Su.14. Identification of Hla Class I-Restricted β-Cell Epitopes in Type 1 Diabetes

2006 ◽  
Vol 119 ◽  
pp. S164
Author(s):  
Qin Ouyang ◽  
Constadina Panagiotopoulos ◽  
Rusung Tan
Keyword(s):  
Type 1 Diabetes ◽  
Hla Class I ◽  
Class I ◽  
Β Cell

scholarly journals Potential Mimicry of Viral and Pancreatic β Cell Antigens Through Non-Spliced and cis-Spliced Zwitter Epitope Candidates in Type 1 Diabetes

2021 ◽  
Vol 12 ◽  
Author(s):  
Michele Mishto ◽  
Artem Mansurkhodzhaev ◽  
Teresa Rodriguez-Calvo ◽  
Juliane Liepe
Keyword(s):  
Type 1 Diabetes ◽  
T Cell ◽  
Viral Infections ◽  
Hla Class I ◽  
Class I ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells

Increasing evidence suggests that post-translational peptide splicing can play a role in the immune response under pathological conditions. This seems to be particularly relevant in Type 1 Diabetes (T1D) since post-translationally spliced epitopes derived from T1D-associated antigens have been identified among those peptides bound to Human Leucocyte Antigen (HLA) class I and II complexes. Their immunogenicity has been confirmed through CD4+ and CD8+ T cell-mediated responses in T1D patients. Spliced peptides theoretically have a large sequence variability. This might increase the frequency of viral-human zwitter peptides, i.e. peptides that share a complete sequence homology irrespective of whether they originate from human or viral antigens, thereby impinging upon the discrimination between self and non-self antigens by T cells. This might increase the risk of autoimmune responses triggered by viral infections. Since enteroviruses and other viral infections have historically been associated with T1D, we investigated whether cis-spliced peptides derived from selected viruses might be able to trigger CD8+ T cell-mediated autoimmunity. We computed in silico viral-human non-spliced and cis-spliced zwitter epitope candidates, and prioritized peptide candidates based on: (i) their binding affinity to HLA class I complexes, (ii) human pancreatic β cell and medullary thymic epithelial cell (mTEC) antigens’ mRNA expression, (iii) antigen association with T1D, and (iv) potential hotspot regions in those antigens. Neglecting potential T cell receptor (TCR) degeneracy, no viral-human zwitter non-spliced peptide was found to be an optimal candidate to trigger a virus-induced CD8+ T cell response against human pancreatic β cells. Conversely, we identified some zwitter peptide candidates, which may be produced by proteasome-catalyzed peptide splicing, and might increase the likelihood of pancreatic β cells recognition by virus-specific CD8+ T cell clones, therefore promoting β cell destruction in the context of viral infections.

scholarly journals Demonstration of islet-autoreactive CD8 T cells in insulitic lesions from recent onset and long-term type 1 diabetes patients

2012 ◽  
Vol 209 (1) ◽  
pp. 51-60 ◽  
Author(s):  
Ken T. Coppieters ◽  
Francesco Dotta ◽  
Natalie Amirian ◽  
Peter D. Campbell ◽  
Thomas W.H. Kay ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
T Cell ◽  
Direct Proof ◽  
Hla Class I ◽  
Cd8 T Cell ◽  
Class I ◽  
Β Cell ◽  
Cell Reactivity

A direct association of islet-autoreactive T cells with β cell destruction in human pancreatic islets from type 1 diabetes (T1D) patients has never been demonstrated, and little is known about disease progression after diagnosis. Frozen pancreas samples were obtained from 45 cadaveric T1D donors with disease durations ranging from 1 wk to >50 yr, 14 nondiabetic controls, 5 nondiabetics with islet autoantibodies, 2 cases of gestational diabetes, and 6 T2D patients. Sections were systematically analyzed for the presence of insulin-sufficient β cells, CD8+ insulitic lesions, and HLA class I hyperexpression. Finally, consecutive sections from HLA-A2–expressing individuals were probed for CD8 T cell reactivity against six defined islet autoantigens associated with T1D by in situ tetramer staining. Both single and multiple CD8 T cell autoreactivities were detected within individual islets in a subset of patients up to 8 yr after clinical diagnosis. Pathological features such as HLA class I hyperexpression and insulitis were specific for T1D and persisted in a small portion of the patients with longstanding disease. Insulitic lesions consistently presented in a multifocal pattern with varying degrees of infiltration and β cell loss across affected organs. Our observations provide the first direct proof for islet autoreactivity within human islets and underscore the heterogeneous and chronic disease course.

