HLA-DRB1 polymorphisms and autoimmune responses to desmogleins in Japanesepatients with pemphigus

Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are caused by autoanti bodies against keratinocyte adhesion molecules desmoglein 3 (Dsg3) and desm oglein 1 (Dsg1), respectively. To determine possible major histocompatibili ty complex (MIC) class II associations with autoantibody responses to desmo gleins, haplotype and allele distributions, along with molecular polymorphi sms of HLA-DR and -DQ genes were analyzed based on the polymerase chain rea ction-restriction fragment length polymorphism (PCR-RFLP) results in 85 Jap anese patients with pemphigus. Each of 55 PV patients carried at least one allele of HLA-DRB1*04 and DRB1*14 subtypes, with significant increases of H LA-DRB1*0406/DQA1*0301/DQB1*0302, DRB1*14/DQA1*0104/DQB1*05 and DRB1*1406/D QA1*0503/DQB1*0301 haplotypes compared to normal controls. The HLA-DRB1*04 and DRB1*14 alleles carried by PV patients shared hydrophobic amino acid re sidues Phe(26), Leu(67) and Val(86), as well as hydrophilic amino acid resi dues at positions 70 and 71 on the DRB1 beta chain. HLA-DR/DQ distributions did not differ among PV patients according to the presence or absence of a nti-Dsg1 co-existing with anti-Dsg3. Thirty PF patients, all producing auto antibodies only to Dsg1, showed more diverse HLA-DR/DQ distributions, shari ng hydrophobic amino acid residues at positions 26 and 67, as well as hydro philic amino acid residues at positions 70 and 71, of the DRB1 chain. These findings suggest that autoantibody responses to desmogleins might be regul ated by amino acid residues at positions 26, 67, 70, 71 and 86 at peptide b inding sites of HLA-DRB1 molecules, and that autoimmune responses to Dsg3 m ight be more strictly regulated by specific amino acid residues at these po sitions on the HLA-DRB1 chain than responses to Dsg1.