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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.

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The novel HLA-DRB1*03:215 allele, first described in a potential bone marrow donor from Brazil.

Asunto(s)

Alelos , Cadenas HLA-DRB1 , Prueba de Histocompatibilidad , Humanos , Cadenas HLA-DRB1/genética , Prueba de Histocompatibilidad/métodos , Exones , Análisis de Secuencia de ADN/métodos , Donantes de Tejidos , Brasil , Secuenciación de Nucleótidos de Alto Rendimiento/métodos

RESUMEN

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.

Asunto(s)

Autoanticuerpos , Desmogleína 1 , Desmogleína 3 , Inmunohistoquímica , Pénfigo , Humanos , Pénfigo/inmunología , Desmogleína 3/inmunología , Autoanticuerpos/inmunología , Autoanticuerpos/sangre , Femenino , Masculino , Persona de Mediana Edad , Adulto , Anciano , Desmogleína 1/inmunología , Ensayo de Inmunoadsorción Enzimática , Adulto Joven , Immunoblotting , Cadenas HLA-DRB1/genética , Cadenas HLA-DRB1/inmunología , Anciano de 80 o más Años , Adolescente

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Multiple sclerosis (MS) is a chronic and demyelinating disease with an autoimmune origin, which leads to neurodegeneration and progressive disability. Approximately 30 to 50% of patients do not respond optimally to disease-modifying therapies (DMTs), and therapeutic response may be influenced by genetic factors such as genetic variants. Therefore, our study aimed to investigate the association of the HLA-DRB1*0403 genetic variant and therapeutic response to DMTs in MS. We included 105 patients with MS diagnosis. No evidence of disease activity based on the absence of clinical relapse, disability progression or radiological activity (NEDA-3) was used to classify the therapeutic response. Patients were classified as follows: (a) controls: patients who achieved NEDA-3; (b) cases: patients who did not achieve NEDA-3. DNA was extracted from peripheral blood leukocytes. HLA-DRB1*0403 genetic variant was analyzed by quantitative polymerase chain reaction (qPCR) using TaqMan probes. NEDA-3 was achieved in 86.7% of MS patients treated with DMTs. Genotype frequencies were GG 50.5%, GA 34.3%, and AA 15.2%. No differences were observed in the genetic variant AA between patients who achieved NEDA-3 versus patients who did not achieve NEDA-3 (48.7% vs. 43.1%, p = 0.6). We concluded that in Mexican patients with MS, HLA-DRB1*0403 was not associated with the therapeutic response to DMTs.

Asunto(s)

Esclerosis Múltiple , Humanos , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/genética , Cadenas HLA-DRB1/genética , Predisposición Genética a la Enfermedad , Estudios de Casos y Controles , Genotipo

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HLA-DMB allele frequencies and HLA-DBM-DRB1-DQB1 extended haplotypes were studied for the first time in Amerindians (Cuenca city area, Ecuador). It was found that most common extended haplotypes gathered the most frequent HLA-DRB1 Amerindian alleles. HLA-DMB polymorphism studies may be important to uncover HLA and diseases pathogenesis and also in an extended HLA haplotype frameshift. HLA-DM molecule has a crucial role together with CLIP protein in HLA class II peptide presentation. HLA extended haplotypes including complement and non classical genes alleles are proposed to HLA and disease studies.

Asunto(s)

Antígenos HLA-D , Antígenos HLA-DQ , Humanos , Alelos , Ecuador , Frecuencia de los Genes , Haplotipos , Antígenos HLA-D/genética , Antígenos HLA-DQ/genética , Cadenas beta de HLA-DQ/genética , Cadenas HLA-DRB1/genética

