Membrane-bound Fas ligand accelerates autoimmune disease in an induced murine model of systemic lupus erythematosus (123.3)

Abstract

Abstract Lpr and gld, are loss of function mutations in the Fas death receptor and its ligand, respectively. However, in addition to its pro-apoptotic activity, FasL can also trigger the production of pro-inflammatory cytokines. The lpr and gld mutations normally result in a lymphoproliferative syndrome and exacerbate clinical disease in SLE autoimmune-prone strains of mice. Unexpectedly, the lpr and gld mutations were reported to attenuate disease progression in mice injected with pristane, an agent known to induce SLE. FasL is a transmembrane protein with a matrix metalloproteinase (MMP) cleavage site in the ectodomain. MMP cleavage inactivates membrane-bound FasL (mFasL) and releases a soluble form, sFasL, reported to have both antagonist and agonist activity. To better understand the impact of FasL cleavage, we have eliminated the cleavage site through targeted mutation, to produce the ΔCS line. ΔCS mice express more mFasL and fail to make sFasL. Pristane-injected ΔCS mice exhibit a markedly exacerbated disease profile associated with a striking change in ANA specificity, increased proteinuria and kidney pathology, a massive increase in spleen size due to infiltrating granulocytes and macrophages, a bias toward a Th2 response, and a trend towards increased numbers of Th17 T cells, compared to control mice. These results demonstrate that cleavage plays an important role in limiting the pro-inflammatory activity of FasL in the context of pristane-induced autoimmunity.