Background
The HLA-DQA1*05 and HLA-DQB1*02 alleles are the main genetic factors predisposing to Coeliac disease (CeD.). These alleles encode the HLA-DQ2.5 class II heterodimer, which is expressed on Antigen Presenting Cells (APC) and is responsible for presenting gliadin-derived peptides to CD4+ T cells. Our previous studies demonstrated a significant higher expression of DQA1*05 and DQB1*02 risk alleles compared to the DQ alleles not CeD-associated (1,2), in patients carrying a heterozygous HLA-DQ2 genotype. Notably, the high expression of risk alleles affects the amount of HLA-DQ2.5 molecules on APC surface and the strength of gluten-specific CD4+T cell response. During the analysis of mechanism that determines the HLA-DQA1*05 and HLA-DQB1*02 differential expression, we found an antisense long non-coding RNA, HLA-DQB1-AS1, whose sequence is complementary to a region of the intron-4/exon-5 of the HLA-DQB1 gene.
Objective:
Our objective was to investigate the expression and the function of HLA-DQB1-AS1, to establish the relation with transcription and expression of HLA-DQB*02 risk allele.
Results. We demonstrated, by qPCR, that HLA-DQB1-AS1 RNA is strictly related to the HLA-DQB1*02 expression, in APC from patients carrying HLA-DQ2 predisposing genotype, while APC carrying different HLA-DQ alleles do not express HLA-DQB1-AS1 transcript. In addition, the HLA-DQB1-AS1 lncRNA correlates with the allelic dosage of HLA-DQB*02 since is more abundant in homozygous respect to heterozygous cells. Transfection experiments in which we expressed ectopic HLA-DQB1-AS1 showed an increase of HLA-DQB*02 mRNA.
Conclusions. Our data support the function of HLA-DQB1-AS1 as regulator of the expression of HLA-DQB1*02 CeD risk allele and, as consequence, modulates the amount of DQ2.5 molecules involved in gliadin peptides presentation and antigen-specific CD4+ T cell activation. Studies are ongoing to determine the mechanism by which the HLA-DQB1-AS1 affects the expression of parental gene HLA-DQB1*02, to assess the involvement of transcriptional, post-transcriptional or epigenetics pathways