Class I and class II MHC polymorphisms in Mexican patients with Behçet’s disease

doi:10.1016/j.imlet.2004.03.017

Immunology Letters

Volume 93, Issues 2–3, 15 May 2004, Pages 211-215

https://doi.org/10.1016/j.imlet.2004.03.017 Get rights and content

Abstract

Behçet’s disease is a multi-system inflammatory disorder of unknown etiology. The disease is more prevalent in Eastern Mediterranean countries and Japan where there is a linkage to HLA-B51. Mexican Mestizos are suitable subjects for studying the role of ethnicity in the susceptibility to Behçet’s disease. High-resolution HLA class I and class II typing was performed by polymerase chain reaction sequence-specific oligonucleotide (PCR-SSO) reverse dot blot and PCR-single-strand polymorphism in 32 patients with Behçet’s disease and 99 healthy ethnically-matched controls. A significant increased frequency of HLA-B^*44 (P=0.02; OR = 2.78; CI 95% = 1.1–7.7), HLA-B^*52 (P=0.02; OR = 5.33; CI 95% = 1.07–29.1), and HLA-B^*56 (P=0.003; OR = 4.19; CI 95% = 3.37–5.21) as well as HLA-DRB1^*01 and HLA-DRB1^*13 (P=0.007; OR = 3.36; CI 95% = 1.22–9.27) was found in Mexican patients with Behçet’s disease when compared to controls. The low frequency of native markers in Mexican Mestizo patients with Behçet’s disease suggests that genetic admixture between Eastern Mediterraneans and Orientals with Amerindians is a recent event that increased the risk of developing Behçet’s disease in the Mexican population.

Introduction

In 1937, Hulusi Behçet described a syndrome evidenced by recurrent oral and genital ulcerations, and uveitis often leading to blindness. Nowadays it is considered as a systemic vasculitis that also affect the joints, the skin, all sizes of blood vessels, lungs, central nervous system, and the gastrointestinal tract [1].

The etiology of Behçet’s disease is unknown, however, it has been suggested that some environmental factors such as certain streptococci, Escherichia coli, Herpes simplex virus, parvovirus B19, mycobacterial heat shock protein-derived peptides, and staphylococcal superantigens can trigger the disease manifestations in genetically susceptible individuals [2], [3], [4], [5], [6]. The prevalence of Behçet’s disease is considerably higher in countries from the Mediterranean region to Japan, along the Silk road. The highest incidence occurs in the population of Turkey. It has been suggested that the disease susceptibility genes might have been spread along this trading route by nomadic tribes or migrating Turks, or that this geographic predilection may be a reflection of the increased frequency of HLA-B51 in the healthy population [7], [8], [9]. Indeed, the association of HLA-B51 with Behçet’s disease has been regarded as the strongest evidence of genetic contribution described to date [10]. Moreover, allelic association, genotypic differentiation, and stratification analyses in different ethnic groups have supported the direct role of HLA-B51 in the disease pathogenesis, and all other associations with neighboring gene or markers e.g., MICA (MHC class I chain-related gene A), could be explained by linkage disequilibrium with HLA-B51 [11]. Certainly, the presence of HLA-B51 negative patients suggest the influence of other genetic factors and/or of environmental or infectious agents.

Mexican Mestizo individuals who have a proportion of 56% Native American Indian genes, 40% Caucasian genes, and 4% African genes [12] are suitable subjects for studying the role of ethnicity in the susceptibility to Behçet’s disease. Mestizo population represents a complex mixture of European (Caucasian) and American native inhabitants (Mongoloid). Mestizos constitute the core of the Mexican and the Latin American populations. This complex genetic process initiated in the 16th century, has expanded during the course of time and continues to be a dynamic process. Hence, class I and class II MHC genotypes were studied in Mexican Mestizo patients in order to elucidate the genetic factors behind Behçet’s disease.