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B cells, follicular helper T (Tfh) cells and follicular regulatory T (Tfr) cells are part of a circuit that may play a role in the development or progression of rheumatoid arthritis (RA). With the aim of providing further insight into this topic, here we evaluated the frequency of different subsets of Tfh and Tfr in untreated and long-term treated RA patients from a cohort of Argentina, and their potential association with particular human leukocyte antigen (HLA) class-II variants and disease activity. We observed that the frequency of total Tfh cells as well as of particular Tfh subsets and Tfr cells were increased in seropositive untreated RA patients. Interestingly, when analyzing paired samples, the frequency of Tfh cells was reduced in synovial fluid compared to peripheral blood, while Tfr cells levels were similar in both biological fluids. After treatment, a decrease in the CCR7loPD1hi Tfh subset and an increase in the frequency of Tfr cells was observed in blood. In comparison to healthy donors, seropositive patients with moderate and high disease activity exhibited higher frequency of Tfh cells while seropositive patients with low disease activity presented higher Tfr cell frequency. Finally, we observed that HLA-DRB1*09 presence correlated with higher frequency of Tfh and Tfr cells, while HLA-DRB1*04 was associated with increased Tfr cell frequency. Together, our results increase our knowledge about the dynamics of Tfh and Tfr cell subsets in RA, showing that this is altered after treatment.

Asunto(s)

Artritis Reumatoide , Linfocitos T Reguladores , Humanos , Células T Auxiliares Foliculares , Cadenas HLA-DRB1/genética , Linfocitos T Colaboradores-Inductores

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Interstitial lung abnormalities (ILA) are defined as the presence of different patterns of increased lung density, including ground glass attenuation and reticular opacities on chest high-resolution computed tomography (HRCT). In this study, we included 90 subjects with ILA and 189 healthy controls (HC) from our Aging Lung Program. We found that subjects with ILA are older, have a significant smoking history, and have worse pulmonary function than HC (p < 0.05). When we evaluated the allele frequencies of the human leukocyte antigen (HLA) system, we found that HLA-DRB1*07 was associated with a higher risk for ILA (p < 0.05, OR = 1.95, 95% CI = 1.06-3.57). When we compared subjects with subpleural ILA vs. HC, the association with HLA-DRB1*07 became stronger than the whole ILA group (p < 0.05, OR = 2.29, 95% CI = 1.24-4.25). Furthermore, subjects with subpleural ILA and central ILA display differences in allele frequencies with HLA-DRB1*14 (3.33% vs. 13.33%, p < 0.05) and *15 (3.33% vs. 20%, p < 0.05). Our findings indicate that the HLA-DRB1*07 allele contributes to the risk of ILA, especially those of subpleural locations.

Asunto(s)

Pulmón , Tomografía Computarizada por Rayos X , Humanos , Cadenas HLA-DRB1/genética , Alelos , Frecuencia de los Genes/genética , Tomografía Computarizada por Rayos X/métodos

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The novel HLA-DRB1*03:196 allele, first described in a potential bone marrow donor from Brazil.

Asunto(s)

Trasplante de Médula Ósea , Polimorfismo de Nucleótido Simple , Alelos , Brasil , Cadenas HLA-DRB1/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos

RESUMEN

OBJECTIVE: This study aimed to determine the relation between titres of anti-Porphyromonas gingivalis (P. gingivalis) antibody and rheumatoid arthritis (RA) HLA-DRB1 susceptibility region associated with shared epitope (SE) using the Gregersen's and de Vries's classification methods. MATERIAL AND METHODS: In this cross-sectional study, results of immunoglobulin G1 (IgG1) and immunoglobulin G2 (IgG2) anti-P. gingivalis antibodies, anti-citrullinated protein antibodies (ACPA), diagnosis for RA, and periodontal disease (PD), and a genetic study of the HLA DRB1 region were obtained from 50 patients with RA and 50 control individuals. RESULTS: Anti-P. gingivalis antibody levels and PD parameters were similar in control and RA groups. Anti-P. gingivalis antibodies were not associated with SE or ACPA. There was no association between ACPA and SE. However, de Vries' classification in RA patients revealed an association between the HLA DRB1 neutral alleles and higher titres of anti-P. gingivalis antibodies as follows: IgG1 anti-P. gingivalis ≥ 1:400 (p = .039); IgG2 anti-P. gingivalis ≥ 1:400 with neutral/neutral genotype (N/N), being exclusive for RA (p = .008); and IgG2 anti-P. gingivalis ≥ 1:200 and N/N (p = .016). CONCLUSIONS: Although no association was found between SE and anti-P. gingivalis antibodies; according to the de Vries' classification, there was an existing association between HLA DRB1 neutral alleles, with high titres of IgG anti-P.gingivalis antibodies for RA, focussing on novel associations between P.gingivalis and RA.

