scholarly journals On the perils of poor editing: regulation of peptide loading by HLA-DQ and H2-A molecules associated with celiac disease and type 1 diabetes

2012 ◽  
Vol 14 ◽  
Author(s):  
Robert Busch ◽  
Alessandra De Riva ◽  
Andreas V. Hadjinicolaou ◽  
Wei Jiang ◽  
Tieying Hou ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Celiac Disease ◽  
Mhc Class Ii ◽  
Human Leukocyte ◽  
Peptide Binding Specificity ◽  
Risk Alleles ◽  
Hla Dq ◽  
Peptide Loading ◽  
Underlying Mechanisms

This review discusses mechanisms that link allelic variants of major histocompatibility complex (MHC) class II molecules (MHCII) to immune pathology. We focus on HLA (human leukocyte antigen)-DQ (DQ) alleles associated with celiac disease (CD) and type 1 diabetes (T1D) and the role of the murine DQ-like allele, H2-Ag7 (I-Ag7 or Ag7), in murine T1D. MHCII molecules bind peptides, and alleles vary in their peptide-binding specificity. Disease-associated alleles permit binding of disease-inducing peptides, such as gluten-derived, Glu-/Pro-rich gliadin peptides in CD and peptides from islet autoantigens, including insulin, in T1D. In addition, the CD-associated DQ2.5 and DQ8 alleles are unusual in their interactions with factors that regulate their peptide loading, invariant chain (Ii) and HLA-DM (DM). The same alleles, as well as other T1D DQ risk alleles (and Ag7), share nonpolar residues in place of Asp at β57 and prefer peptides that place acidic side chains in a pocket in the MHCII groove (P9). Antigen-presenting cells from T1D-susceptible mice and humans retain CLIP because of poor DM editing, although underlying mechanisms differ between species. We propose that these effects on peptide presentation make key contributions to CD and T1D pathogenesis.

scholarly journals 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 ◽  
2019 ◽  
Vol 8 (7) ◽  
pp. 751 ◽  
Author(s):  
Farina ◽  
Picascia ◽  
Pisapia ◽  
Barba ◽  
Vitale ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Celiac Disease ◽  
Cd4 T Cells ◽  
High Expression ◽  
Transcriptional Level ◽  
Risk Alleles ◽  
Hla Dq ◽  
Hla Dqa1

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.

Association of HLA-DRB1 and -DQ Alleles and Haplotypes with Type 1 Diabetes in Jordanians

2020 ◽  
Vol 20 (6) ◽  
pp. 895-902 ◽  
Author(s):  
Sawsan I. Khdair ◽  
Wassan Jarrar ◽  
Yazun Bashir Jarrar ◽  
Safa’a Bataineh ◽  
Omar Al-Khaldi
Keyword(s):  
Type 1 Diabetes ◽  
Human Leukocyte ◽  
Positive Association ◽  
Insulin Dependent Diabetes Mellitus ◽  
Class Ii ◽  
Protective Role ◽  
Hla Class Ii ◽  
Dependent Diabetes Mellitus ◽  
Risk Alleles

Background: The Human Leukocyte Antigen (HLA) class II genes, particularly the HLADR and -DQ loci, have been shown to play a crucial role in Type 1 Diabetes (T1D) development. Objective: This study is the first to examine the contribution of the HLA-DR/DQ alleles and haplotypes to T1D susceptibility in Jordanians. Methods: Polymerase chain reaction sequence-specific primers (PCR-SSP) were used to genotype 41 Jordanian healthy controls and 50 insulin-dependent diabetes mellitus (IDDM) patients. Results: The following alleles were found to be significant high risk alleles in T1D Jordanian patients: DRB1*04 (OR=3.95, p<0.001), DRB1*0301(OR=5.27, p<0.001), DQA1*0301 (OR=5.67, p<0.001), DQA1*0501(OR=3.18, p=0.002), DQB1*0201(OR=2.18, p=0.03), DQB1*0302 (OR=5.67, p<0.001). However, Jordanians harboring the DRB1*0701 (OR=0.37, p=0.01), DRB1*1101 (OR=0.2, p=0.01), DQA1*0505 (OR=0.31, p=0.02), DQA1*0103 (OR=0.33, p=0.04), DQA1*0201 (OR=0.45, p=0.04), DQB1*0301 (OR=0.23, p=0.001), DQB1*0501 (OR=0.18, p=0.009) alleles had a significantly lower risk of developing T1D. Conclusion: A strong positive association of DRB1*04-DQA1*0301-DQBl*0302 (OR=5.67, p<0.001) and DRB1*0301-DQA1*0501-DQB1*0201 (OR=6.24, p<0.001) putative haplotypes with IDDM was evident in Jordanian IDDM patients whereas DRB1*1101-DQA1*0505- DQB1*0301 (OR=0.23, p=0.03) was shown to have a protective role against T1D in Jordanians. Our findings show that specific HLA class II alleles and haplotypes are significantly associated with susceptibility to T1D in Jordanians.

Sa1331 HLA-DQ Genotype Distribution in Type 1 Diabetes Mellitus Patients With Concomitant Celiac Disease

2012 ◽  
Vol 142 (5) ◽  
pp. S-274-S-275
Author(s):  
Sjoerd Feitze Bakker ◽  
Maarten E. Tushuizen ◽  
J. Bart A. Crusius ◽  
Suat Simsek ◽  
Chris J. Mulder ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 1 Diabetes ◽  
Celiac Disease ◽  
Type 1 Diabetes Mellitus ◽  
Genotype Distribution ◽  
Hla Dq

HLA-DQ types of celiac disease in Libyan children with type 1 diabetes mellitus

2012 ◽  
Vol 24 (1) ◽  
pp. 59-63 ◽  
Author(s):  
Millad Ghawil ◽  
Valeria Miotti ◽  
Elio Tonutti ◽  
Alfred Tenore ◽  
Ibtisam Hadeed ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 1 Diabetes ◽  
Celiac Disease ◽  
Type 1 Diabetes Mellitus ◽  
Hla Dq
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