Section snippets

Patients

The study included 32 subjects all of whom fulfilled the International Study Group diagnostic criteria for Behçet’s disease [13]. Age ranged from 12 to 56 years (mean 33.9 years). There were 18 females (64%) and 10 males (36%). Disease duration was from 3 months to 25 years (mean 6.5 years). Patient’s clinical characteristics are shown in Table 1. All patients were Mexican Mestizos. A Mexican Mestizo is defined as an individual who was born in Mexico and is a descendant of the native

HLA-B locus

A statistically increased frequency of HLA-B^*44 (P=0.02; OR = 2.78; CI 95% = 1.1–7.7), HLA-B^*52 (P=0.02; OR = 5.33; CI 95% = 1.07–29.1), and HLA-B^*56 (P=0.003; OR = 4.19; CI 95% = 3.37–5.21) was observed in patients with Behçet’s disease when compared to healthy controls (Table 2). No difference was found in the frequency of HLA-B^*51 [9% versus 5% (P=0.24; OR = 1.88; CI 95% = 0.58–5.93)] among patients and controls (Table 2).

HLA-DRB1 locus

Significant increased frequencies of HLA-DRB1^*01 and HLA-DRB1^*13 were

Discussion

In this study, the association between polymorphisms in the HLA-B and HLA-DR loci with genetic susceptibility to develop Behçet’s disease in Mexican Mestizo patients was evaluated.

A significant association was found between HLA-B44, B52, and B56 with Behçet’s disease in our population. It is worth to mention that the alleles HLA-B^*51 and HLA-B^*52 belong to the serologically defined B5 major allele. Members of this group share the amino acid alanine at position 26, which contributes to the

Acknowledgements

This work was supported in part by a research grant from the Fundación Miguel Alemán, AC, Mexico City. Elena Soto-Vega is recipient of a Ph.D. scholarship from the Consejo Nacional de Ciencia y Tecnologı́a (CONACYT), Mexico.

References (27)

R.P Eglin et al.
Detection of RNA complementary to the herpes simplex virus in mononuclear cells from patients with Behçet’s syndrome and recurrent oral ulcers
Lancet
(1982)
E Isogai et al.
Chemiluminescence of neutrophils from patients with Behçet’s disease and its correlation with an increased proportion of uncommon serotypes of Streptococcus sanguis in the oral flora
Arch. Oral. Biol.
(1990)
F Choukri et al.
HLA-B^*51 and B^*15 alleles confer predisposition to Behçet’s disease in Moroccan patients
Hum. Immunol.
(2001)
T Sakane et al.
Current concepts: Behçet’s disease
N. Eng. J. Med.
(1999)
T Lehner
The role of heat shock protein
Int. Rev. Immunol.
(1997)
T Lehner et al.
Association between the 65-kilodalton heat shock protein, Streptococcus sanguis, and the corresponding antibodies in Behçet’s disease
Infect. Immun.
(1991)
K Yokota et al.
Characterization of Streptococcus sanguis isolated from patients with Behçet’s disease
Microbiol. Immunol.
(1995)
V Kaklamanis et al.
Behçet’s disease
Semin. Arthritis Rheum.
(1998)
A Gül
Behçet’s disease: an update on the pathogenesis
Clin. Exp. Rheumatol.
(2001)
I Krause et al.
Association of HLA-B5 with clinical expression and severity of Behçet’s disease in Israel
J. Clin. Rheumatol.
(1999)

A Gül et al.

Evidence for linkage of the HLA-B locus in Behçet’s disease, obtained using the transmission disequilibrium test

Arthritis Rheum.

(2001)

M Zierhut et al.

Immunology and functional genomics of Behçet’s disease

Cell Mol. Life Sci.

(2003)

R Lisker et al.

Gene frequencies and admixture estimates in a Mexico City population

Am. J. Phys. Anthropol.