Asunto(s)

Artritis Reumatoide , Porphyromonas gingivalis , Alelos , Artritis Reumatoide/diagnóstico , Artritis Reumatoide/genética , Autoanticuerpos , Estudios Transversales , Predisposición Genética a la Enfermedad , Cadenas HLA-DRB1/genética , Humanos , Péptidos Cíclicos

RESUMEN

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.

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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.

Asunto(s)

Humanos , Cadenas alfa de HLA-DQ/genética , Esclerosis Múltiple/genética , Esclerosis Múltiple/diagnóstico por imagen , Imagen por Resonancia Magnética , Estudios Retrospectivos , Genes MHC Clase II , Predisposición Genética a la Enfermedad , Alelos , Cadenas beta de HLA-DQ , Cadenas HLA-DRB1/genética , Frecuencia de los Genes

RESUMEN

Human papillomavirus (HPV) infection is a necessary cause for cervical cancer (CC), but it also depends on genetic factors, such as HLA polymorphism. However, few reports addressed the role of amino acids residues at the HLA peptide-binding cleft in HPV-related cervical disease. Therefore, we aimed to investigate the association between HLA-B, HLA-C, and HLA-DRB1 polymorphism and amino acid residues composing the pockets of the peptide-binding cleft of the respective polypeptide chains with cervical intraepithelial neoplasia (CIN II/III). HLA typing was performed by PCR-SSOP in 184 women with CIN II/III and 174 controls from South Brazil. Associations were estimated by multivariate logistic regression. FDR test was performed to correct the p-value for multiple comparisons. HLA-DRB1*13:01 was associated with protection against CIN II/III, while HLA-C*03:04 was associated with susceptibility. The amino acid residues isoleucine, tyrosine, and leucine at positions 95, 116, and 163 of HLA-C, respectively, were associated with CIN II/III susceptibility. In contrast, serine at positions 11 and 13 of HLA-DRB1 was associated with protection against the disease. Our results confirm previously reported associations between HLA and cervical diseases caused by HPV and suggest a role for amino acid residues at different positions of HLA-C and HLA-DRB1 in CIN II/III. This finding may be further explored to better understand the genetic risk and the influence of immune response to CC development.

Asunto(s)

Lesiones Precancerosas , Displasia del Cuello del Útero , Neoplasias del Cuello Uterino , Alelos , Femenino , Humanos , Papillomaviridae/genética , Neoplasias del Cuello Uterino/genética , Displasia del Cuello del Útero/genética

RESUMEN

Systemic Lupus Erythematosus (SLE) is an autoimmune inflammatory disorder for which Major Histocompatibility Complex (MHC) genes are well identified as risk factors. SLE patients present different clinical phenotypes, which are partly explained by admixture patterns variation among Mexicans. Population genetic has insight into the high genetic variability of Mexicans, mainly described through HLA gene studies with anthropological and biomedical importance. A prospective, case-control study was performed. In this study, we recruited 146 SLE patients, and 234 healthy individuals were included as a control group; both groups were admixed Mexicans from Mexico City. The HLA typing methods were based on Next Generation Sequencing and Sequence-Based Typing (SBT). The data analysis was performed with population genetic programs and statistical packages. The admixture estimations based on HLA-B and -DRB1 revealed that SLE patients have a higher Southwestern European ancestry proportion (48 ± 8%) than healthy individuals (30 ± 7%). In contrast, Mexican Native American components are diminished in SLE patients (44 ± 1%) and augmented in Healthy individuals (63 ± 4%). HLA alleles and haplotypes' frequency analysis found variants previously described in SLE patients from Mexico City. Moreover, a conserved extended haplotype that confers risk to develop SLE was found, the HLA-A∗29:02∼C∗16:01∼B∗44:03∼DRB1∗07:01∼DQB1∗02:02, pC = 0.02, OR = 1.41. Consistent with the admixture estimations, the origin of all risk alleles and haplotypes found in this study are European, while the protection alleles are Mexican Native American. The analysis of genetic distances supported that the SLE patient group is closer to the Southwestern European parental populace and farthest from Mexican Native Americans than healthy individuals. Heterogeneity of genetic admixture determines SLE susceptibility and protection in Mexicans. HLA sequencing is helpful to determine susceptibility alleles and haplotypes restricted to some populations.

