Proteasomal processing of nuclear autoantigens in systemic autoimmunity

Autoimmune diseases are believed to rise from a breakdown of tolerance and a deregulation of the immune system to discriminate effectively between "self'-and "non-self'. Although the origins of autoimmunity and the factors leading to overt autoimmune diseases are largely unclear, genetic background, hormones, and environmental agents are found to be involved. The production of autoantibodies, against distinct "self'-proteins of the cell nucleus constitutes one of the autoimmune manifestations that characterize systemic autoimmunity. While molecular mechanisms of anti-nuclear autoimmune responses remain poorly understood, processing and presentation of intracellular autoantigens to T cells constitutes a central issue in the generation of antigen-driven autoimmunity. Intracellular proteins, including nuclear autoantigens, are degraded by the proteasomal pathway that clears away endogenous proteins, regulates numerous cellular processes, and delivers immunocompetent peptides to the antigen presenting machinery. Since antigen processing is a key step for the maintenance of peripheral tolerance, in this article, we discuss the role of proteasome-dependent antigen processing in systemic autoimmunity. (c) 2004 Elsevier B.V. All rights, reserved.