(1986)

Cited by (25)

Behçet disease in Latin American countries: A systematic literature review of demographic and clinical features, and HLA-B*51 allele frequency
2023, Reumatologia Clinica
To describe the demographic and clinical features, as well as the frequency of the HLA-B*51 allele in Behçet disease (BD) patients in Latin American countries.
A systematic literature review of PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines was conducted without performing a meta-analysis. We included observational studies (cross-sectional or cohort) of BD patients fulfilling the International Study Group for BD classification criteria and reported the demographic, clinical, and laboratory features of the disease in adult patients.
Twelve studies were included in the SLR. Information from 532 patients across 5 Latin American countries was included for the analysis. Mean age at disease diagnosis was 33 years, 58.3% were female and 41.7% male; most patients were non-Caucasian. The most common clinical manifestations were recurrent oral ulcers and genital ulcers, followed by skin, eye, joint, neurological, gastrointestinal, vascular, and cardiac involvement. The prevalence of BD was described in 2 studies, 1 conducted in Brazil that reported a prevalence of .3/100,000 inhabitants, and another in Colombia with a prevalence of 1.1/100,000 inhabitants. The frequency of HLA-B*51 allele in BD patients was 38%, 30.1%, and 9% in Argentina, Brazil, and Mexico, respectively.
The prevalence of BD in the Latin American countries seems to be low, as well as the frequency of HLA-B*51 allele. However, the strength of association between HLA-B*51 and BD remains high in our population. The key clinical features of BD are like those reported in countries/regions where BD is endemic.
Describir las características demográficas, clínicas y la frecuencia del alelo HLA-B*51 en pacientes con enfermedad de Behçet (EB) en países de América Latina.
Se llevó a cabo una revisión sistemática de la literatura (RSL) según la guía PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) sin realizar un metaanálisis final. Se incluyeron estudios observacionales (transversales o de cohortes) de pacientes con EB que cumplieron con los criterios de clasificación del Grupo Internacional de Estudio de la EB e informaron las características demográficas, clínicas y de laboratorio en pacientes adultos con EB.
Doce estudios fueron incluidos para la RSL. La información de 532 pacientes provenientes de 5 países de América Latina se incluyó para el análisis. La edad media al diagnóstico fue de 33 años, el 58,3% fueron mujeres y el 41,7% hombres; la mayoría de los pacientes fueron no caucásicos. Las manifestaciones clínicas más comunes fueron las úlceras orales y genitales recurrentes, seguidas del compromiso cutáneo, ocular, articular, neurológico, gastrointestinal, vascular y cardíaco. La prevalencia de la EB fue descrita en 2 estudios, uno realizado en Brasil que reportó una prevalencia de 0,3/100.000 habitantes, y otro en Colombia con una prevalencia de 1,1/100.000 habitantes. La frecuencia del HLA-B*51 en pacientes con EB fue del 38%, 30,1% y 9% en Argentina, Brasil y México, respectivamente.
La prevalencia de la EB en los países latinoamericanos parece ser baja, así como la frecuencia del alelo HLA-B*51. Sin embargo, la fuerza de asociación entre el HLA-B*51 y la EB sigue siendo alta en nuestra población. Las características clínicas claves de la EB son similares a las reportadas en países/regiones donde es endémica.
Characteristics of Behcet's Disease in the American Southwest
2019, Seminars in Arthritis and Rheumatism
Citation Excerpt :
A unique aspect of the present study relative to previous US-based studies is the identification of a large proportion of Hispanic Americans and Native Americans from the American Southwest that have previously been rather understudied and incompletely described populations in terms of BD (Table 4). Clinical descriptions of substantial BD cohorts have been reported previously in Spanish, South American, and Mexican patients as well as in Mexican Amerindians, but only a few cases in Hispanic Americans and Native Americans in the USA [1,26–33]. Based on the present American Southwest cohort, the first observation is that BD occurs more frequently in Hispanic Americans and Native Americans in the Southwestern US than has been previously recognized; and the general clinical manifestations of BD in these populations are very similar to that of BD in European Americans and Silk Road Americans (Table 3).
