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Genetic deficiency of Itgb2 or ItgaL prevents autoimmune diabetes through distinctly different mechanisms in NOD/LtJ mice.

Glawe JD, Patrick DR, Huang M, Sharp CD, Barlow SC, Kevil CG - Diabetes (2009)

Bottom Line: However, ItgaL deficiency did not alter NOD T-cell adhesion to or transmigration across islet endothelial cells.Adoptive transfer of ItgaL-deficient splenocytes into NOD/Rag-1 mice did not result in development of diabetes, suggesting a role for ItgaL in NOD/LtJ T-cell activation.Together, these data demonstrate that genetic deficiency of Itgb2 or ItgaL confers protection against autoimmune diabetes through distinctly different mechanisms.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Louisiana State University Health Sciences Center Shreveport, Shreveport, Louisiana, USA.

ABSTRACT

Objective: Insulitis is an important pathological feature of autoimmune diabetes; however, mechanisms governing the recruitment of diabetogenic T-cells into pancreatic islets are poorly understood. Here, we determined the importance of leukocyte integrins beta(2)(Itgb2) and alphaL (ItgaL) in developing insulitis and frank diabetes.

Research design and methods: Gene-targeted mutations of either Itgb2 or ItgaL were established on the NOD/LtJ mouse strain. Experiments were performed to measure insulitis and diabetes development. Studies were also performed measuring mutant T-cell adhesion to islet microvascular endothelial cells under hydrodynamic flow conditions. T-cell adhesion molecule profiles and adoptive transfer studies were also performed.

Results: Genetic deficiency of either Itgb2 or ItgaL completely prevented the development of hyperglycemia and frank diabetes in NOD mice. Loss of Itgb2 or ItgaL prevented insulitis with Itgb2 deficiency conferring complete protection. In vitro hydrodynamic flow adhesion studies also showed that loss of Itgb2 completely abrogated T-cell adhesion. However, ItgaL deficiency did not alter NOD T-cell adhesion to or transmigration across islet endothelial cells. Adoptive transfer of ItgaL-deficient splenocytes into NOD/Rag-1 mice did not result in development of diabetes, suggesting a role for ItgaL in NOD/LtJ T-cell activation.

Conclusions: Together, these data demonstrate that genetic deficiency of Itgb2 or ItgaL confers protection against autoimmune diabetes through distinctly different mechanisms.

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Related in: MedlinePlus

Genetic deficiency of Itgb2 or ItgaL confers protection against autoimmune diabetes in NOD/LtJ mice. A: Blood glucose measurements from wild-type, Itgb2−/− , and ItgaL−/−  NOD/LtJ mice over time. B: The percent of mice remaining normoglycemic over time between wild-type, Itgb2−/− , and ItgaL−/−  NOD/LtJ mice. C– E: Representative hematoxylin and eosin stains of islet histopathology from wild-type, Itgb2−/− , and ItgaL−/−  NOD/LtJ mice, respectively. F: The insulitis score between the different genotypes of NOD/LtJ mice. *P < 0.01 vs. mutant NOD/LtJ strains, n = 20 mice per genotype. ***P < 0.001, n = 15 mice per genotype. (A high-quality digital representation of this figure is available in the online issue.)
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Figure 1: Genetic deficiency of Itgb2 or ItgaL confers protection against autoimmune diabetes in NOD/LtJ mice. A: Blood glucose measurements from wild-type, Itgb2−/− , and ItgaL−/− NOD/LtJ mice over time. B: The percent of mice remaining normoglycemic over time between wild-type, Itgb2−/− , and ItgaL−/− NOD/LtJ mice. C– E: Representative hematoxylin and eosin stains of islet histopathology from wild-type, Itgb2−/− , and ItgaL−/− NOD/LtJ mice, respectively. F: The insulitis score between the different genotypes of NOD/LtJ mice. *P < 0.01 vs. mutant NOD/LtJ strains, n = 20 mice per genotype. ***P < 0.001, n = 15 mice per genotype. (A high-quality digital representation of this figure is available in the online issue.)

Mentions: Blood glucose data obtained from NOD/LtJ wild-type, Itgb2−/− NOD/LtJ, and ItgaL−/− NOD/LtJ mice demonstrate that loss of either Itgb2 or ItgaL offers protection from diabetes.Figure 1A reports that Itgb2 and ItgaL knockout mice maintained normal blood glucose levels throughout the study, whereas wild-type NOD/LtJ mice showed a marked increase between weeks 14 and 16, plateauing at 400 mg/dl by week 24. Only 20% of NOD/LtJ wild-type mice remained normoglycemic by week 30, whereas ItgaL−/− and Itgb2−/−mice remained normoglycemic for the entire study period (Fig. 1B). These results clearly reveal an important pathophysiological role for Itgb2 and ItgaL during the onset of diabetes.


