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- Aydemir, Özkan, et al.
(author)
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Polymorphisms in Intron 1 of HLA-DRA Differentially Associate with Type 1 Diabetes and Celiac Disease and Implicate Involvement of Complement System Genes C4A and C4B
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In: eLife. - 2050-084X.
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Journal article (peer-reviewed)abstract
- Polymorphisms in genes in the human leukocyte antigen (HLA) class II region comprise the most important inherited risk factors for many autoimmune diseases including type 1 diabetes (T1D) and celiac disease (CD): both diseases are positively associated with the HLA- DR3 haplotype (DRB1*03:01-DQA1*05:01-DQB1*02:01). Studies of two different populations have recently documented that T1D susceptibility in HLA-DR3 homozygous individuals isstratified by a haplotype consisting of three single nucleotide polymorphisms (“tri-SNP”) in intron 1 of the HLA-DRA gene. In this study, we use a large cohort from the longitudinal “The Environmental Determinants of Diabetes in the Young” (TEDDY) study to further refine the tri-SNP association with T1D and with autoantibody-defined T1D endotypes. We found that the tri-SNP association is primarily in subjects whose first-appearing T1D autoantibody is to insulin. In addition, we discovered that the tri-SNP is also associated with celiac disease (CD), and that the particular tri-SNP haplotype (“101”) that is negatively associated with T1D risk is positively associated with risk for CD. The opposite effect of the tri-SNP haplotype on two DR3-associated diseases can enhance and refine current models of disease prediction based on genetic risk. Finally, we investigated possible functional differences between the individuals carrying high and low-risk tri-SNP haplotypes, and found that differences in complement system genes C4A and C4B may underlie the observed divergence in disease risk.
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| 2. |
- Bogdani, Marika, et al.
(author)
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The Vbeta13 T Cell Receptor Monoclonal Antibody Reduces Hyaluronan and CD68+, CD3+, and CD8+ Cell Infiltrations to Delay Diabetes in Congenic BB DRLyp/Lyp Rats
- 2021
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In: Frontiers in Endocrinology. - : Frontiers Media SA. - 1664-2392. ; 12
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Journal article (peer-reviewed)abstract
- The depleting Vβ13a T cell receptor monoclonal antibody (mAb) 17D5 prevents both induced and spontaneous autoimmune diabetes in BB rats. Here it was tested in congenic DRLyp/Lyp rats, all of which spontaneously developed diabetes. Starting at 40 days of age, rats were injected once weekly with either saline, His42 Vβ16 mAb, or 17D5 mAb and monitored for hyperglycemia. Diabetes occurred in 100% (n = 5/5) of saline-treated rats (median age, 66 days; range 55–73), and in 100% (n = 6/6) of His42-treated rats (median age, 69 days; range 59–69). Diabetes occurred in fewer (n = 8/11, 73%) 17D5-treated rats at a later age (median 76 days, range 60–92). Three (27%) of the 17D5-treated rats were killed at 101–103 days of age without diabetes (17D5 no-diabetes rats). Survival analysis demonstrated that 17D5 mAb delayed diabetes onset. Saline- and His42-treated rats had severely distorted islets with substantial loss of insulin-positive cells. These rats exhibited prominent hyaluronan (HA) staining, with the intra-islet HA+ accumulations measuring 5,000 ± 2,400 µm2 and occupying 36 ± 12% of islet area, and severe (grade 4) insulitis with abundant infiltration by CD68+, CD3+, and CD8+ cells. The 17D5 mAb-treated rats with delayed diabetes onset exhibited less severe insulitis (predominantly grade 3). In contrast, the 17D5 no-diabetes rats had mostly normal islets, with insulin+ cells representing 76 ± 3% of islet cells. In these rats, the islet HA deposits were significantly smaller than in the diabetic rats; the intra-islet HA+ areas were 1,200 ± 300 µm2 and accounted for 8 ± 1% of islet area. Also, islet-associated CD68+ and CD3+ cells occurred less frequently (on average in 60 and 3% of the islets, respectively) than in the diabetes rats (present in >95% of the islets). No CD8+ cells were detected in islets in all 17D5 no-diabetes rats. We conclude that mAb 17D5 delayed diabetes in DRLyp/Lyp rats and markedly reduced expression of HA and concomitant infiltration of CD68+, CD3+, and CD8+ cells. Our findings underscore the importance of refining immune suppression in prevention or intervention clinical trials to use mAb reagents that are directed against specific T cell receptors.