The goal of this study was to determine the characteristics of Behçet's disease (BD) in the American Southwest.
This was a cross-sectional study of BD patients clinically encountered during a 2-year period. All subjects fulfilled the International Study Group criteria (ISG) or International Criteria for Behcet's Disease (ICBD). Age, gender, clinical characteristics, substance use, and HLA-B51 status were determined.
63 patients (female: male ratio: 4.7:1) fulfilled ISG criteria and 76 the ICBD criteria (estimated prevalence of 8.9–10.6 per 100,000). 84.1% (53/63) were initially diagnosed with non-BD primary diagnoses including inflammatory arthritis (15.9%), fibromyalgia (7.9%), vasculitis (7.9%), or systemic lupus erythematosus (7.9%). Common BD manifestations were oral aphthous ulcers (100%), acneiform lesions (69.8%), genital aphthous ulcers (61.9%), papulopustular lesions (52.4%), pseudofolliculitis (42.9%), inflammatory arthritis (41.3%), anterior uveitis (23.8%), posterior uveitis (15.9%), pathergy (15.9%), deep vein thrombosis (14.3%), non-ocular vasculitis (11.1%), erythema nodosum (7.9%), arterial thrombosis (6.3%), and retinal vasculitis (1.6%). BD ethnic proportions were 49.2% Hispanic American (HA), 31.7% European-American (EA), 14.3% Native American (NA), and 1.7% Silk Road. HLA-B51 was present more in NA (89.0%, p = 0.02) and HA (74.2%, p = 0.02) compared to EA (42.1%). Therapy of BD was conventional, except for the frequent use of hydroxychloroquine.
BD is common in the American Southwest with a prevalence of 8.9–10.6 cases per 100,000. BD patients are commonly initially diagnosed with alternative primary conditions. Hydroxychloroquine may be an effective alternative therapy for BD. This is one of the first reports of BD in HA and NA populations.
Behçet's disease: 2 case report
2016, Revista Mexicana de Oftalmologia
La enfermedad de Behçet es una dolencia crónica-recurrente que se caracteriza por la presencia de vasculitis multisistémica con manifestaciones mucocutáneas y oculares. La mayoría de estas se autolimitan sin dejar secuelas, excepto por las oculares. Las variadas manifestaciones clínicas y la falta de pruebas patognomónicas hacen de la enfermedad de Behçet un reto diagnóstico cuya prevalencia en México se desconoce. El propósito de este reporte es la presentación de 2 casos de la enfermedad con diferentes características, por la importancia del diagnóstico, sus secuelas, y además, su baja prevalencia. Se presenta el caso de paciente femenino que ingresa al servicio de oftalmología por hiperemia conjuntival y disminución de agudeza visual de ojo izquierdo de 5 meses de evolución. A la exploración se observan úlceras en mucosa oral, lesiones induradas en miembros inferiores y uveítis. Se realizan pruebas diagnósticas complementarias y se inicia tratamiento, mostrando buena evolución general. A pesar del manejo la mejoría visual es poca. El segundo paciente se presenta en el servicio de urgencias de oftalmología por dolor ocular e hiperemia conjuntival de ojo izquierdo de una semana de evolución. Ya con diagnóstico de enfermedad de Behçet, el paciente presenta úlceras bucales, placas eritematosas en miembros inferiores y uveítis. Se inicia tratamiento tópico con mejoría sintomatológica. Las implicaciones oculares en la enfermedad de Behçet son serias. La inflamación ocular recurrente es común y lleva a un daño permanente a menos que se instituya un tratamiento efectivo. El diagnóstico y tratamiento precoz disminuyen la afección ocular.
