RESUMEN
Vogt-Koyanagi-Harada syndrome (VKH) is a multisystem autoimmune disorder mediated by cytotoxic T cells targeting melanocytes antigen(s). A strong major histocompatibility complex (MHC) association with HLA-DRB1*04:05 has been demonstrated in different populations. We investigated the contribution of HLA-A*, -B*, -C*, -DRB1*, and -DQB1* genes, belonging to the human leukocyte antigen (HLA), to the expression of VKH and we analyzed the influence of gender on the HLA association. A total of 76 patients and 256 healthy Mexican Mestizo individuals were included. HLA-A, B, C, and DQB1 typing was performed using the polymerase chain reaction, and hybridization was done using sequence specific probes. DRB1 alleles were defined by means of sequence base typing. The frequency of DRB1*04:05 (odds ratio=2.95) and DRB1*04:04 (odds ratio=2.79) were found to be significantly increased in the patients, conferring a similar risk. Gender stratification analysis showed that these alleles were associated with female gender only. No HLA class I or class II alleles were significantly deviated in males. The frequency of DRB1*04:07 was increased in the whole group, upon withdrawal from analysis the DRB1*04:04 and *04:05 positive patients. A trend of DRB1 alleles contributing to the expression of VKH is suggested: DRB1*04:05=*04:04>*04:07>*01:01>*01:02. Although none of the results were significant after the p value was corrected, the data are consistent with those in numerous other studies, suggesting that several different DRB1* alleles may be involved in the etiopathogenesis of the disease by presenting an overlapping set of ocular peptides to the T cells, which in turn may trigger the autoimmune response that is present in the patients.
Asunto(s)
Ojo/inmunología , Cadenas HLA-DRB1 , Síndrome Uveomeningoencefálico/inmunología , Adolescente , Adulto , Anciano , Alelos , Estudios de Casos y Controles , Niño , Ojo/patología , Femenino , Expresión Génica , Frecuencia de los Genes , Antígenos HLA-A/genética , Antígenos HLA-A/inmunología , Antígenos HLA-B/genética , Antígenos HLA-B/inmunología , Antígenos HLA-C/genética , Antígenos HLA-C/inmunología , Antígenos HLA-DQ/genética , Antígenos HLA-DQ/inmunología , Cadenas HLA-DRB1/genética , Cadenas HLA-DRB1/inmunología , Humanos , México/epidemiología , Persona de Mediana Edad , Factores Sexuales , Síndrome Uveomeningoencefálico/etnología , Síndrome Uveomeningoencefálico/genética , Síndrome Uveomeningoencefálico/patologíaRESUMEN
Vogt-Koyanagi-Harada's syndrome (VKH) is an autoimmune disease prevalent in Mongoloids with evident participation of HLA. The aim of this study was to identify the class II DNA sequences involved in the etiopathogenesis of VKH in Mexican Mestizos. This study included 46 VKH patients and 170 controls. 75% were females (mean age at onset of 33.5 years). The disease evolved to chronicity (68%) and 25% of the patients were unresponsive to corticotherapy. DNA typing of HLA-DRB1, DQA1 and DQB1 was done following the 12th International Histocompatibility protocols. VKH was strongly dependent of DRB1 gene; DRB1*04 was found in 78.2% of the patients vs. 50.6% of the controls (p = 0.001). No particular DRB*04 subtype was significantly increased, suggesting that residues E-9 V-11; H-13; H-33 and Y-37 shared by all DR4s are implicated in susceptibility to VKH. However DRB1*0101 (p = 0.009, OR = 4.2) was clearly associated. This allele shares the motif LLEQRRAAG located at position 67-74 and 86 of DRB1 with *0405 associated in Japanese. Two HLA associated mechanisms may be triggering the autoimmune phenomena. One involving critical polymorphic residues expressed in different alleles. Secondly, some peptides may anchor to the conserved residues leaving other sequences to bind to the T cell receptor.
