This consortium will explore whether a common process occurs in systemic autoimmune diseases that produces a cyclical pattern of inflammation and attack by the body's immune system against the body's own tissues.
Systemic autoimmune diseases include Lupus (which affects multiple organs), Polymyositis (which affects muscles), and Scleroderma (affecting the skin). Although these diseases have different clinical features, they share several similarities. All involve immune attacks by antibodies (called autoantibodies), which mistake specific proteins and nucleic acids derived from the body's own cells as foreign. All three diseases also involve activation of an immune system protein, called interferon-alpha (IFN-α, or interferon), which initiates inflammation. The researchers hypothesize that autoantibodies binding to self antigens may be responsible for inducing interferon and the resultant inflammatory response in all three of these diseases. This process involves the interaction between innate immune cells, called dendritic cells (DCs) and certain “receptors” within cells, called Toll-like receptors.
Ordinarily, DCs trigger these receptors to stimulate the production of interferon in response to foreign microbes, such as bacteria or viruses. In systemic autoimmune diseases, the researchers suggest, the process works differently. Specific errant antibodies and their cellular targets (“antigens”) trigger interferon production from a type of DC, called “plasmacytoid” DCs. Then, the interferon that is produced works on another type of DC, which presents these antigens from dying cells to other immune cells, perpetuating the autoimmune response. The Uppsala researchers will explore this hypothesis in laboratory tests of patients' samples, while the University of Washington investigators will study patients' samples to address a related hypothesis. This hypothesis suggests that, in each of these diseases, the way in which the mistakenly attacked cells die dictates whether or not interferon is stimulated again to perpetuate this cycle.
Significance: By determining how interferon is activated in these systemic autoimmune diseases, the findings could lead to development of improved therapies that block this activation.