Innate immunity as the trigger of systemic autoimmune diseases

The innate immune system consists of a variety of elements controlling and participating in virtually all aspects of inflammation and immunity. It is crucial for host defense, but on the other hand its improper activation is also thought to be responsible for the generation of autoimmunity and therefore diseases such as autoimmune arthritides like rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS) or inflammatory bowel disease. The innate immune system stands both at the beginning as well as the end of autoimmunity. On one hand, it regulates the activation of the adaptive immune system and the breach of self-tolerance, as antigen presenting cells (APCs), especially dendritic cells, are essential for the activation of naïve antigen specific T cells, a crucial step in the development of autoimmunity. Various factors controlling the function of dendritic cells have been identified that directly regulate lymphocyte homeostasis and in some instances the generation of organ specific autoimmunity. Moreover, microbial cues have been identified that are prerequisites for the generation of several specific autoimmune diseases. On the other hand, the innate immune system is also responsible for mediating the resulting organ damage underlying the clinical symptoms of a given autoimmune disease via production of proinflammatory cytokines that amplify local inflammation and further activate other immune or parenchymal cells in the vicinity, the generation of matrix degrading and proteolytic enzymes or reactive oxygen species directly causing tissue damage. In the last decades, molecular characterization of cell types and their subsets as well as both positive and negative regulators of immunity has led to the generation of various scenarios of how autoimmunity develops, which eventually might lead to the development of targeted interventions for autoimmune diseases. In this review, we try to summarize the elements that are contributing to the initiation and perpetuation of autoimmune responses.