scholarly journals Circulating β cell‐specific CD8 + T cells restricted by high‐risk HLA class I molecules show antigen experience in children with and at risk of type 1 diabetes

2019 ◽  
Vol 199 (3) ◽  
pp. 263-277 ◽  
Author(s):  
L. Yeo ◽  
I. Pujol‐Autonell ◽  
R. Baptista ◽  
M. Eichmann ◽  
D. Kronenberg‐Versteeg ◽  
...  
Keyword(s):  
At Risk ◽  
T Cells ◽  
Type 1 Diabetes ◽  
High Risk ◽  
Cd8 T Cells ◽  
Hla Class I ◽  
Class I ◽  
Β Cell ◽  
Hla Class I Molecules

scholarly journals Differential HLA Association of GAD65 and IA2 Autoantibodies in North Indian Type 1 Diabetes Patients

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Neihenuo Chuzho ◽  
Neeraj Kumar ◽  
Neetu Mishra ◽  
Nikhil Tandon ◽  
Uma Kanga ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Genetic Association ◽  
Human Leucocyte Antigen ◽  
Hla Class I ◽  
Class Ii ◽  
Class I ◽  
North India ◽  
Β Cell ◽  
Hla Association

The human leucocyte antigen (HLA) association with type 1 diabetes (T1D) is well known but there are limited studies investigating the association between β-cell autoantibodies and HLA genes. We evaluated the prevalence of GAD65 and IA-2 autoantibodies (GADA and IA2A) in 252 T1D patients from North India and investigated the genetic association of GADA and IA2A with HLA class I and class II genes/haplotypes. GADA and IA2A were detected in 50.79% and 15.87% of T1D patients, respectively, while only 8.73% had both GADA and IA2A. HLA-DRB1 ∗ 03 was observed to be significantly higher in GADA+ T1D patients as compared to GADA– (91.41% vs. 66.13%, Bonferroni- corrected   P   P c = 1.11 × 10 − 5 ; OR = 5.45 ; 95% CI: 2.67-11.08). Similarly, HLA-DQB1 ∗ 02 was found to be significantly increased in GADA+ patients (94.53%, P c = 2.19 × 10 − 5 ; OR = 6.27 ; 95% CI: 2.7-14.49) as compared to GADA– (73.39%). The frequencies of HLA-DRB1 ∗ 04 and DQB1 ∗ 03 were increased in IA2A+ patients (45.0% and 52.5%, respectively) as compared to that in IA2A– (25.94% and 33.96%, respectively). Further, the frequency of DRB1 ∗ 03-DQB1 ∗ 02 haplotype was found to be significantly increased in GADA+ T1D patients as compared to GADA- (60.55% vs. 41.94%, P = 3.94 × 10 − 5 ; OR = 2.13 ; 95 % CI = 1.49 -3.03). Similarly, HLA-DRB1 ∗ 04-DQB1 ∗ 03 haplotype was found to be significantly increased in IA2A+ T1D patients compared to IA2A– patients (22.5% vs. 12.97%; P = 0.041 ; OR = 1.95 ; 95 % CI = 1.08 -3.52). None of the HLA class I genes (HLA-A, B, and Cw) was found to be associated with GADA or IA2A in people with T1D. Our findings suggest that HLA-DRB1 ∗ 03/DQB1 ∗ 02 and HLA-DRB1 ∗ 04/DQB1 ∗ 03 might play an important role in the development of GADA and IA2A, respectively.

scholarly journals HLA class I genes modulate disease risk and age at onset together with DR-DQ in Chinese patients with insulin-requiring type 1 diabetes

