HLA-DQA1 and HLA-DQB1 Alleles, Conferring Susceptibility to Celiac Disease and Type 1 Diabetes, are More Expressed Than Non-Predisposing Alleles and are Coordinately Regulated.

Farina Farina,Vitale Vitale,Franzese Franzese,Mozzillo Mozzillo,Picascia Picascia,Del Pozzo G Del Pozzo G,Gianfrani Gianfrani,Pisapia Pisapia,Barba Barba

doi:10.3390/cells8070751

Farina Farina, Vitale Vitale + Show 7 more

Open Access

https://doi.org/10.3390/cells8070751

Copy DOI

Abstract

HLA DQA1*05 and DQB1*02 alleles encoding the DQ2.5 molecule and HLA DQA1*03 and DQB1*03 alleles encoding DQ8 molecules are strongly associated with celiac disease (CD) and type 1 diabetes (T1D), two common autoimmune diseases (AD). We previously demonstrated that DQ2.5 genes showed a higher expression with respect to non-CD associated alleles in heterozygous DQ2.5 positive (HLA DR1/DR3) antigen presenting cells (APC) of CD patients. This differential expression affected the level of the encoded DQ2.5 molecules on the APC surface and established the strength of gluten-specific CD4+ T cells response. Here, we expanded the expression analysis of risk alleles in patients affected by T1D or by T1D and CD comorbidity. In agreement with previous findings, we found that DQ2.5 and DQ8 risk alleles are more expressed than non-associated alleles also in T1D patients and favor the self-antigen presentation. To investigate the mechanism causing the high expression of risk alleles, we focused on HLA DQA1*05 and DQB1*02 alleles and, by ectopic expression of a single mRNA, we modified the quantitative equilibrium among the two transcripts. After transfection of DR7/DR14 B-LCL with HLA-DQA1*05 cDNA, we observed an overexpression of the endogenous DQB1*02 allele. The DQ2.5 heterodimer synthesized was functional and able to present gluten antigens to cognate CD4+ T cells. Our results indicated that the high expression of alpha and beta transcripts, encoding for the DQ2.5 heterodimeric molecules, was strictly coordinated by a mechanism acting at a transcriptional level. These findings suggested that, in addition to the predisposing HLA-DQ genotype, also the expression of risk alleles contributed to the establishment of autoimmunity.

Highlights

The human leukocyte antigen (HLA) class II heterodimeric molecules, composed by the alpha and beta chains, are encoded by many different alleles, which generate the high polymorphism characteristic of this locus
The autoimmune diseases, such as celiac disease and type 1 diabetes, are polygenic disorders, the main genetic risk factor is represented by HLA class II genes
A number of experimental evidences demonstrated that the expression of these molecules, irrespective of the nature of the antigen, influences the achievement of the HLA-peptide complex threshold, needed for activation and proliferation of autoreactive CD4+ T cells [16,17]

Summary

Introduction

The human leukocyte antigen (HLA) class II heterodimeric molecules, composed by the alpha and beta chains, are encoded by many different alleles, which generate the high polymorphism characteristic of this locus. The genes encoding DR and DQ isotypes are the main risk factors associated with several autoimmune diseases. Type 1 diabetes (T1D) and celiac disease (CD) are autoimmune disorders, affecting between 0.5% and 1% of the general population. Subjects at high risk to develop T1D carry either DQ2.5 haplotype, encoded by DQA1*05:01 and DQB1*02:01 or DQ8 haplotype, encoded by DQA1*03:01 and DQB1*03:02 [4]., whereas the most prominent association of CD is with HLA-DQ2.5 molecules [5]. The alleles encoding DQ2.5 molecule are in linkage disequilibrium (LD) with HLA-DRB1*03, while the DQ8 alleles are in LD with

Methods

Results

Conclusion