Molecular mimicry between varicella, measles virus and Hsp60 in type 1 diabetes associated HLA-DR3/DR4 molecules

2020 ◽  
Vol 14 (6) ◽  
pp. 1783-1789
Author(s):  
Fatima Zohra Meziane ◽  
Majda Dali-Sahi ◽  
Nouria Dennouni-Medjati ◽  
Houssam Boulenouar ◽  
Youssouf Kachekouche ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Measles Virus ◽  
Molecular Mimicry ◽  
Hla Dr3

scholarly journals Proinsulin peptide promotes autoimmune diabetes in a novel HLA-DR3-DQ2-transgenic murine model of spontaneous disease

Diabetologia ◽  
2019 ◽  
Vol 62 (12) ◽  
pp. 2252-2261 ◽  
Author(s):  
Johan Verhagen ◽  
Norkhairin Yusuf ◽  
Emma L. Smith ◽  
Emily M. Whettlock ◽  
Kerina Naran ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Autoimmune Diabetes ◽  
Diabetes Incidence ◽  
Human Type ◽  
Insulin Promoter ◽  
Human Type 1 Diabetes ◽  
Hla Dr3 ◽  
Peptide Region

Abstract Aims/hypothesis The molecular basis for the pathological impact of specific HLA molecules on autoimmune diseases such as type 1 diabetes remains unclear. Recent natural history studies in children have indicated a link between specific HLA genotypes and the first antigenic target against which immune responses develop. We set out to examine this link in vivo by exploring the diabetogenicity of islet antigens on the background of a common diabetes-associated HLA haplotype. Methods We generated a novel HLA-transgenic mouse model that expresses high-risk genes for type 1 diabetes (DRB1*03:01-DQA1*05:01-DQB1*02:01) as well as human CD80 under the rat insulin promoter and human CD4, on a C57BL/6 background. Adjuvanted antigen priming was used to reveal the diabetogenicity of candidate antigens and peptides. Results HLA-DR3-DQ2+huCD4+IA/IE−/−RIP.B7.1+ mice spontaneously developed autoimmune diabetes (incidence 46% by 35 weeks of age), accompanied by numerous hallmarks of human type 1 diabetes (autoantibodies against GAD65 and proinsulin; pancreatic islet infiltration by CD4+, CD8+ B220+, CD11b+ and CD11c+ immune cells). Disease was markedly accelerated and had deeper penetrance after adjuvanted antigen priming with proinsulin (mean onset 11 weeks and incidence 100% by 20 weeks post challenge). Moreover, the diabetogenic effect of proinsulin located to the 15-residue B29-C11 region. Conclusions/interpretation Our study identifies a proinsulin-derived peptide region that is highly diabetogenic on the HLA-DR3-DQ2 background using an in vivo model. This approach and the peptide region identified may have wider implications for future studies of human type 1 diabetes.

Association of high-affinity autoantibodies with type 1 diabetes high-risk HLA haplotypes

2021 ◽  
Author(s):  
Taylor M Triolo ◽  
Laura Pyle ◽  
Hali Broncucia ◽  
Taylor Armstrong ◽  
Liping Yu ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
High Risk ◽  
Islet Autoimmunity ◽  
Initial Visit ◽  
Prevention Study ◽  
High Affinity ◽  
Z Scores ◽  
Hla Haplotypes ◽  
Hla Dr3