Behçet's disease is a cronic-recurrent pathology that is characterized by the presence of multisistemic vasculitis with mucocutaneus and ocular manifestations. Clinical data is mostly selflimited and leaves no permanent damage, except for ocular manifestations. The variety of clinical characteristics and the absence of pathognomonic evidence make Behçet's disease a challenge with unknown prevalence in Mexico. The purpose of this report is to describe two clinical cases that presented with different characteristics, for the importance of correct diagnosis, the knowledgement of its effects, and the low prevalence of the disease. We present a female patient with 5 months of left eye conjunctival redness and decreased visual acuity. At the physical examination, she presents aphthous ulcers in oral mucous, erythema nodosum in legs, and uveitis. Diagnostic tests are made and systemic and local treatment is started with good general results. In spite of the treatment, visual acuity didn’t improve much. Second patient presents in Ophthalmology Urgency Service due to 1 week left eye pain and conjunctival redness. Already diagnosed with Behçet's disease, he presented erythema nodosum in legs, aphthous ulcers and uveitis. Topical treatment is started with clinical improvement. Ocular affection in Behçet's disease is serious. Recurrent ocular inflammation is common and leads to permanent damage unless effective treatment is established. Early diagnosis and treatment of the disease can reduce ocular damage.
HLA polymorphism and Behçet's disease in Moroccan population
2009, Pathologie Biologie
Nous avons étudié les différentes associations entre la maladie de Behçet et les allèles HLA classe I et II dans la population marocaine. L’évaluation de la distribution des allèles HLA impliqués dans la pathologie a été réalisée en fonction des signes cliniques et du sexe.
Les patients atteints de la maladie de Behçet ont été comparés à des témoins sains non apparentés et appariés par âge et origine ethnique. Le typage HLA a été réalisé par microlymphocytotoxicité pour la classe I (A et B) et en biologie moléculaire (polymerase chain reaction-sequence specific primers) pour la classe II (DR et DQ).
En plus de l’allèle B51, les allèles A2, -B5102, -B58 et -B72 prédisposent à la maladie et les allèles A23, -A33, -B18, -B41 et -B49 présentent plutôt une corrélation négative chez nos patients. Les allèles A2 et -B72 sont spécifiques aux hommes, -A68 et -B58 aux femmes, alors que -B51 et -B5102 sont prédisposants à la maladie pour les deux sexes. L’allèle -B51 est lié à l’atteinte muqueuse, -B72 à l’atteinte vasculaire et -B58 à l’atteinte cutanée. L’haplotype A2-B51 présente une corrélation positive avec cette pathologie. Pour la classe II, aucun des allèles DRB1* n’est incriminé, en revanche, l’allèle DQB1*02 semble assurer la protection des patients.
L’allèle HLA-B51 montre une forte corrélation positive avec la maladie de Behçet. D’autres gènes de l’HLA classe I semblent aussi être impliqués dans la susceptibilité ou la protection contre cette pathologie.
We have study the various associations between Behçet disease and alleles HLA class I and II in Moroccan population. The distribution of HLA alleles involved in the disease is assessed according to clinical signs and sex.
Patients suffering from Behçet's disease have been compared to healthy controls matched by age and ethnic origin. The HLA typing has been conducted by using microlymphocytotoxicity for the class I (A and B) and molecular biology (polymerase chain reaction-sequence specific primers) for the class II (DR and DQ).
In addition to the allele B51, -A2, -B5102, -B58 and -B72 predispose to the Behçet's disease and the alleles A23, -A33, -B18, -B41 and -B49 have a negative correlation in our Moroccan patients. The alleles A2 and -B72 are specific to men, -A68 and -B58 to women, whereas -B51 and -B5102 are predisposing to the Behçet's disease of both genders. The allele B51 is related to the mucous manifestations, -B72 to the vascularitis manifestations and -B58 to the cutaneous manifestations. The haplotypes A2-B51 has a high positive correlation with this Behçet's disease. Concerning class II, none of the alleles DRB1* is implicated in the pathology even though the allele DQB1*02 ensures the patients’ protection.
The allele HLA-B51 shows a high positive correlation with the Behçet's disease. Other genetic factors seem to be implicated in susceptibility or protection against the disease.
