Roles for Catharsis S, L, and B in Insulitis and Diabetes in the NOD Mouse

• Published in: Journal of autoimmunity Vol. 34; no. 2; p. 96
• 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: 06.08.2009
• ISSN: 0896-8411; 1095-9157
• DOI: 10.1016/j.jaut.2009.07.003

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.