Abstract Objective ECL assays are high-affinity autoantibody (Ab) tests that are more specific than Abs detected by traditional radiobinding assays (RBA) for risk screening and prediction of progression to type 1 diabetes. We sought to characterize the association of high-risk HLA haplotypes and genotypes with electrochemiluminescence (ECL) positivity and levels in relatives of individuals with type 1 diabetes. Methods We analyzed 602 participants from the TrialNet Pathway to Prevention Study who were positive for at least one RBA diabetes related Ab (GADA or IAA) and for whom ECL and HLA data were available. ECL and RBA Ab levels were converted to SD units away from mean (Z-scores) for analyses. Results Mean age at initial visit was 19.4+13.7 years; 344 (57.1%) were female and 104 (17.3%) carried the high-risk HLA- DR3/4*0302 genotype. At initial visit 424/602 (70.4%) participants were positive for either ECL-GADA or ECL-IAA, and 178/602 (29.6%) were ECL negative. ECL and RBA-GADA positivity were associated with both HLA-DR3 and DR4 haplotypes (all p<0.05), while ECL and RBA-GADA z-score titers were higher in participants with HLA-DR3 haplotypes only (both p<0.001). ECL-IAA (but not RBA-IAA) positivity was associated with the HLA-DR4 haplotype (p<0.05). Conclusions ECL-GADA positivity is associated with the HLA-DR3 and HLA-DR4 haplotypes and levels are associated with the HLA-DR3 haplotype. ECL-IAA positivity is associated with HLA-DR4 haplotype. These studies further contribute to the understanding of genetic risk and islet autoimmunity endotypes in type 1 diabetes.

scholarly journals Genetic Variation Within the HLA-DRA1 Gene Modulates Susceptibility to Type 1 Diabetes in HLA-DR3 Homozygotes

Diabetes ◽  
2019 ◽  
Vol 68 (7) ◽  
pp. 1523-1527 ◽  
Author(s):  
Özkan Aydemir ◽  
Janelle A. Noble ◽  
Jeffrey A. Bailey ◽  
Åke Lernmark ◽  
Patrick Marsh ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Genetic Variation ◽  
Hla Dr3

scholarly journals Antibodies from a Patient with Type 1 Diabetes and Celiac Disease Bind to Macrophages that Express the Scavenger Receptor CD163

2011 ◽  
Vol 25 (6) ◽  
pp. 327-329 ◽  
Author(s):  
Brigitte Sonier ◽  
Alexander Strom ◽  
Gen-Sheng Wang ◽  
Christopher Patrick ◽  
Jennifer A Crookshank ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Celiac Disease ◽  
Molecular Mimicry ◽  
Scavenger Receptor ◽  
Cross Reactivity ◽  
Rat Jejunum ◽  
The Novel ◽  
Blood Monocytes ◽  
Specific Subset

Antibodies against the wheat storage globulin Glo-3A from a patient with both type 1 diabetes (T1D) and celiac disease were enriched to identify potential molecular mimicry between wheat antigens and T1D target tissues. Recombinant Glo-3A was used to enrich anti-Glo-3A immunoglobulin G antibodies from plasma by batch affinity chromatography. Rat jejunum and pancreas, as well as human duodenum and monocytes were probed, and binding was evaluated by immunohistochemistry and confocal microscopy. Glo-3A-enriched antibodies bound to a specific subset of cells in the lamina propria of rat jejunum that co-localized mostly with a marker of resident, alternatively activated CD163-positive (CD163+) macrophages. Blood monocytes and macrophage-like cells in human duodenum were also labelled with the enriched antibodies. Blocking studies revealed that binding to CD163+macrophages was not due to cross-reactivity with anti-Glo-3A antibodies, but rather to non-Glo-3A antibodies co-purified during antibody enrichment. The novel finding of putative autoantibodies against tolerogenic intestinal CD163+macrophages suggests that regulatory macrophages were targeted in this patient with celiac disease and T1D.

Evidence for Environmental Triggers for Type 1 Diabetes in Patients with HLA-DR4 and HLA-DR3 Haplotypes from the United Arab Emirates

2019 ◽  
Author(s):  
Guan K. Tay ◽  
Halima Al Naqbi ◽  
Aurélie Mawart ◽  
Zahrah Baalfaqih ◽  
Anoud Almaazmi ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
United Arab Emirates ◽  
Hla Dr3

Index60 Is More Strongly Associated with the Highest Type 1 Diabetes (T1D) Risk HLA DR3-DQ2/DR4-DQ8 (DQ2/DQ8) Genotype than Glucose Measures

Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 205-LB
Author(s):  
MARIA J. REDONDO ◽  
SUSAN GEYER ◽  
HEBA M. ISMAIL ◽  
KEVAN C. HEROLD ◽  
ALBERTO PUGLIESE ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Hla Dr3

scholarly journals Type 1 Diabetes in the Spanish Population: additional factors to Class II HLA-DR3 and -DR4

BMC Genomics ◽  
2005 ◽  
Vol 6 (1) ◽  
Author(s):  
Elena Urcelay ◽  
José L Santiago ◽  
Hermenegildo de la Calle ◽  
Alfonso Martínez ◽  
Julián Méndez ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Class Ii ◽  
Spanish Population ◽  
Hla Dr3

High-risk genotypes HLA-DR3-DQ2/DR3-DQ2 and DR3-DQ2/DR4-DQ8 in co-occurrence of type 1 diabetes and celiac disease

Autoimmunity ◽  
2016 ◽  
Vol 49 (4) ◽  
pp. 240-247 ◽  
Author(s):  
Darja Smigoc Schweiger ◽  
Andrijana Mendez ◽  
Sabina Kunilo Jamnik ◽  
Nina Bratanic ◽  
Natasa Bratina ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Celiac Disease ◽  
High Risk ◽  
Hla Dr3

scholarly journals Sequence homology of the diabetes-associated autoantigen glutamate decarboxylase with coxsackie B4-2C protein and heat shock protein 60 mediates no molecular mimicry of autoantibodies.

1994 ◽  
Vol 180 (2) ◽  
pp. 721-726 ◽  
Author(s):  
W Richter ◽  
T Mertens ◽  
B Schoel ◽  
P Muir ◽  
A Ritzkowsky ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Sequence Homology ◽  
Glutamate Decarboxylase ◽  
Pancreatic Beta Cells ◽  
Molecular Mimicry ◽  
Heat Shock Protein 60 ◽  
Coxsackievirus B4

Molecular mimicry between viral antigens and host proteins was often suggested to be involved in induction of autoimmune diseases. In type 1 diabetes where pancreatic beta cells are destroyed by autoimmune phenomena, a linear sequence homology between a major autoantigen, glutamate decarboxylase (GAD), and the 2C protein of coxsackie B4 was identified. In addition, a sequence homology between GAD and the mycobacterial heat shock protein 60 was described and the suggestions were made that molecular mimicry between GAD, coxsackievirus B4-2C protein, and/or heat shock protein 60 (hsp60) may be actively involved in an autoimmune reaction towards the pancreatic beta-cells. Our group was the first to isolate human monoclonal autoantibodies to GAD (MICA 1-6) from a patient with newly diagnosed type 1 diabetes. The MICA allowed a detailed characterization of the diabetes associated self-epitopes in GAD and represent a set of GAD autoantibodies present in sera from patients with type 1 diabetes. Using deletion mutants of GAD we demonstrated that the regions of GAD covering the homology sequences to coxsackievirus B4 and to the hsp60 were absolutely required for binding of the MICA to GAD. We now designed an antibody-based analysis to ask whether molecular mimicry between GAD and coxsackie B4-2C or hsp60 is relevant in type 1 diabetes. Since part of the MICA recognize conformational epitopes, they allow to test for conformational molecular mimicry in viruses that have been incriminated in the development of type 1 diabetes. Our data reveal no crossreactivity between the diabetes associated GAD epitopes defined by the MICA and hsp60, rubellavirus, cytomegalovirus, and coxsackie B1-B6 virus antigens. Neither coxsackie B4-specific antibodies in sera from normal individuals nor GAD-positive sera from patients with type 1 diabetes indicated a crossreactivity between coxsackie B4-2C and GAD. Although the regions in GAD homologous to coxsackie B4-2C and hsp60 represented parts of GAD indispensible for binding of diabetes associated autoantibodies they did not mediate a crossreactivity of autoantibodies between GAD and these two proteins. No evidence for molecular mimicry between GAD and a whole panel of foreign antigens was detected by autoantibodies in type 1 diabetes.

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