* alleles between the control group and leprosy patient subgroups presenting different forms of the disease showed that the HLA-DRB1*16 (16.13% vs. 8.24%, OR = 4.10, CI = 1.27-13.27, p = 0.010) and HLA-DRB1*14 (5% vs. 3.53%, OR = 4.63, CI = 1.00-21.08, p = 0.032) alleles were significantly more frequent in patients with different clinical subtypes of leprosy. The sample size was a limitation in this study. Nevertheless, the results demonstrated the existence of a genetic susceptibility associated with the clinical forms of leprosy. The low frequency of the HLA-DRB1*11 allele should be further studied to investigate the possible protective effect of this allele.

Os alelos HLA-DRB1, que codificam uma sequência de aminoácidos (QKRAA/QRRAA/RRRAA) nas posições 70 a 74 da terceira região hipervariável da cadeia β1 do gene DRB1, denominada epítopo compartilhado (EC), estão associados a maior suscetibilidade e gravidade para artrite reumatoide (AR) em diversas populações. OBJETIVO: Determinar a frequência dos alelos HLA-DRB1 em pacientes brasileiros com AR, e sua associação a fator reumatoide (FR) e anticorpos antipeptídeos citrulinados (ACPA). MATERIAL E MÉTODOS: Foram incluídos 412 pacientes com AR e 215 controles. A tipificação HLA-DRB1 foi realizada pela reação em cadeia da polimerase (PCR) usando primers específicos e hibridização com oligonucleotídeos de sequência específica (SSOP). A pesquisa de ACPA foi determinada pela técnica de ELISA, e a do FR por nefelometria. Para análises estatísticas foram utilizados os testes do qui-quadrado e t de Student e a regressão logística. RESULTADOS: Alelos HLA-DRB1*04:01, *04:04 e *04:05 associaram-se à AR (P < 0,05)); a despeito do amplo intervalo de confiança, vale a pena ressaltar a associação observada entre o alelo DRB1*09:01 e a doença (P < 0,05). Alelos HLA-DRB1 EC+ foram observados em 62,8% dos pacientes e em 31,1% do grupo-controle (OR 3,62; P < 0,001) e estiveram associados a ACPA (OR 2,03; P < 0,001). Alelos DRB1-DERAA mostraram efeito protetor para AR (OR 0,42; P < 0,001). CONCLUSÃO: Em uma amostra de pacientes brasileiros com AR de etnia majoritariamente mestiça, alelos HLA-DRB1 EC+ estiveram associados à suscetibilidade à doença e à presença de ACPA.

The HLA-DRB1 alleles encoding an amino acid sequence (QKRAA/QRRAA/RRRAA) at position 70 74 of the third hypervariable region of the β1 chain of the HLA-DRB1 gene, called shared epitope (SE), are associated with increased susceptibility to and severity of rheumatoid arthritis (RA) in different populations. OBJECTIVE: To determine the frequency of HLA-DRB1 alleles in Brazilian patients with RA and their association with rheumatoid factor (RF) and anti-citrullinated peptide antibodies (ACPA). METHODS: Four hundred and twelve patients with RA (ACR 1987) and 215 controls were included. HLA-DRB1 typing was performed by use of polymerase chain reaction (PCR) with specific primers and hybridization with sequence-specific oligonucleotide probe (SSOP). ACPA was measured by use of the ELISA technique and RF by nephelometry. The statistical analysis comprised the chi-square and Student t tests and logistic regression. RESULTS: HLA-DRB1*04:01, *04:04, *04:05 alleles were associated with RA (P < 0.05); despite the wide confidence interval, it is worth noting the association between the DRB1*09:01 allele and RA (P < 0.05). HLA-DRB1 SE+ alleles were observed in 62.8% of the patients and in 31.1% of controls (OR 3.62; P < 0.001) and were associated with ACPA (OR 2.03; P < 0.001). DRB1-DERAA alleles showed a protective effect against RA (OR 0.42; P < 0.001). CONCLUSION: In a sample of Brazilian patients with RA, most of whom of mixed heritage, HLA-DRB1 SE+ alleles were associated with susceptibility to disease and presence of ACPA.

