Critical role of cathepsin-inhibitors forautoantigen processing and autoimmunity

摘要

The cysteinal lysosomal proteases, cathepsin S and cathepsin L have been shownto process invariant chain (Ii), thereby facilitating MHC class II maturation.However, their role in autoantigen processing is not established. Sjogren's syndrome(SS) is an autoimmune disorder characterized by lymphocytic infiltrates anddestruction of the salivary and lacrimal glands and systemic production ofautoantibodies to the ribonucleoprotein (RNP) particles SS-A/Ro and SS-B/La(Fox et al., 1986; Chan et al., 1991; Kruize et al., 1995). Previously, we reported a120 kD a-fodrin autoantigen on the development of autoimmune exocrinopathy inSS model mice and identified autoantigen-specific T cell responses associated withThl cytokine production of interleukin (IL)-2 and interferon (IFN)-y (Haneji et al.,1994, 1997). Insulin-dependent diabetes mellitus (IDDM) is a T-cell-mediated,organ-specific autoimmune disease that occurs in humans and in animal models suchas the non-obese diabetic (NOD) mouse (Katz et al., 1993; Haskins and McDuffie,1990). The autoimmune diabetes in NOD mice is characterized by lymphocyticinfiltration of the islets (insulitis) followed by destruction of islet fl-cells. Evidence forthe role of CD4 Thl cells in IDDM derives from recent studies of the NOD mousein which the identical glutamic acid decarboxylase (GAD) and proinsulin are key /3-cell autoantigens recognized by both T cells and B cells (Kaufman et al., 1993; Liuet al., 2002).