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The MHC class II transactivator (MHCIITA) gene was originally identified as a defective gene associated with bare lymphocyte syndrome, a severe combined immunodeficiency syndrome. Evidence indicates that MHCIITA is a master switch of antigen presentation in antigen‐presenting cells.1 A recent paper describes how a –168A ‐>G polymorphism in the type III promoter of the MHC2TA gene was associated with increased susceptibility to rheumatoid arthritis, multiple sclerosis and myocardial infarction, as well as lower expression of MHC2TA after stimulation of leukocytes with interferon‐gamma (IFN‐γ).2,3 However, similar replicated studies in two other European populations did not find this association.4,5
Systemic lupus erythematosus (SLE) is an autoimmune disease that is characterized by a complex set of immunological abnormalities that result in dysfunction of several organs. It has been reported that enhanced MHC class II antigen expression occurs in lupus nephritis in human and mice models.6,7 Therefore, particular alleles of the polymorphic gene involved in the regulation of MHC class II expression might be involved in the predisposition to SLE. We report here the association between a –168A ‐>G polymorphism in the human MHC2TA gene and SLE. DNA samples were obtained from 180 Japanese patients with SLE (average age at onset: 26.4 ± 11.7 years) and 175 Japanese healthy controls. All the patients with SLE fulfilled the American College of Rheumatology criteria for SLE.8 Informed consent was obtained from each individual in this study. Genomic DNA was isolated from peripheral blood mononuclear cells. Genotypes of –168A ‐>G (rs3087456) were determined by a TaqMan fluorogenic 5′ nuclease assay (Applied Biosystems, Tokyo, Japan) as described elsewhere.9 Association between SLE susceptibility and –168A ‐>G polymorphism was estimated by the Chi‐square test that was implemented in R software package version 2.0.1 (http://www.r‐project.org/).
As shown in table 11,, we found a significant difference in allele frequencies for the single nucleotide polymorphism (SNP; –168A ‐>G) in individuals with SLE (p=0.008). The presence of G at position –168 was frequent in normal Japanese individuals, in contrast to the study by Swanberg et al.2 In SLE patients, A at position –168 was significantly associated with a decreased risk of developing SLE (p=0.006; OR=1.91). However, G at position –168 was not associated with an increased risk of developing SLE (p=0.497). Therefore, we concluded that –168 A dominance is protective against the occurrence of SLE.
Upregulation of CIITA is reported to direct T cells differentiating to the Th1 but not to the Th2 lineage.10 The expression of MHC2TA mRNA has been shown to be lower in cells from individuals with genotype GG than in cells from individuals with other genotypes, by activation with IFN‐γ (2). If that is the case, –168 A dominance might be associated with high expression of MHCIITA, resulting in the predominance of Th1 lineage over Th2, and this phenotype might be associated with protection against the occurrence of SLE. Further studies are needed to confirm the biological effects of SNP (–168A ‐>G) in association with the differentiation of Th1 and Th2 lineage cells and also to study its role in the pathogenesis of SLE.
IFN‐γ - interferon‐gamma
MHCIITA - MHC class II transactivator
SLE - systemic lupus erythematosus
Competing interests: None declared.