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BACKGROUND: Antigens from the Rh and Kell systems are recognized as the most immunogenic in clinical practice. This study evaluated the possible molecular mechanisms involved in the interaction of antigenic peptides with the DRB1 molecules, which help to explain the high frequency of anti-K and association of D + C antibodies in transfusion and incompatible pregnancy. STUDY DESIGN AND METHODS: We included 201 patients with antibodies against antigens from the Rh and Kell systems and compare them with 174,015 controls. HLA-DRB1 genotyping and in silico analysis were performed. The NetMHCIIpan software was used to identify RhD-, RhCE-, and KEL-derived anchor peptides that bind to DRB1 molecules. RESULTS: HLA-DRB1*15 is associated with an increased risk of D, C, E, and K alloimmunization, while the HLA-DRB1*01 and *12 alleles are overrepresented in patients with anti-C and anti-D, respectively. In silico analysis showed that three polymorphic points (60I, 68S, and 103S) common to C and D antigens can be presented by several DRB1 molecules, including DRB1*15:01. The DRB1*09:01 molecule, although not showing statistical significance, was able to interact strongly with almost all five anchor peptides from the sequence containing the polymorphic determinants of E antigen, except 217-WMFWPSVNS-225. CONCLUSION: The DRB1*15 molecule has specific physicochemical characteristics in residues 11P and 13R in the P4 pocket that can favor the response to various antigenic peptides. Anti-K alloimmunization is unrestricted for interaction with specific DRB1 molecules, which suggests that almost all individuals in our population have DRB1 molecules capable of binding to KEL-derived anchor peptides and produce anti-K when stimulated.

Asunto(s)

Cadenas HLA-DRB1/inmunología , Glicoproteínas de Membrana/inmunología , Metaloendopeptidasas/inmunología , Sistema del Grupo Sanguíneo Rh-Hr/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Femenino , Cadenas HLA-DRB1/genética , Humanos , Masculino , Glicoproteínas de Membrana/química , Metaloendopeptidasas/química , Persona de Mediana Edad , Péptidos/química , Péptidos/inmunología , Sistema del Grupo Sanguíneo Rh-Hr/química , Adulto Joven

RESUMEN

BACKGROUND: We took advantage of the 2015-2016 Brazilian arbovirus outbreak (Zika [ZIKV]/dengue/chikungunya viruses) associated with neurological complications to type HLA-DRB1/DQA1/DQB1 variants in patients exhibiting neurological complications and in bone marrow donors from the same endemic geographical region. METHODS: DRB1/DQA1/DQB1 loci were typed using sequence-specific oligonucleotides. In silico studies were performed using X-ray resolved dimer constructions. RESULTS: The DQA1*01, DQA1*05, DQB1*02, or DQB1*06 genotypes/haplotypes and DQA1/DQB1 haplotypes that encode the putative DQA1/DQB1 dimers were overrepresented in the whole group of patients and in patients exhibiting peripheral neurological spectrum disorders (PSD) or encephalitis spectrum disorders (ESD). The DRB1*04, DRB1*13, and DQA1*03 allele groups protected against arbovirus neurological manifestation, being underrepresented in whole group of patients and ESD and PSD groups. Genetic and in silico studies revealed that DQA1/DQB1 dimers (1) were primarily associated with susceptibility to arbovirus infections; (2) can bind to a broad range of ZIKV peptides (235 of 1878 peptides, primarily prM and NS2A); and (3) exhibited hydrophilic and highly positively charged grooves when compared to the DRA1/DRB1 cleft. The protective dimer (DRA1/DRB1*04) bound a limited number of ZIKV peptides (40 of 1878 peptides, primarily prM). CONCLUSION: Protective haplotypes may recognize arbovirus peptides more specifically than susceptible haplotypes.