Genetic deficiency of Itgb2 or ItgaL prevents autoimmune diabetes through distinctly different mechanisms in NOD/LtJ mice.

Glawe JD, Patrick DR, Huang M, Sharp CD, Barlow SC, Kevil CG - Diabetes (2009)

Genetic deficiency of Itgb2 or ItgaL confers protection against autoimmune diabetes in NOD/LtJ mice. A: Blood glucose measurements from wild-type, Itgb2−/− , and ItgaL−/−  NOD/LtJ mice over time. B: The percent of mice remaining normoglycemic over time between wild-type, Itgb2−/− , and ItgaL−/−  NOD/LtJ mice. C– E: Representative hematoxylin and eosin stains of islet histopathology from wild-type, Itgb2−/− , and ItgaL−/−  NOD/LtJ mice, respectively. F: The insulitis score between the different genotypes of NOD/LtJ mice. *P < 0.01 vs. mutant NOD/LtJ strains, n = 20 mice per genotype. ***P < 0.001, n = 15 mice per genotype. (A high-quality digital representation of this figure is available in the online issue.)
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2682677&req=5

Figure 1: Genetic deficiency of Itgb2 or ItgaL confers protection against autoimmune diabetes in NOD/LtJ mice. A: Blood glucose measurements from wild-type, Itgb2−/− , and ItgaL−/− NOD/LtJ mice over time. B: The percent of mice remaining normoglycemic over time between wild-type, Itgb2−/− , and ItgaL−/− NOD/LtJ mice. C– E: Representative hematoxylin and eosin stains of islet histopathology from wild-type, Itgb2−/− , and ItgaL−/− NOD/LtJ mice, respectively. F: The insulitis score between the different genotypes of NOD/LtJ mice. *P < 0.01 vs. mutant NOD/LtJ strains, n = 20 mice per genotype. ***P < 0.001, n = 15 mice per genotype. (A high-quality digital representation of this figure is available in the online issue.)
Mentions: Blood glucose data obtained from NOD/LtJ wild-type, Itgb2−/− NOD/LtJ, and ItgaL−/− NOD/LtJ mice demonstrate that loss of either Itgb2 or ItgaL offers protection from diabetes.Figure 1A reports that Itgb2 and ItgaL knockout mice maintained normal blood glucose levels throughout the study, whereas wild-type NOD/LtJ mice showed a marked increase between weeks 14 and 16, plateauing at 400 mg/dl by week 24. Only 20% of NOD/LtJ wild-type mice remained normoglycemic by week 30, whereas ItgaL−/− and Itgb2−/−mice remained normoglycemic for the entire study period (Fig. 1B). These results clearly reveal an important pathophysiological role for Itgb2 and ItgaL during the onset of diabetes.

Bottom Line: However, ItgaL deficiency did not alter NOD T-cell adhesion to or transmigration across islet endothelial cells.Adoptive transfer of ItgaL-deficient splenocytes into NOD/Rag-1 mice did not result in development of diabetes, suggesting a role for ItgaL in NOD/LtJ T-cell activation.Together, these data demonstrate that genetic deficiency of Itgb2 or ItgaL confers protection against autoimmune diabetes through distinctly different mechanisms.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Louisiana State University Health Sciences Center Shreveport, Shreveport, Louisiana, USA.

ABSTRACT

Objective: Insulitis is an important pathological feature of autoimmune diabetes; however, mechanisms governing the recruitment of diabetogenic T-cells into pancreatic islets are poorly understood. Here, we determined the importance of leukocyte integrins beta(2)(Itgb2) and alphaL (ItgaL) in developing insulitis and frank diabetes.

Research design and methods: Gene-targeted mutations of either Itgb2 or ItgaL were established on the NOD/LtJ mouse strain. Experiments were performed to measure insulitis and diabetes development. Studies were also performed measuring mutant T-cell adhesion to islet microvascular endothelial cells under hydrodynamic flow conditions. T-cell adhesion molecule profiles and adoptive transfer studies were also performed.

Results: Genetic deficiency of either Itgb2 or ItgaL completely prevented the development of hyperglycemia and frank diabetes in NOD mice. Loss of Itgb2 or ItgaL prevented insulitis with Itgb2 deficiency conferring complete protection. In vitro hydrodynamic flow adhesion studies also showed that loss of Itgb2 completely abrogated T-cell adhesion. However, ItgaL deficiency did not alter NOD T-cell adhesion to or transmigration across islet endothelial cells. Adoptive transfer of ItgaL-deficient splenocytes into NOD/Rag-1 mice did not result in development of diabetes, suggesting a role for ItgaL in NOD/LtJ T-cell activation.

Conclusions: Together, these data demonstrate that genetic deficiency of Itgb2 or ItgaL confers protection against autoimmune diabetes through distinctly different mechanisms.

Show MeSH
Related in: MedlinePlus