Roles for cathepsins S, L, and B in insulitis and diabetes in the NOD mouse

• Published in: Journal of autoimmunity Vol. 34; no. 2; pp. 96 - 104
• Main Authors: Hsing, Lianne C, Kirk, Elizabeth A, McMillen, Timothy S, Hsiao, Shuo-Hung, Caldwell, Mark, Houston, Barbara, Rudensky, Alexander Y, LeBoeuf, Renee C
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier Ltd 01.03.2010; Elsevier
• Subjects: Age of Onset; Allergy and Immunology; Animals; Biological and medical sciences; Cathepsin; Cathepsin B - genetics; Cathepsin B - immunology; Cathepsin B - metabolism; Cathepsin L - genetics; Cathepsin L - immunology; Cathepsin L - metabolism; Cathepsins - genetics; Cathepsins - immunology; Cathepsins - metabolism; CD4 Antigens - biosynthesis; Cell Movement - genetics; Diabetes Mellitus, Type 1 - genetics; Diabetes Mellitus, Type 1 - metabolism; Diabetes Mellitus, Type 1 - pathology; Diabetes Mellitus, Type 1 - physiopathology; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Female; Forkhead Transcription Factors - biosynthesis; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Lymphopenia; Medical sciences; Mice; Mice, Congenic; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, Knockout; Mouse; NOD; Pancreatitis; Sialadenitis; T-Lymphocyte Subsets - pathology; T-Lymphocytes, Regulatory - pathology; Type 1 diabetes; Cathepsin; NOD; Mouse; Type 1 diabetes; Endocrinopathy; Immunopathology; Insulitis; Animal model; Cathepsin L; Enzyme; Cysteine endopeptidases; Autoimmune disease; Cathepsin S; Peptidases; Immunology; Animal; Cathepsin B; Hydrolases; Non obese diabetic mouse
• ISSN: 0896-8411; 1095-9157
• DOI: 10.1016/j.jaut.2009.07.003

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.