My laboratory studies systemic lupus erythematosus (SLE), a heterogeneous autoimmune disease associated with tissue damage in skin, kidneys, lung, heart, brain, and vasculature. Although long thought to be a B cell-mediated disease involving the formation of immune complexes between nuclear antigen and autoantibody (IgG-immune complexes; IgG-ICs), recent studies have implicated most hematopoietic cell types in disease. Further, discoveries of many genes, proteins, and molecular events that are mutated, aberrantly expressed, or under\/over-activated or dysregulated, suggests a complex etiology beyond B cells, autoantibody, and immune complexes.<\/p>\n
Murine studies in my laboratory identified a lysosome defect in multiple hematopoietic cell types in the spontaneous MRL\/lpr model of lupus. Lysosomes are intracellular organelles that function as the \u201cgut\u201d of cells, degrading \u201cobsolete\u201d intracellular material during autophagy or phagocytosed\/endocytosed extracellular pathogens and dead cell debris entering the cell through surface receptors. In macrophages, we found that chronic Fcgamma RI (FcgRI) signal transduction diminishes lysosome acidification causing undegraded IgG-ICs (bound by FcgRI) to recycle back to the plasma membrane. This perpetuates FcgRI signaling creating a feedforward loop of sustained lysosome dysfunction and the recycling and accumulation of surface IgG-ICs.<\/p>\n
We are currently translating of our murine findings to human SLE to establish whether restoring lysosome function could be a strategy to treat disease. In considering therapeutic potential, it is noteworthy that our murine findings show lysosome dysfunction in genetically unrelated models of spontaneous murine lupus (MRL\/lpr and NZM2410). This finding raises the possibility that multiple pathways, possibly driven by independent genetic changes, could culminate into central event(s) that drive disease. This would be consistent with Genome Wide Association Studies (GWAS) implicating numerous SNP in human lupus populations. Our current efforts focus on defining whether lysosome dysfunction occurs in human SLE, whether it associates with active disease, and whether the underlying molecular events identified in mice are also evident in human SLE.<\/p>\n