Diabetologia ◽  
2021 ◽  
Author(s):  
Ziyu Jiang ◽  
Wenqian Ren ◽  
Hua Liang ◽  
Jinhua Yan ◽  
Daizhi Yang ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Disease Risk ◽  
Hla Class I ◽  
Class I ◽  
Chinese Patients ◽  
Onset Age ◽  
Disease Heterogeneity ◽  
Negatively Associated ◽  
Healthy Control

Abstract Aims/hypothesis The study aimed to investigate the effects of HLA class I genes on susceptibility to type 1 diabetes with different onset ages, in addition to the well-established effects of HLA class II genes. Methods A total of 361 patients with type 1 diabetes (192 patients with onset <18 years and 169 patients with onset ≥18 years) and 500 healthy control participants from China were enrolled and genotyped for the HLA-A, -B, -C, -DQA1, -DQB1 and -DRB1 genes using next-generation sequencing. Results The susceptible DR3 (β = −0.09, p = 0.0009) and DR4-DQ8 (β = −0.13, p = 0.0059) haplotypes were negatively associated with onset age, while the protective DR11 (β = 0.21, p = 0.0314) and DR12 (β = 0.27, p < 0.0001) haplotypes were positively associated with onset age. After adjustment for linkage disequilibrium with DR-DQ haplotypes, A*11:01:01 was positively associated with onset age (β = 0.06, p = 0.0370), while the susceptible C*15:02:01 was negatively associated with onset age (β = −0.21, p = 0.0050). The unit for β was double square-root (fourth root) transformed years of change in onset age associated with per copy of the HLA haplotype/allele. In addition, B*46:01:01 was protective (OR 0.41, 0.46; pc [corrected for multiple comparisons] = 0.0044, 0.0040), whereas A*24:02:01 (OR 2.71, 2.25; pc = 0.0003, 0.0002) and B*54:01:01 (OR 3.96, 3.79; pc = 0.0018, 0.0004) were predisposing in both the <18 group and the ≥18 group compared with healthy control participants. In the context of DR4-DQ4, A*11:01:01 (61.29% vs 28.26%, pc = 0.0144) was increased while the predisposing A*24:02:01 (19.35% vs 47.83%, pc = 0.0403) was decreased in patients with onset ≥18 years when compared with patients with onset <18 years. Conclusions/interpretation In addition to DR-DQ haplotypes, novel HLA class I alleles were detected to play a role in susceptibility to type 1 diabetes with different onset ages, which could improve the understanding of disease heterogeneity and has implications for the design of future studies. Graphical abstract

scholarly journals Effect of HLA Class I and Class II Alleles on Progression From Autoantibody Positivity to Overt Type 1 Diabetes in Children With Risk-Associated Class II Genotypes

Diabetes ◽  
2010 ◽  
Vol 59 (12) ◽  
pp. 3253-3256 ◽  
Author(s):  
K. Lipponen ◽  
Z. Gombos ◽  
M. Kiviniemi ◽  
H. Siljander ◽  
J. Lempainen ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Hla Class I ◽  
Class Ii ◽  
Class I

The association of specific HLA class I and II alleles with type 1 diabetes among Filipinos

2002 ◽  
Vol 59 (6) ◽  
pp. 452-469 ◽  
Author(s):  
T.L. Bugawan ◽  
W. Klitz ◽  
M. Alejandrino ◽  
J. Ching ◽  
A. Panelo ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Hla Class I ◽  
Class I

109-OR: Genetic Discrepancy of HLA Class I Alleles in Chinese Patients with Type 1 Diabetes at Different Onset Ages

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 109-OR
Author(s):  
ZIYU JIANG ◽  
WENQIAN REN ◽  
YINGXIN XIAN ◽  
JINHUA YAN ◽  
DAIZHI YANG ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Hla Class I ◽  
Class I ◽  
Chinese Patients

A gene telomeric of the HLA class I region is involved in predisposition to both type 1 diabetes and coeliac disease

1999 ◽  
Vol 54 (2) ◽  
pp. 162-168 ◽  
Author(s):  
B.A. Lie ◽  
L.M. Sollid ◽  
H. Ascher ◽  
J. Ek ◽  
H.E. Akselsen ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Coeliac Disease ◽  
Hla Class I ◽  
Class I ◽  
Class I Region
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