Introducción: El alto polimorfismo del sistema HLA, hace que su tipificación sea una herramienta de gran valor al establecer asociación con diferentes enfermedades, patrones inmunológicos, antropogenéticos, así como para establecer probabilidades de encontrar donantes compatibles con receptores de diferentes tipos de trasplante de órganos. Objetivo: Establecer las frecuencias alélicas, genotípicas y haplotípicas en pacientes atendidos en la Clínica Colsanitas SA. Metodología: Se incluyeron un total de 561 pacientes atendidos en el Laboratorio Clínico de La Clínica Colsanitas SA, en 8 sedes en diferentes ciudades del Colombia, durante el período comprendido entre enero de 2004 a agosto de 2008. Se realizó tipificación de HLA -A,-B,-DRB1 por PCR SSP. Las frecuencias alélicas, genotípicas y haplotípicas fueron estimadas mediante el paquete estadístico Stata y el paquete de análisis genético Genepop. Resultados: Fue posible la identificación de 19, 28 y 15 alelos de los loci HLA A-B-DRB1 respectivamente, de los cuales los más frecuentes fueron A*24 (26.2%), A*02 (26%), B*35 (22.7%), DRB1*04 (24%). Los genotipos más frecuentes encontrados fueron A*02,24 (14.2%), B*07,35 (5.5%), DRB1*01,04 y DRB1*04,04 (6.9%). Los haplotipos más frecuentes fueron: HLA A*24, B*35 (9.2%), A*24, DRB1*04 (8.1%); B* 35, DRB1*04 (7.8%), A*2 DRB1*04 (7.4%). Conclusión: Los resultados obtenidos permiten tener referencia para aplicaciones en la población estudiada, así como para establecer probabilidades de compatibilidad en la creciente área de trasplante de órganos.

Introduction: The high polymorphism of the HLA system allows its typification to be used as valuable tool in establishing association to various illnesses, immune and genetic profiles; it also provides a guide to identifying compatibility among donors and receptors of organs transplants. Objective: To establish HLA-A, HLA-B, and HLA.DRB1 allele, genotype and haplotype frequencies among patients treated at Clinica Colsanitas SA. Methods: 561 patients coming from different regions in Colombia, who were attended in 8 centers of the clinical laboratory of the Clinica Colsanitas in different cities of the country from January 2004 to August 2008, were included in this study. All were HLA-A,-B, and -DRB1 typified via SSP PCR. Allele, genotype and haplotype frequencies were estimated with STATA Software Version 9.0 and the GENEPOP genetic analysis package. Results: 19, 28, and 15 different alleles were identified for loci HLA-A,-B and -DRB1, respectively. Alleles found most frequently were A*24 (26.2%), A*02 (26%), B*35(22.7%), and DRB1*04 (24%). The most frequent genotypes were A*02,24 (14.2%), B*07,35 (5.5%), DRB1*01,04, and DRB1*04,04 (6.9%); while most the frequent haplotypes were HLA A*24, B*35 (9.2%), A*24, DRB1*04 (8.1%); B*35, DRB1*04 (7.8%), A*2 DRB1*04 (7.4%). Conclusion: The results obtained provide a useful reference framework for the population studied, allowing compatibility probability calculations to be performed for organ transplants.

Our objective was to determine whether the presence of the human leukocyte antigen HLA-DRB1 locus is associated with production of anti-cyclic citrullinated peptide antibodies (anti-CCP Abs) and to what extent they are associated with increased susceptibility to and severity of rheumatoid arthritis (RA) in Egyptian patients. Twenty-nine RA patients gave informed consent to participate in a case-control study that was approved by the Ain Shams University Medical Ethics Committee. RA disease activity and severity were determined using the simplified disease activity index and Larsen scores, respectively. We used a wide scale national study on the pattern of HLA typing in normal Egyptians as a control study. Anti-CCP Abs and HLA-DRB1 typing were determined for all subjects. The alleles most strongly associated with RA were HLA-DRB1 [*01 , *04 and *06] (41.4%). RA patients with serum anti-CCP Ab titers above 60 U/mL had a significantly higher frequency of HLA-DRB1*01 (58.3%) and HLA-DRB1*04 alleles (83.3%). Significant positive correlations were found between serum and synovial anti-CCP Ab titer, RA disease activity, and severity (r = 0.87, 0.66 and 0.63, respectively; P < 0.05). HLA-DRB1 SE+ alleles [*01 and *04] were highly expressed among Egyptian RA patients. The presence of these alleles was associated with higher anti-CCP Ab titer, active and severe RA disease. Early determination of HLA-DRB1 SE+ alleles and serum anti-CCP Ab could facilitate the prediction of the clinical course and prognosis of RA when first evaluated leading to better disease control.