The cell nucleus is a prominent target of autoantibodies in systemic autoimmune disorders. Approximately 2% of the population in Europe and North America suffers from systemic rheumatic diseases, such as rheumatoid arthritis, systemic lupus erythematosus (SLE), and scleroderma. The molecular mechanisms of systemic autoimmunity are largely unknown despite its high prevalence. Contributing factors that have been considered include (1) genetic predisposition, (2) influence of hormones, and (3) environmental factors. The latter are mainly correlated with the generation of scleroderma, as xenobiotic-induced subsets of this disease have been observed in individuals exposed to silica (SiO(2)) dusts, organic solvents, heavy metals, and certain drugs. In addition to the epidemiological relevance, animal models of xenobiotic-induced autoimmunity serve as elegant tools for controlled induction of antigen-driven autoimmune responses. Because antigen processing and presentation constitute the basis for every antigen-driven autoimmune response, effects of xenobiotics on degradation of nuclear autoantigens have been characterized to elucidate molecular mechanisms of autoimmunity that target the cell nucleus. By means of a cell-based disease model, it has been shown that xenobiotics such as mercuric chloride, platinum salts, and silica (nano)particles specifically alter structure, function, and proteolysis in the cell nucleus. Signature proteins of the cell nucleus redistribute to aberrant, nucleoplasmic clusters, where they colocalize with proteasomes and are subjected to proteasomal proteolysis. Recruitment of nuclear autoantigens to proteasomal degradation is correlated with autoimmune responses that specifically target these antigens in both animal models of xenobiotic-induced autoimmunity and patients with idiopathic scleroderma.