Major histocompatibility complex class I-deficient NOD-B2mnull mice are diabetes and insulitis resistant

Serreze, David; Leiter, Edward H.; Christianson, Gregory J.; Greiner, Dale L.; Roopenian, Derry C.

doi:10.2337/diabetes.43.3.505

Cited by 173 publications

(144 citation statements)

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“…The prevalence of autoimmune diseases, such as insulin-dependent diabetes mellitus, associated with mitochondrial diseases may be explained by increased MHC I expression due to decreased ROS production in these patients and subsequent development of autoimmunity (28 -30). On the other hand, MHC I-deficient nonobese diabetic, ␤ 2 -microglobulin-null mice are diabetes and insulitis resistant (31).…”

Section: Resultsmentioning

confidence: 99%

Role of MHC Class I in Immune Surveillance of Mitochondrial DNA Integrity

Wang

Roifman

et al. 2003

The Journal of Immunology

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Mitochondrial DNA is subject to increased rates of mutations due to its proximity to the source of reactive oxygen species. Here we show that increased MHC class I (MHC I) expression serves to alert the immune system to cells with mitochondrial mutations. MHC I is overexpressed in fibroblasts with mitochondrial dysfunction from patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes and in lymphocytes from purine nucleoside phosphorylase-deficient immune-deficient mice with mitochondrial DNA deletions. Consistent with a role of MHC I in the elimination of cells containing mitochondrial DNA mutations, mice deficient in MHC I accumulate mitochondrial DNA deletions in various tissues. These observations in both mice and humans suggest a role for the immune system in preventing reversion of mitochondrial DNA back into a parasitic state following deleterious mutations affecting mitochondrial oxidative phosphorylation.

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Section: Resultsmentioning

confidence: 99%

Role of MHC Class I in Immune Surveillance of Mitochondrial DNA Integrity

Wang

Roifman

et al. 2003

The Journal of Immunology

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“…MIP-1␣ can stimulate macrophage secretion of IL-1, IL-6, and TNF-␣, which may promote NO production by macrophages and induce Fas-mediated apoptosis of islet ␤ cells (36,37). MIP-1␣ also preferentially attracts CD8 ϩ T cells, which are required for the development of diabetes and are a source of MIP-1␣ in vivo (34,38,39). Thus, inhibition of MIP-1␣ by IL-4 may help protect islet ␤ cells from attack by effector CD8 ϩ T cells.…”

Section: Discussionmentioning

confidence: 99%

Differential Expression of CC Chemokines and the CCR5 Receptor in the Pancreas Is Associated with Progression to Type I Diabetes

Cameron

Arreaza

Grattan

et al. 2000

The Journal of Immunology

133

107

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We investigated the biological role of CC chemokines in the Th1-mediated pathogenesis of spontaneous type I diabetes in nonobese diabetic (NOD) mice. Whereas an elevated ratio of macrophage inflammatory protein-1α (MIP-1α):MIP-1β in the pancreas correlated with destructive insulitis and progression to diabetes in NOD mice, a decreased intrapancreatic MIP-1α:MIP-1β ratio was observed in nonobese diabetes-resistant (NOR) mice. IL-4 treatment, which prevents diabetes in NOD mice by polarizing intraislet Th2 responses, decreased CCR5 expression in islets and potentiated a high ratio of MIP-1β and monocyte chemotactic protein-1 (MCP-1): MIP-1α in the pancreas. Furthermore, NOD.MIP-1α−/− mice exhibited reduced destructive insulitis and were protected from diabetes. Neutralization of MIP-1α with specific Abs following transfer of diabetogenic T cells delayed the onset of diabetes in NOD.Scid recipients. These studies illustrate that the temporal expression of certain CC chemokines, particularly MIP-1α, and the CCR5 chemokine receptor in the pancreas is associated with the development of insulitis and spontaneous type I diabetes.

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“…Moreover, a direct role for class I genes has been demonstrated in CD8 þ T-cell mediated destruction of b-cells in the nonobese diabetic mouse model of T1D. [28][29][30][31][32][33] These reports indicate that HLA-A and/or -B, or other loci in high LD with the associated alleles, may be particularly important in the processes between initiation of autoimmunity and progression to overt disease. Furthermore, HLA class II-independent associations with HLA-A and -B have also been reported with other AIDs.…”

Section: Confirmation Of Mhc Class I Associationsmentioning

confidence: 99%

Genetic variants of the HLA-A, HLA-B and AIF1 loci show independent associations with type 1 diabetes in Norwegian families

et al. 2008

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The main genetic predisposition to type 1 diabetes (T1D) is known to be conferred by the HLA-DRB1, -DQA1 and -DQB1 genes in the major histocompatibility complex (MHC). Other genetic factors within this complex are known to contribute, but their identity has often been controversial. This picture is shared with several other autoimmune diseases (AIDs). Moreover, as common genetic factors are known to exist between AIDs, associations reported with other AIDs may also be involved in T1D. In this study, we have used these observations in a candidate gene approach to look for additional MHC risk factors in T1D. Using complementary conditional methods (involving conditional logistic regression and family-based haplotype tests) and analyses of linkage disequilibrium (LD) patterns, we confirmed association for alleles of the HLA-A and HLA-B genes and found preliminary evidence for a novel association of a single-nucleotide polymorphism (rs2259571) in the AIF1 gene, independent of the DRB1-DQA1-DQB1 genes and of each other. However, no evidence of independent associations for a number of previously suggested candidate polymorphisms was detected. Our results illustrate the importance of a comprehensive adjustment for LD effects when performing association studies in this complex.

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Major histocompatibility complex class I-deficient NOD-B2mnull mice are diabetes and insulitis resistant

Cited by 173 publications

References 0 publications

Role of MHC Class I in Immune Surveillance of Mitochondrial DNA Integrity

Role of MHC Class I in Immune Surveillance of Mitochondrial DNA Integrity

Differential Expression of CC Chemokines and the CCR5 Receptor in the Pancreas Is Associated with Progression to Type I Diabetes

Genetic variants of the HLA-A, HLA-B and AIF1 loci show independent associations with type 1 diabetes in Norwegian families

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