The prototype of systemic autoimmune disorders, systemic lupus erythematosus, is characterized by a loss in immunological tolerance to a variety of ubiquitous self-antigens, such as chromatin, double-stranded DNA, ribonucleoproteins, and complement. These immune irregularities are postulated to be a consequence of changes in the activation thresholds and functions of immune cells, variations in the cytokine milieu produced, alterations in the clearance of apoptotic and necrotic debris by phagocytotic cells, and modulations in antigen presentation capacities. The lupus model provides a framework to interpret the genetic interactions that progressively increase disease pathogenesis in mouse model systems. The remaining questions focus on the identification of the specific disease alleles and the characterization of the molecular mechanisms responsible for driving disease. Although identification of the disease-causing genes still remains a challenge, advances in technology and the persistent efforts of many investigators are beginning to break down the major obstacles of positional cloning strategies. As disease alleles are identified in mouse models of systemic autoimmunity, this new information will undoubtedly increase the understanding of disease progression in humans.
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