Asunto(s)

Arbovirus , Alelos , Arbovirus/genética , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Cadenas alfa de HLA-DQ , Cadenas beta de HLA-DQ/genética , Cadenas HLA-DRB1/genética , Haplotipos , Humanos , Síndrome , Virus Zika , Infección por el Virus Zika

RESUMEN

HLA-DRB1 shared epitope (SE) alleles are important genetic contributors for the risk of developing anti-citrullinated protein antibodies (ACPA)-positive rheumatoid arthritis (RA), particularly in Caucasians. We aimed to analyze the contribution of HLA-DRB1 alleles and single nucleotide polymorphisms (SNPs) within the major histocompatibility complex (MHC) region to the susceptibility to develop ACPA-positive RA in a Latin American (LA) population with admixed ancestry. A total of 289 ACPA-positive RA patients and 510 controls were enrolled in this study. The presence of HLA-DRB1*04:01, *09:01 and *10:01 was increased in ACPA-positive RA patients compared with healthy controls (p < 0.0001, p < 0.001 and p < 0.01, respectively), whereas DRB1*07:01 and *08:02 was associated with a decreased risk of ACPA-positive RA (p < 0.001 and p < 0.01, respectively). These results showed a strong correlation with estimates from studies in Asians but not in Caucasian populations. The present study describes the protective effects of the HLA-DRB1*07:01 and *08:02 alleles in ACPA-positive RA patients in a LA population for the first time. Identifying relationships between HLA-DRB1 alleles and RA is important for identifying disease associations in different ethnic groups in order to reach a better understanding of RA worldwide.

RESUMEN

INTRODUCTION: Autoimmune thyroid disease (AITD) is the most common autoimmune disorder worldwide. Remarkably, it is commonly accompanied by other autoimmune diseases, such as rheumatoid arthritis (RA). The immunopathogenic mechanisms behind the coexistence of these disorders are still not completely understood. Immunogenetics influences the physiopathology of these diseases since ethnicity plays an essential role in the inheritance of susceptibility markers. METHODS: High-resolution HLA class II typing was performed using a sequence-based method. RESULTS: The allele frequency of HLA-DRB1∗04:04 and -DRB1∗03:01 were significantly increased in patients with AITD and RA compared to healthy individuals, pC â€‹= â€‹0.021, OR â€‹= â€‹2.4, 95%CI â€‹= â€‹1.19-4.75 and pC â€‹= â€‹0.009, OR â€‹= â€‹3.4, 95%CI â€‹= â€‹1.42-7.93, respectively. Remarkably, these patients have a combined risk given by susceptibility HLA-DRB1 alleles that contain the shared epitope, pC â€‹= â€‹0.03, OR â€‹= â€‹1.7, IC95% â€‹= â€‹1.07-2.76, and a lack of protective alleles carrying aspartic acid70, pC â€‹= â€‹0.009, OR â€‹= â€‹0.5, IC95% â€‹= â€‹0.32-0.84. DISCUSSION: The results suggest that patients with AITD and RA have an immunogenetic mechanism that combines the susceptibility alleles associated with both diseases. Importantly, it seems to be linked mainly to the lack of protective alleles with aspartic acid in the position 70, along with the presence of susceptibility alleles that have the sequences QRRAA, QKRAA, and RRRAA at positions 70-74. CONCLUSION: Patients with AITD and RA have a characteristic immunogenetic signature, which could be useful for determining multiple autoimmunities and assessing their relatives' risk of developing it.

