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Roles for cathepsins S, L, and B in insulitis and diabetes in the NOD mouse
Lianne C Hsing1, Elizabeth A Kirk, Timothy S McMillen
1Department of Immunology and Howard Hughes Medical Institute, University of Washington, Seattle, WA 98109-8050, USA.
Abstract:
We developed a panel of non-obese diabetic (NOD) mice deficient in major lysosomal cysteine proteases (cathepsins S, L and B) to identify protease enzymes essential for autoimmune diabetes. Null alleles for cathepsins (Cts) S, L or B were introgressed onto the NOD genetic background with 19 Idd markers at homozygosity. Diabetes onset was determined among females aged up to 6 months. We evaluated insulitis and sialadenitis in tissues using histology and computer assisted morphology. NOD mice deficient in Ctss or Ctsb were partially protected from diabetes with incidence at 33% and 28%, respectively, versus wild-type NOD (69%; p < 0.00001). NODs lacking cathepsin L (Ctsl-/-) are completely protected from IDDM, as originally shown by others. Ctsl, Ctss, or Ctsb heterozygous mice were able to develop IDDM, although incidence levels were significantly lower for Ctsb+/- (50%) and Ctsl+/- (55%) as compared to NODs (69%; p < 0.03). Ctsl-/- mice contain functional, diabetogenic T cells and an enriched Foxp3+ regulatory T cell population, and diabetes resistance was due to the presence of an expanded population of regulatory T cells. These data provide additional information about the potency of the diabetogenic T cell population in Ctsl-/- mice which were comparable in potency to wild-type NOD mice. These data illustrate the critical contribution of each of these proteases in determining IDDM in the NOD mouse and provide a useful set of models for further studies.
Insights
Mice lacking cathepsin L (Ctsl-/-) are fully protected from autoimmune diabetes. Deficiencies in cathepsin S (Ctss) or cathepsin B (Ctsb) also partially protected NOD mice, highlighting protease roles in diabetes development.
Area of Science:
- Immunology
- Endocrinology
- Genetics
Background:
- Autoimmune diabetes, specifically Type 1 diabetes, is a complex autoimmune disease characterized by the destruction of insulin-producing beta cells in the pancreas.
- Lysosomal cysteine proteases, particularly cathepsins, play roles in antigen processing and presentation, crucial steps in immune responses, including autoimmunity.
- The non-obese diabetic (NOD) mouse is a widely used genetic model for studying the pathogenesis of autoimmune diabetes.
Purpose of the Study:
- To investigate the specific roles of major lysosomal cysteine proteases (cathepsins S, L, and B) in the development of autoimmune diabetes.
- To determine if deficiencies in these cathepsins can confer protection against diabetes onset in the NOD mouse model.
- To elucidate the immunological mechanisms underlying diabetes resistance in protease-deficient mice.
Main Methods:
- Generation of NOD mice with targeted null mutations for cathepsin S (Ctss), cathepsin L (Ctsl), and cathepsin B (Ctsb).
- Introgression of these null alleles onto the NOD genetic background, ensuring homozygosity for 19 Idd markers.
- Assessment of diabetes incidence, insulitis, and sialadenitis in female mice up to 6 months of age using histology and computer-assisted morphology.
Main Results:
- NOD mice deficient in Ctss or Ctsb showed partial protection from diabetes (33% and 28% incidence, respectively) compared to wild-type NOD mice (69%).
- NOD mice lacking cathepsin L (Ctsl-/-) were completely protected from autoimmune diabetes.
- Heterozygous deficiencies for Ctsb and Ctsl also resulted in significantly lower diabetes incidence compared to wild-type NOD mice.
Conclusions:
- Cathepsins S, L, and B are critical proteases involved in the development of autoimmune diabetes in the NOD mouse model.
- Complete absence of cathepsin L confers complete resistance to diabetes, primarily due to an expanded population of regulatory T cells.
- These protease-deficient NOD mouse models are valuable tools for further dissecting the mechanisms of autoimmune diabetes.
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