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
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 expressi...
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MDPI AG
2019-07-01
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| Online Access: | https://www.mdpi.com/2073-4409/8/7/751 |
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| author | Federica Farina Stefania Picascia Laura Pisapia Pasquale Barba Serena Vitale Adriana Franzese Enza Mozzillo Carmen Gianfrani Giovanna Del Pozzo G |
| author_facet | Federica Farina Stefania Picascia Laura Pisapia Pasquale Barba Serena Vitale Adriana Franzese Enza Mozzillo Carmen Gianfrani Giovanna Del Pozzo G |
| author_sort | Federica Farina |
| collection | DOAJ |
| description | 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<sup>+</sup> 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<sup>+</sup> 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. |
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| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-12T07:37:16Z |
| publishDate | 2019-07-01 |
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| spelling | doaj.art-4f7b79a59a904663a5804cdea790af0f2023-09-02T21:27:48ZengMDPI AGCells2073-44092019-07-018775110.3390/cells8070751cells8070751HLA-DQA1 and HLA-DQB1 Alleles, Conferring Susceptibility to Celiac Disease and Type 1 Diabetes, Are More Expressed Than Non-Predisposing Alleles and Are Coordinately RegulatedFederica Farina0Stefania Picascia1Laura Pisapia2Pasquale Barba3Serena Vitale4Adriana Franzese5Enza Mozzillo6Carmen Gianfrani7Giovanna Del Pozzo G8Institute of Genetics and Biophysics “Adriano Buzzati Traverso”-CNR, 80131 Naples, ItalyInstitute of Biochemistry and Cell Biology-CNR, 80131 Naples, ItalyInstitute of Genetics and Biophysics “Adriano Buzzati Traverso”-CNR, 80131 Naples, ItalyInstitute of Genetics and Biophysics “Adriano Buzzati Traverso”-CNR, 80131 Naples, ItalyInstitute of Biochemistry and Cell Biology-CNR, 80131 Naples, ItalyDepartment of Translational Medical Science (DISMET), Section of Pediatrics, University of Naples Federico II, 80131 Naples, ItalyDepartment of Translational Medical Science (DISMET), Section of Pediatrics, University of Naples Federico II, 80131 Naples, ItalyInstitute of Biochemistry and Cell Biology-CNR, 80131 Naples, ItalyInstitute of Genetics and Biophysics “Adriano Buzzati Traverso”-CNR, 80131 Naples, ItalyHLA 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<sup>+</sup> 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<sup>+</sup> 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.https://www.mdpi.com/2073-4409/8/7/751autoimmunityrisk genesexpressionregulation |
| spellingShingle | Federica Farina Stefania Picascia Laura Pisapia Pasquale Barba Serena Vitale Adriana Franzese Enza Mozzillo Carmen Gianfrani Giovanna Del Pozzo G 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 Cells autoimmunity risk genes expression regulation |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | autoimmunity risk genes expression regulation |
| url | https://www.mdpi.com/2073-4409/8/7/751 |
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