MHC class II alleles and haplotypes in patients with pemphigus vulgaris from India

Abstract

Pemphigus vulgaris (PV) is a blistering disease of the skin and mucous membranes characterized by an autoantibody response against a keratinocyte adhesion molecule, desmoglein 3, causing acantholysis and blister formation. We compared high resolution MHC class II alleles and haplotype frequencies (HLA-DRB, DQA1 and DQB1) in 37 patients with PV to 89 haplotypes of normal relatives from New Delhi and Ahmedabad. We found that PV patients had significantly increased frequencies of DRB1*1404 (P < 0.0001), DQA1*0101 (P = 0.001), and DQB1*0503 (P < 0.0001). These associations were due to the increased frequencies of the haplotype HLA-DRB1*1404, DRB3*0202, DQA1*0101, DQB1*0503 in patients compared to control haplotypes (p < 0.0001). Also, patients from Ahmedabad had a significant increase in HLA-DQB1*0302 (p = 0.03). An identical amino acid sequence (Leu-Leu-Glu-Arg-Arg-Arg-Ala-Glu), in positions 67-74 of the beta domain of DRB alleles is restricted to some DR14 alleles. Therefore, there are three possible explanations for class II allele involvement in autoantibody in PV patients with class II haplotypes marked by HLA-DR14. First, the class II alleles could be markers for an unidentified susceptibility gene in linkage disequilibrium with them. Second, the primary association could be with DQB1*0503 and the association with HLA-DR14 alleles would be the result of linkage disequilibrium. Third, the HLA-DRB1 locus susceptibility could involve a specific amino acid sequence in the third hypervariable region shared by several HLA-DR14 alleles.

HLA Class II Allele Associations in Korean Patients with Pemphigus

“…This allelic distribution/frequency pattern is, to some extent, different from those observed in Jewish, non-Jewish Caucasians and in some Oriental populations [2, 3, 4, 5, 6, 7]. These results may indicate that the relationship (or specificity) between HLA class II allele and the susceptibility to PV and PF varies among races and/or populations.…”

“…Among European Caucasians and American Caucasians, there appear to be additional genes (DRB1*14, DQB1*03 and DQB1*05 alleles) significantly associated with PV [3, 4]. Among Oriental PV patients from Japan and India, there were significant associations with DRB1*14 (DRB1*1405 subtype in Japanese, DRB1*1404 subtype in Indians) and DQB1*0503 (which is considered to be linked with DRB1*14) alleles [6, 7]. Compared to those populations, Korean patients with PV show a difference.…”

“…Recently, genetic susceptibilities associated with DRB1*14, DQA1*01 and DQB1*05 alleles have also been suggested to be implicated with the disease process of PV in a few Oriental populations [6, 7]. This paper presents the findings on the distribution/frequencies of HLA class II alleles of Korean patients with PV and PF.…”

“…While autoantibodies directed against the epidermal cadherins (desmoglein 3/1) are believed to be the cause of the pathology [1], the primary causative agent(s) of the disease remains unknown. Studies at the population level have demonstrated associations between pemphigus (pemphigus vulgaris, PV, and pemphigus foliaceus, PF) and particular HLA haplotypes, suggesting that there may be a genetic predisposition for the disease [2, 3, 4, 5, 6, 7]. …”

Pemphigus Vulgaris: Update on Etiopathogenesis, Oral Manifestations, and Management

“…Rare familial cases of PV have been reported (Starzycki et al, 1998). HLA class II allele associations in PV are found with HLA-DR4 (DRB1*0402), DRw14 (DRB1*1041), and DQB1*0503 (Sinha et al, 1988;Ahmed et al, 1990Ahmed et al, , 1991Ahmed et al, , 1993Matzner et al, 1995;Carcassi et al, 1996;Delgado et al, 1996Delgado et al, , 1997Lombardi et al, 1996;Nishikawa et al, 1996;Miyagawa et al, 1997;Mobini et al, 1997a;Loiseau et al, 2000). Asian alleles of the HLA-B15 family, including the allele B*1507, are significantly increased in comparison with normal controls, in Japanese patients with PV-but HLA class l alleles are not changed (Miyagawa et al, 2002).…”