The HLA-B*51 Allele is strongly associated with Behçet Disease in an Argentinean population
2020, Reumatologia Clinica
Citation Excerpt :
Lavalle, et al. found that the HLA-B*5 allele was more frequent in Mexican Mestizo patients with BD than ethnically matched controls (70% vs. 31%, p < 0.05).8 On the other hand, Soto Vega et al., found no association between HLA-B*51 allele and BD among Mexican Mestizo patients and controls [9% vs. 5%, OR = 1.88 (95%CI = 0.58–5.93, p = 0.24)].9 Table 3 shows the HLA-B*51 allele frequencies in our BD patients and the Mexican Mestizo patients from Soto Vega study.
To assess the association between the HLA-B*51 allele and Behçet Disease (BD) in Argentinean patients.
We enrolled 34 consecutive Argentinean patients with definitive diagnosis of BD between October 2016 and March 2017. None of the patients had the HLA-B*51 allele determined at study entry. Unrelated controls (n = 240) were randomly obtained from the national cadaveric donor database. Demographic and clinical features of the patients were recorded by attending physicians through a questionnaire.
Mean age of cases was 42 years old. Nineteen (55.8%) were male, and the mean age at diagnosis was 35 years old; twenty (58.8%) were Mestizos, 8 (23.5%) were Caucasian, and 6 (17.6%) were Amerindians. Thirteen (38.2%) of 34 cases were HLA-B*51 allele positive; 11 were heterozygous and 2 homozygous for the allele. Thirty-four (14.2%) of 240 controls were positive for the HLA-B*51 allele. The association between BD and HLA-B*51 allele was greater than that of control group (OR = 3.75; p = 0.0012).
The HLA-B*51 allele is strongly associated with BD in Argentinean patients. Our finding is consistent with previous studies indicating that the HLA-B*51 allele is an important susceptibility gene in BD regardless the geographical region and ethnicity.
Evaluar la asociación entre el alelo HLA-B*51 y la enfermedad de Behçet (EB) en pacientes argentinos.
Incluimos en forma consecutiva 34 pacientes argentinos con diagnóstico definitivo de EB entre los meses de octubre de 2016 y marzo de 2017. Ninguno de los pacientes tenía el alelo HLA-B*51 determinado al inicio del estudio. Los controles no relacionados (n = 240) se obtuvieron al azar de la base nacional de datos de donantes cadavéricos. Las características demográficas y clínicas de los pacientes fueron registradas por los médicos asistentes a través de un cuestionario.
La edad promedio de los casos fue de 42 años. Diecinueve (55,8%) fueron varones, y la edad promedio en el momento del diagnóstico fue de 35 años; 20 (58,8%) fueron mestizos, 8 (23,5%) caucásicos y 6 (17,6%) amerindios. Trece (38,2%) de los 34 casos fueron positivos para el alelo HLA-B*51; 11 de ellos fueron heterocigotas y 2 homocigotas para dicho alelo. Treinta y cuatro (14,2%) de los 240 controles fueron positivos para el alelo HLA-B*51. La asociación entre la EB y el alelo HLA-B*51 fue mayor que en el grupo control (OR = 3,75; p = 0,0012).
El alelo HLA-B*51 está fuertemente asociado con la EB en pacientes argentinos. Nuestro hallazgo es consistente con estudios previos que indican que el alelo HLA-B*51 es un gen de susceptibilidad importante en la EB independientemente de la región geográfica y la etnia.
Clinical Characteristics and Outcomes of Mexican Patients with Behçet's Syndrome
2023, Journal of Clinical Rheumatology

View all citing articles on Scopus

¹: Co-corresponding author.

View full text

Class I and class II MHC polymorphisms in Mexican patients with Behçet’s disease

Abstract

Introduction

Section snippets

Patients

HLA-B locus

HLA-DRB1 locus

Discussion

Acknowledgements

Lancet

Arch. Oral. Biol.

Hum. Immunol.

Current concepts: Behçet’s disease

N. Eng. J. Med.

The role of heat shock protein

Int. Rev. Immunol.

Association between the 65-kilodalton heat shock protein, Streptococcus sanguis, and the corresponding antibodies in Behçet’s disease

Infect. Immun.

Characterization of Streptococcus sanguis isolated from patients with Behçet’s disease

Microbiol. Immunol.

Behçet’s disease

Semin. Arthritis Rheum.

Behçet’s disease: an update on the pathogenesis

Clin. Exp. Rheumatol.

Association of HLA-B5 with clinical expression and severity of Behçet’s disease in Israel