Epistasis between DSG1 and HLA class II genes in pemphigus foliaceus

Abstract

Pemphigus foliaceus (PF) is

Polymorphisms in the 2q33 and 3q21 chromosome regions including T-cell coreceptor and ligand genes may influence susceptibility to pemphigus foliaceus

“…Associations were also seen with IL6, IL4, IL10, PDCD1, CD40 and BLYS [17][18][19], but not with TNF, LTA, DSG1, BAX, TP53, and CD19 polymorphisms [17,20 -22]. Epistasis has been demonstrated between CD40 and BLYS, CD40L, and BLYS, and between DSG1 and HLA class II genes [17,23]. Because much remains to be known about pathogenesis of this disease, analyses of additional genomic regions are necessary.…”

Polymorphisms of HLA microsatellite marker in Tunisian pemphigus foliaceus

“…To date, the strongest genetic associations have described with human leukocyte antigen (HLA) class II alleles. Thus, susceptibility to PF has been correlated with the presence of DR4, DR14 and DR1 alleles in different ethnic groups [1][2][3][4].…”

A Truncated Alternative Spliced Isoform of Human Desmoglein 1 Contains a Specific T Cell Epitope Binding to the Pemphigus Foliaceus-Associated HLA Class II DRβ1*0102 Molecule

“…In multiple sclerosis, specific T cell responses directed against X2MBP were associated with the disease (30). To test the possibility that peptides of the Dsg1-truncated isoform bind to HLA class II molecules that predispose to PF, we synthetized four overlapping 20-mer peptides between EC2 domain and INT6 peptide (EC2/INT6 211-230, EC2/INT6 216 -235, EC2/INT6 221-240, and EC2/INT6 226 -245) and evaluated by a competitive ELISA, their relative binding capacity to HLA class II, DR␤1*0102, and DR␤1*0402, which were previously demonstrated to be associated with the disease in French PF patients (17,19). Interestingly, the EC2/INT6 216 -235 peptide bound to the DR␤1*0101, *0102, *0401, and *0402 molecules, because it exhibited toward all these molecules IC 50 values inferior to the binding activity threshold of 1000 nM (Table II).…”

“…Genomic DNA was extracted from whole blood (2 ml) of pemphigus patients using QIAamp DNA Blood Midi Kit (Qiagen) and used for HLA class II DR␤1 typing as described previously (19).…”

“…Like in most autoimmune diseases, HLA class II genes contribute to genetic susceptibility of PF, particularly DR1, DR4, and DR14. Several alleles of these haplotypes are associated with PF, including DRB1*0102, which has been found recurring in different studies (16 -19), notably those involving French PF patients (17,19). The major mechanism proposed to explain the association between MHC class II genes and autoimmune diseases is that disease-associated alleles can efficiently accommodate autoantigen-derived peptides initiating and sustaining the autoreactive T cell response.…”