Studies on the pathogenesis of Systemic Capillary Leak Syndrome

Systemic Capillary Leak Syndrome (SCLS, Clarkson syndrome) is a rare disorder, characterized by intermittent episodes of severe hypotension and anasarca. Although 80% of SCLS patients have a monoclonal gammopathy of unknown significance (MGUS), its role in disease pathogenesis is unclear. We found elevated levels of cytokines associated with endothelial permeability (VEGF and Ang2) in serum of asymptomatic SCLS patients compared to healthy donors, and levels increased further during acute episodes. We purified monoclonal IgG (“paraprotein”) from the serum of SCLS patients to assess its role in endothelial function. Immunofluorescence demonstrated that SCLS‐associated paraprotein, but not monoclonal IgG from MGUS patients without SCLS or polyclonal IgG from age‐matched healthy donors, bound to quiescent endothelial cell monolayers. SCLS serum (acute or convalescent) failed to induce apoptosis of human microvascular endothelial cells, as assessed by Caspase 3/7 activation, either in the presence or absence of the proapoptotic factor TNF‐alpha. Ongoing studies will determine how paraprotein binding influences endothelial activation and/or permeability, which may lead to new treatment approaches for SCLS.