Asunto(s)
Antígenos HLA-DQ/genética , Antígenos HLA-DR/genética , Síndrome Uveomeningoencefálico/genética , Adulto , Alelos , Femenino , Frecuencia de los Genes , Cadenas alfa de HLA-DQ , Cadenas beta de HLA-DQ , Cadenas HLA-DRB1 , Humanos , Masculino , México , Síndrome Uveomeningoencefálico/etnología , Síndrome Uveomeningoencefálico/inmunologíaRESUMEN
PURPOSE: To analyze the genetic background of human leukocyte antigens (HLA) of Vogt-Koyanagi-Harada (VKH) disease in Mexican Mestizo patients in order to establish whether the pathogenesis is related to the same genes or sequences described in other populations. PATIENTS AND METHODS: In 48 VKH patients, we performed HLA class I and class II typing using the standard microlymphocytotoxicity tests; a group of 100 nonrelated healthy subjects were analyzed for comparison. Antigen and gene frequencies were calculated for every antigen tested in patients and in controls. RESULTS: The frequency of HLA-DR4 was significantly increased in VKH Mexican patients (x2Y = 19.95; p = 0.00001; pc = 0.0002; RR = 5.3; EF = 0.52); a discrete increase in DR1 was also found (p = 0.02). HLA-DQ8 also showed a significant association with the disease with a lower RR (3.2) and EF (0.41) than DR4. CONCLUSION: The strong association found with HLA-DR4 and the slight DR1 increase shown in Mexican patients with VKH suggest that a common shared sequence present in the third hypervariable region of DRB1 genes is relevant for the expression of the disease. The stronger association with DR4 than the one with DQ8 suggests that the DR locus carries the primary susceptibility genes involved in the pathogenesis of VKH.
Asunto(s)
Antígenos HLA-DR/genética , Indígenas Norteamericanos/genética , Síndrome Uveomeningoencefálico/genética , Población Blanca/genética , Adolescente , Adulto , Alelos , Niño , Susceptibilidad a Enfermedades , Femenino , Frecuencia de los Genes , Genes MHC Clase II/genética , Genotipo , Antígenos HLA-DQ/genética , Antígenos de Histocompatibilidad Clase I/genética , Humanos , Masculino , México , Persona de Mediana Edad , Síndrome Uveomeningoencefálico/etnologíaRESUMEN
BACKGROUND: Vogt-Koyanagi-Harada (VKH) syndrome is associated with human leukocyte antigen (HLA)-B54, -DR4, -DR beta 1*0405, -DQ4, and -DR53 in Japanese patients. Disease-associated HLA specificities may differ among races. This study examined HLA associations with VKH syndrome in Hispanic patients living in southern California, a racial subgroup at increased risk for the disease. METHODS: Human leukocyte antigen specificities were determined on 25 Hispanic patients with VKH syndrome and compared with HLA specificities of 217 healthy Hispanic control subjects. Inclusion criteria for study patients were nontraumatic panuveitis with exudative retinal detachments, with or without extraocular manifestations. Tests were performed using standard cytotoxic assays. RESULTS: HLA-DR4 was present in 14 (56%) patients with VKH syndrome and in 62(29%) control subjects (relative risk = 1.96). HLA-DR1 was present in 9 (36%) patients with VKH syndrome and in 19 (9%) control subjects (relative risk = 4.11). HLA-DR1 and DR4 share a common epitope within the DR beta 1 gene. HLA-DR1 and/or DR4 were present in 21 (84%) patients with VKH syndrome and in 76 (35%) control subjects (relative risk = 2.40). CONCLUSIONS: HLA-DR1 and -DR4 were found in a significantly disproportionate number of Hispanic patients with VKH syndrome living in southern California. HLA-DR4, although not HLA-DR1, has been previously associated with VKH syndrome in other groups. These associations suggest a common immunogenic predisposition to VKH among different racial groups, and suggest that a common epitope shared by DR1 and DR4 may be involved in the pathogenesis of the disease.