Abstract

The DR5-DQ7/DR7-DQ2 genotype is very frequent among patients affected by celiac disease (CD), in Europe. This genotype, associated to high risk of CD, carries the HLA-DQA1*05 and HLA-DQB1*02 predisposing alleles, in trans configuration. The alleles encode the DQ2.5 heterodimer responsible of gluten peptide presentation on the surface of antigen-presenting cells (APCs), and consequent pathogenic CD4+ T cell activation. We demonstrated that DR5/DR7 APCs induce an anti-gluten CD4+ T cell response, of comparable intensity to that observed with APCs carrying DR1/DR3 genotype, which risk alleles are in cis configuration. In addition, we showed that DR5/DR7 APCs from celiac patients stimulated an effector CD4+ T cell response higher with respect to that induced by DR5/DR7 APCs from healthy subjects. To explain these findings, we assessed the DQ2.5 RNA and protein quantity. We showed that the expression of DQA1*05 and DQB1*02 risk alleles is much higher than the expression of non-CD-associated alleles, in agreement with the previous results obtained with DR1/DR3 genotype. The differential expression of transcripts influences the quantity of DQα1*05 and DQβ1*02 chains and, as consequence, the cell surface density of DQ2.5 heterodimers. Moreover, both RNA and proteins, are more abundant in APCs from celiac patients than controls. Finally, to unravel the mechanism regulating the expression of predisposing DQA1*05 and DQB1*02 alleles, we quantified the new synthetized RNA and found that the differential expression is explained by their transcription rate. Our results confirmed that the strength of antigen-specific CD4+ T cell response is mainly determined by the amount of gluten in the diet and provided a new possible approach for a personalized diagnosis and for risk stratification.

Highlights

  • The DR5-DQ7/DR7-DQ2 genotype is very frequent among patients affected by celiac disease (CD), in Europe

  • The DQ2.5 heterodimer is encoded by DQA1*05 and DQB1*02 alleles located on opposite chromosomes and in linkage disequilibrium (LD) with DRB1*05(or DRB1*11) and DRB1*07 alleles, in individuals with the DR5/DR7 g­ enotype[1]

  • CD-associated DQA1*05 and DQB1*02 alleles are in cis configuration, that these risk alleles are significantly more expressed than non-associated ones on the other chromosome

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Summary

Introduction

The DR5-DQ7/DR7-DQ2 genotype is very frequent among patients affected by celiac disease (CD), in Europe. The differential expression of transcripts influences the quantity of DQα1*05 and DQβ1*02 chains and, as consequence, the cell surface density of DQ2.5 heterodimers Both RNA and proteins, are more abundant in APCs from celiac patients than controls. The preferential expression of risk alleles induces high expression of DQα1*05 and DQβ1*02 protein chains, resulting in a comparable amount of DQ2.5 heterodimers on cell surface of the antigen presenting cells (APC) in celiac patients carrying DQ2.5 genes both in homozygous and heterozygous assets. This result supported our interest for DR5/DR7 ­genotype[5] highly frequent in Southern Italy, from where our patients come. We assessed the transcripts and protein levels and investigated on the possible mechanism that might explain the risk alleles differential expression

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