RESUMEN

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease with an increased prevalence in Mexico. Although its etiology is unknown, its development can be influenced by environmental factors such as smoking and viral infections. But among the factors influencing susceptibility, it is the genetic factors that predominate, mainly the HLA-DRB1 genes, and specifically the alleles that have the shared epitope (SE). A transversal study was performed, in which 31 patients (28 women and 3 men) with RA, treated at the autoimmunity clinic of the High Specialty Hospital Ciudad Salud in Tapachula, Chiapas, southern México, were enrolled. Clinical, biochemical, and demographic data were analyzed; ESR (erythrocyte sedimentation rate), CRP (C-reactive protein), RF (rheumatoid factor), and ACPA (anticitrullinated peptide antibody) were recorded. All patients had at least one positive RA biological marker. For HLA alleles frequencies comparison, we enrolled ethnically matched healthy controls in a ratio of 3:1 for 25 cases and 4:1 for 6 cases in order to guarantee the balance between groups regarding the mean of age and proportion of gender (males vs females). HLA-DRB1*04 was found to be significantly increased in patients compared with ethnically matched healthy controls (p 0.0007, OR: 2.8, 95% CI 1.5-5.1); contrarily, DRB1*08 showed a protective effect (p 0.005, OR 0.1). This paper confirmed the involvement of HLA genes on risk determination for RA in a population of Mexican Mestizos from Tapachula, Chiapas. Key Points • HLA-DRB1*04 confirms the increased risk of rheumatoid arthritis. • HLA-DRB1*08 showed a more definite protective effect in southern Mexicans mestizos, a population with more Amerindian ancestry.

Asunto(s)

Artritis Reumatoide , Predisposición Genética a la Enfermedad , Alelos , Artritis Reumatoide/genética , Femenino , Genotipo , Cadenas HLA-DRB1/genética , Humanos , Masculino , México

RESUMEN

INTRODUCTION: Systemic lupus erythematosus (SLE) is an autoimmune inflammatory disorder for which Major Histocompatibility Complex (MHC) genes are well-identified as risk factors. SLE patients have different phenotypes or clinical presentations, which vary among Mexicans. This variation could be explained by ethnicity and admixture. Since socioeconomic status probably limits and change the patterns of migration, this factor could favor inbreeding and homogamy in some geographic areas. Consequently, it could alter or restrict the possibilities of admixture too. Therefore, the socioeconomic status may also have implications in the susceptibility and the clinical heterogeneity of SLE in Mexican patients. METHODS: One hundred twenty-three SLE patients and 234 healthy individuals with Mexican admixed ancestry were recruited. HLA alleles were analyzed using the HLA typing method based on Sequence-based typing (SBT). RESULTS: As expected, it was found an increased frequency of the HLA-DRB1*03:01 allele in all socioeconomic groups when compared with healthy individuals. The susceptibility allele found in the low-income SLE patients was HLA-DRB1*04:05 whereas, the susceptibility alleles for the high-income SLE patients were HLA-DRB1*07:01 (pC = 0.03, OR = 2.0) and HLA-DRB1*11:04 (pC = 0.0004, OR = 5.1). Additionally, the frequencies of two protective alleles HLA-DRB1*14:06 (pC = 0.01, OR = 0.28) and HLA-DRB1*16:02 (pC = 0.04, OR = 0.22) were found diminished. These findings correlate with the admixture differences between low-income and high-income SLE patients. The clinical manifestations showed a different distribution between both groups. Arthritis and neurological disorder were prevalent in low-income SLE patients, while the hematological disorder was prevalent in high-income SLE patients. CONCLUSIONS: These findings suggest that HLA class II DRB1 genes contribute to the susceptibility and protection to develop SLE differently depending on socioeconomic status. Due to this, the clinical manifestations vary among patients and it could be related to different admixture charge.Key Point• HLA class II DRB1 genes contribute to the susceptibility and protection to develop SLE differently depending on socioeconomic status.

Asunto(s)

Predisposición Genética a la Enfermedad , Cadenas HLA-DRB1/genética , Renta , Lupus Eritematoso Sistémico/genética , Clase Social , Adulto , Alelos , Estudios de Casos y Controles , Femenino , Humanos , Masculino , México , Persona de Mediana Edad , Fenotipo , Adulto Joven