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| 3. |
- Fuller, Jessica, et al.
(author)
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Genetic Dissection Reveals Diabetes Loci Proximal to the Gimap5 Lymphopenia Gene.
- 2009
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In: Physiological Genomics. - : American Physiological Society. - 1094-8341 .- 1531-2267. ; 38, s. 89-97
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Journal article (peer-reviewed)abstract
- Congenic DRF.(f/f) rats are protected from type 1 diabetes (T1D) by 34 Mb of F344 DNA introgressed proximal to the Gimap5 lymphopenia gene. To dissect the genetic factor(s) that confer protection from T1D in the DRF.(f/f) rat line, DRF.(f/f) rats were crossed to inbred BBDR or DR.(lyp/lyp) rats to generate congenic sublines that were genotyped, monitored for T1D and positional candidate genes sequenced. All (100%) DR.(lyp/lyp) rats developed T1D by 83 days of age. Reduction of the DRF.(f/f) F344 DNA fragment by 26 Mb (42.52 Mb-68.51 Mb) retained complete T1D protection. Further dissection revealed that a 2 Mb interval of F344 DNA (67.41-70.17 Mb) (Region 1) resulted in 47% protection and significantly delayed onset (p<0.001 compared to DR.(lyp/lyp)). Retaining <1 Mb of F344 DNA at the distal end (76.49-76.83 Mb) (Region 2) resulted in 28% protection and also delayed onset (p<0.001 compared to DR.(lyp/lyp)). Comparative analysis of diabetes frequency in the DRF.(f/f) congenic sublines further refined the RNO4 Region 1 interval to approximately 670 Kb and Region 2 to the 340 Kb proximal to Gimap5. All congenic DRF.(f/f) sublines were prone to low-grade pancreatic mononuclear cell infiltration around ducts and vessels but less than 20% of islets in non-diabetic rats showed islet infiltration. Coding sequence analysis revealed TCR Vbeta 8E, 12 and 13 as candidate genes in Region 1 and Znf467 and Atp6v0e2 as candidate genes in Region 2. Our results show that spontaneous T1D is controlled by at least two genetic loci 7 Mb apart on rat chromosome 4. Key words: Type 1 diabetes, BB rat, T cell receptor, autoimmune.
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| 4. |
- Mordes, John P., et al.
(author)
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Analysis of the rat Iddm14 diabetes susceptibility locus in multiple rat strains: identification of a susceptibility haplotype in the Tcrb-V locus
- 2009
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In: Mammalian Genome. - : Springer Science and Business Media LLC. - 1432-1777 .- 0938-8990. ; 20:3, s. 162-169
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Journal article (peer-reviewed)abstract
- Iddm14 (formerly Iddm4) is a non-MHC-linked genetic locus associated with autoimmune diabetes. Its effects have been well-documented in BB-derived rats in which diabetes is either induced by immunologic perturbation or occurs spontaneously. The role of Iddm14 in non-BB rat strains is unknown. Our goal was to extend the analysis of Iddm14 in new diabetes-susceptible strains and to identify candidate genes in the rat Iddm14 diabetes susceptibility locus that are common to these multiple diabetic strains. To determine if Iddm14 is important in strains other than BB, we first genotyped a (LEW.1WR1 x WF)F2 cohort in which diabetes was induced by perturbation with polyinosinic:polycytidylic acid. We found that Iddm14 is a major determinant of diabetes susceptibility in LEW.1WR1 rats. We then used nucleotide sequencing to establish a strain distribution pattern of polymorphisms (insertions, deletions, and single nucleotide polymorphisms [SNPs]) that predicts susceptibility to diabetes in a panel of inbred and congenic rats. Using the positional information from the congenic strains and the new linkage data, we identified a susceptibility haplotype in the T-cell receptor V beta chain (Tcrb-V) locus. This haplotype includes Tcrb-V13, which is identical in five susceptible strains but different in resistant WF and F344 rats. We conclude that Iddm14 is a powerful determinant of both spontaneous and induced autoimmune diabetes in multiple rat strains, and that Tcrb-V13 SNPs constitute a haplotype of gene elements that may be critical for autoimmune diabetes in rats.
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