A Common Pathway for All Autoimmune Diseases? The Unholy Alliance of Environment, Cell Death and Nucleic Acids

Autoimmune responses directed to macromolecular nucleic acid-protein complexes such as the nucleosome or the spliceosome are a hallmark of systemic lupus erythematosus (SLE) and related autoimmune diseases. In SLE and its animal models reactivity to these targets is believed to be caused by a defective apoptotic waste disposal system and is associated with a type I Interferon (IFN) signature. Furthermore, inappropriate activation of nucleic-acid binding Toll-like receptors (TLR) has been revealed in lupus-like conditions. Similar mechanisms may also be relevant for other systemic autoimmune diseases such as systemic sclerosis, poly/dermatomyositis and primary Sjogren's syndrome where autoantibodies to nucleic acid binding proteins are commonly observed. In contrast to these disorders, rheumatoid arthritis (RA), the most severe and most destructive joint disease, is characterized by the presence of rheumatoid factors and antibodies to citrullinated proteins, while autoimmune reactions to nucleic acid-binding proteins occur less frequently. However, data from RA patients and animal models suggest that they may nevertheless play an important role in the pathogenesis of autoimmune arthritis, as recently proposed for the heterogeneous nuclear ribonucleoprotein A2 (hnRNP-A2). To address the pathogenic role of these autoantigens animal models are indispensable. Of particular interest are models in which disease develops either spontaneously or is induced by immunization with a non-antigenic compound such as the alkane pristane. Unspecific proinflammatory stimuli such as the mineral oil pristane may trigger pathogenic autoimmune reactions which in genetically susceptible individuals may drive chronic inflammation and eventually lead to the development of disease. This review provides an overview of the involvement of RNA- and DNA-associated antigens in systemic autoimmune disorders and discusses recent data from animal models that point to a fundamental role of nucleic-acid associated autoantigens also in arthritic conditions. We will also outline a role of pristane as an inducer of apoptosis and concomitant trigger of autoimmune events.