Faculty Opinions recommendation of Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A.

Author(s):  
Peter Van Endert
Nature ◽  
2007 ◽  
Vol 450 (7171) ◽  
pp. 887-892 ◽  
Author(s):  
Sergey Nejentsev ◽  
◽  
Joanna M. M. Howson ◽  
Neil M. Walker ◽  
Jeffrey Szeszko ◽  
...  

2003 ◽  
Vol 64 (5) ◽  
pp. 553-561 ◽  
Author(s):  
Manu Gupta ◽  
Liene Nikitina-Zake ◽  
Marjan Zarghami ◽  
Mona Landin-Olsson ◽  
Ingrid Kockum ◽  
...  

10.1038/12465 ◽  
1999 ◽  
Vol 5 (9) ◽  
pp. 1026-1031 ◽  
Author(s):  
F. Susan Wong ◽  
Jaana Karttunen ◽  
Caroline Dumont ◽  
Li Wen ◽  
Irene Visintin ◽  
...  

2019 ◽  
Author(s):  
Muhammad Saad Khilji ◽  
Danielle Verstappen ◽  
Tina Dahlby ◽  
Michala Cecilie Burstein Prause ◽  
Celina Pihl ◽  
...  

AbstractA central and still open question regarding the pathogenesis of autoimmune diseases, such as type 1 diabetes, concerns the processes that underlie the generation of MHC-presented autoantigenic epitopes that become targets of autoimmune attack. Proteasomal degradation is a key step in processing of proteins for MHC class I presentation. Different types of proteasomes can be expressed in cells dictating the repertoire of peptides presented by the MHC class I complex. Of particular interest for type 1 diabetes is the proteasomal configuration of pancreatic β cells, as this might facilitate autoantigen presentation by β cells and thereby their T-cell mediated destruction. Here we investigated whether so-called inducible subunits of the proteasome are constitutively expressed in β cells, regulated by inflammatory signals and participate in the formation of active intermediate or immuno-proteasomes.We show that inducible proteasomal subunits are constitutively expressed in human and rodent islets and an insulin-secreting cell-line. Moreover, the β5i subunit is incorporated into active intermediate proteasomes that are bound to 19S or 11S regulatory particles. Finally, inducible subunit expression along with increase in total proteasome activities are further upregulated by non-toxic concentrations of IL-1β stimulating proinsulin biosynthesis. These findings suggest that the β cell proteasomal repertoire is more diverse than assumed previously and may be highly responsive to a local inflammatory islet environment.


2006 ◽  
Vol 958 (1) ◽  
pp. 309-311 ◽  
Author(s):  
L. NIKITINA ZAKE ◽  
M. GHADERI ◽  
Y. S. PARK ◽  
S. BABU ◽  
G. EISENBARTH ◽  
...  

2006 ◽  
Vol 1079 (1) ◽  
pp. 229-239 ◽  
Author(s):  
M. GUPTA ◽  
J. GRAHAM ◽  
B. MCNEENY ◽  
M. ZARGHAMI ◽  
M. LANDIN-OLSSON ◽  
...  

Diabetologia ◽  
2021 ◽  
Author(s):  
Ziyu Jiang ◽  
Wenqian Ren ◽  
Hua Liang ◽  
Jinhua Yan ◽  
Daizhi Yang ◽  
...  

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


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