RESUMEN

Melkersson-Rosenthal syndrome (MRS) is a neuromucocutaneous disease that manifests by the triad of recurrent orofacial edema (frequently as cheilitis granulomatosa), relapsing facial paralysis and plicated tongue. The cause of MRS remains unknown, but genetic predisposal and a relationship with inflammatory bowel disease are suspected. The objective of this research was to compare the frequency of class I and II HLA alleles in patients with a confirmed diagnosis of MRS with those of a healthy control group. We conduct a case-control study and typed of HLA A, B, C, DR, and DQ using molecular techniques. The study included 36 patients with MRS and 297 patients in the control group. There was an increase in the expression of HLA A*02 (p = 0.0269; OR: 1,79 [1,045-2,973]), HLA DRB1*11 (p < 0,0001; OR: 4,009 [2,214-7,277]), HLA DRB1*13 (not statistically significant) and HLA DQB1*03 (p = 0,0177; OR: 1,829 [1,122-2,978]) and low levels of HLA A*01 (p = 0.0046; OR: 0,097 [0,009-0,538]), HLA DRB1*04 (p = 0.0274; OR: 0,228 [0,053-0,844]), HLA DRB1*07 (p = 0,0091; OR: 0,183 [0,043-0,670]) and HLA DQB1*02 (p = 0.0051; OR: 0,312 [0,143-0,721]) in MRS patients compared with the control group. Crohn disease (CD) patients had disparate genetic profiles versus those with MRS. This single-institution study had a small cohort, because this disease is rare. Conclusions: There is a genetic predisposition toward MRS, involving associated and protective genes.

Asunto(s)

Alelos , Cadenas HLA-DRB1/genética , Complejo Mayor de Histocompatibilidad/genética , Síndrome de Melkersson-Rosenthal/genética , Adolescente , Adulto , Anciano , Brasil , Estudios de Casos y Controles , Niño , Preescolar , Enfermedad de Crohn/genética , Femenino , Genes MHC Clase I/genética , Genes MHC Clase II/genética , Predisposición Genética a la Enfermedad , Granulomatosis Orofacial/genética , Cadenas beta de HLA-DQ , Humanos , Lactante , Enfermedades Inflamatorias del Intestino , Masculino , Persona de Mediana Edad , Pacientes , Adulto Joven

RESUMEN

BACKGROUND: Multiple factors are implicated in the etiology and pathogenesis of Abdominal Aortic Aneurysms (AAA). Available literature of genetic studies has previously suggested the possible roles of autoimmunity, genetic predisposition and ethnic susceptibility. Due to the association with autoimmune diseases and proven application in population genetics, we aimed to investigate alleles of the Class II Human Leukocyte Antigens (HLA-DRB1) in the Mexican Mestizo population with aortic aneurysms and determine possible associations with susceptibility. METHODS: We performed a case Control Study; the HLA molecular typing was completed for DRB1 loci by LabType Sequence-Specific Oligonucleotide (SSO) SSO-OneLambda kit (Applied Biosystems; Thermo Fisher Scientific. Inc.) in the studied individuals. Allele frequencies (af) were determined, associations were assessed by chi square or fisher exact tests at significance level (< 0.05), and Odds Ratios (OR) were calculated using the STATA software version 14. RESULTS: The genetic polymorphism of HLA-DRB1 of fifty one patients (70% males with a mean age of 71 years) with atherosclerotic or also known as degenerative AAA were compared with 99 unrelated patients (60% males, mean age 65 years) without the disease [Control group (CG)] from the same ethnic group. We examined a total of 102 Class II HLA-DRB1 alleles of AAA patients and 198 from CG. When comparing af, we observed the HLA-DRB1*01 af of 0.139 in the AAA compared to 0.05 in the CG [p = 0.015, OR 3, 95% confidence interval (CI) 1.29-7.08], the HLA-DRB1*16 af were 0.109 in the AAA and 0.025 in CG (p = 0.006, OR 4.7, 95% CI 1.59-13.98). CONCLUSIONS: Our study confirmed increased frequencies of the alleles HLA-DRB1*01 and HLA-DRB1*16 and their association to the development of AAA in Mexican Mestizo patients. The utility of genetic testing may assist in identifying individuals at genetic risk for the development of this disease in different ethnic groups, who might benefit from earlier ultrasound screening and closer imaging surveillance.

Asunto(s)

Aneurisma de la Aorta Abdominal/genética , Etnicidad/genética , Predisposición Genética a la Enfermedad/genética , Cadenas HLA-DRB1/genética , Polimorfismo Genético , Anciano , Alelos , Aneurisma de la Aorta Abdominal/diagnóstico , Aneurisma de la Aorta Abdominal/etnología , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad/etnología , Humanos , Masculino , México , Persona de Mediana Edad