Cutaneous lupus erythematosus (CLE) refers to dermatologic features of lupus that may or may not be associated with more systemic manifestations of SLE. Common mechanisms are thought to promote CLE and other clinical manifestations of SLE, and therefore a better understanding of the genetic, environmental, and immunoregulatory factors that drive CLE are likely to provide important mechanistic insights for the pathophysiology of both CLE and SLE. There is a general consensus that an environmental trigger initiates disease in genetically predisposed individuals. These environmental triggers (eg UV irradiation) are often associated with tissue damage followed by failure to safely clear cell debris. Despite the numerous murine models of SLE, models that accurately reflect the central features of CLE are much more limited. Although, nucleic acid binding Toll-like receptors have been implicated in the activation of autoreactive B cells, pDCs, cDCs, neutrophils and other SLE-relevant effector cells, TLR9-deficiency alone results in more severe disease in all models of murine SLE through mechanisms that remain unresolved. We have now leveraged the hyperactivity of TLR9-deficient mice to develop a novel ?pseudo-autoantigen? T cell-dependent and type I IFN- dependent model of cutaneous inflammation. Within 4 weeks of self-reactive T cell transfer, these mice develop a skin disease with many of the hallmarks of human CLE - a mononuclear interface dermatitis associated with mucin production in the dermis, antibody deposition at the dermal/epidermal border, and high numbers of IFN? producing CD4 T cells. Self-reactive T cells, activated dendritic cells, inflammatory monocytes, and other myeloid subsets infiltrate the skin of TLR9KO but not TLR9WT recipients, but skin disease only develops if the inducing T cells express FasL. Importantly, as with all murine models of SLE, our model depends on the expression of TLR7, as well as the failure to express TLR9. Therefore it provides a novel, rapid and reproducible system for exploring the role of B cells and TLR9 in the development of cutaneous inflammation and the activation of autoreactive T cells. To address these issues, the specific aims of this application will: (1) Determine the requirement for B cells and their expression of TLRs in the development of Lupus-like skin inflammation; (2) Extend our initial pseudo-autoantigen observations to a novel set of autoreactive T cells, generated by BCR/TLR-activated B cells pulsed with autoantigen/nucleic acid complexes and captured as TCR retrogenic mice. Together these studies should further validate the ability of our model of murine CL to recapitulate the key parameters of human CLE, identify cell types directly impacted by TLR9- deficiency and therefore likely to drive disease onset, and thereby provide important insights regarding the pathophysiology of both CLE and SLE. !
Cutaneous lupus erythematosus (CLE) is a chronic disfiguring autoimmune disease. Current treatments involve very crude and non-specific immunosuppressive agents that have unpleasant side effects. A better understanding of the pathophysiology of the disease and its natural regulators of the disease process have been hampered by the lack of appropriate animal models. We have developed a novel murine model of cutaneous lupus that recapitulates many of the features of the human disease that will allow us to elucidate the distinct roles of TLR7 and TLR9 in the activation of B cells and other myeloid subsets that contribute to skin disease characteristic of patients afflicted with CLE. Insights gained from this project will have important implications for the design of TLR-directed therapeutics for the treatment of patients with SLE and other systemic disorders.
