The focus of our laboratory is to define the role of proteases in immunity and autoimmunity. Traditionally, proteases are viewed as effector molecules owing to their ability to digest extracellular matrix (ECM). More recently, studies have extended the role of proteases beyond the degradation of ECM. For example, we have generated a mouse deficient in cathepsin C (or dipeptidyl peptidase I, DPPI) and established that this protease is crucial in the activation of many serine proteases including lymphocyte-associated granzymes, mast cell-derived chymase, and neutrophil-specific cathepsin G, neutrophil elastase and proteinase 3. We have further shown that DPPI and the serine proteases it activates are key molecules involved in cell-mediated cytotoxicity and leukocyte recruitment at sites of inflammation. The absence of DPPI rendered mice resistant to experimentally induced arthritis and death in a model of sepsis. Therefore, a more complete understanding of the functional physiology of proteases should lead to a better understanding of immune effector cell biology and may potential lead to novel therapeutic interventions.
Rheumatology, arthritis, inflammation and proteases