The immune system is normally protected from exposure to self-DNA during apoptosis due to the rapid engulfment of intact cells as well as by the abundance of extra- and intracellular DNases. However, following tissue necrosis, inflammation or infection, antigen presenting cells (APCs), including dendritic cells (DCs), may be exposed to an increased load of cellular DNA, and inappropriate handling of cellular debris can lead to loss of tolerance. While mammalian DNA was previously thought to be neutral or even inhibitory to APCs, we have recently observed that cellular uptake of naked mammalian DNA or certain DNA containing immune complexes can induce DC activation. The goal of this proposal is to study the basic mechanisms of DC activation by endogenous DNA, including DNA associated with dying cells and with anti- DNA autoantibodies. We hypothesize that the pathological IFN response in SLE is a consequence of mammalian DNA which gains access to the cytoplasm through the uptake of dead or dying cells, and that this response is amplified by a small subset of antigen/anti-DNA immune complexes that have unique binding specificity and engage multiple cellular receptors leading to partial or full DC activation.
The specific aims are: i) to study mechanism(s) allowing endogenous DNA or DNA-containing particles to stimulate DC production of IFN, ii) to determine the role of endogenous antigens, including DNA/nucleosomes, in DC responses to anti-DNA immune complexes, and iii), to determine which signaling pathways are required for DC activation by anti-DNA immune complexes. These studies will allow us to better understand how endogenous genetic material is handled in order to gain fundamental insight into the pathogenesis of autoimmunity. Dr. David Martin, the PI, is an M.D. who has completed residency training in Internal Medicine and a Fellowship in Rheumatology, and wishes to develop an independent research career focusing on the molecular mechanisms of autoimmunity.
| Martin, David A; Zhang, Kang; Kenkel, Justin et al. (2007) Autoimmunity stimulated by adoptively transferred dendritic cells is initiated by both alphabeta and gammadelta T cells but does not require MyD88 signaling. J Immunol 179:5819-28 |
| Peng, Yufeng; Martin, David A; Kenkel, Justin et al. (2007) Innate and adaptive immune response to apoptotic cells. J Autoimmun 29:303-9 |
| Martin, David A; Elkon, Keith B (2006) Intracellular mammalian DNA stimulates myeloid dendritic cells to produce type I interferons predominantly through a toll-like receptor 9-independent pathway. Arthritis Rheum 54:951-62 |
