In SCLS patients, heightened endothelial permeability and plasma extravasation follows a typical prodrome of generalized weakness, fatigue, and myalgias. The most typical presenting signs are the triad of hypotension, hemoconcentration, and hypoalbuminemia. In severe cases, patients may develop generalized edema of the extremities, pleural and pericardial effusions, laryngeal edema with airway obstruction, and even macular edema leading to blindness. Research studies into SCLS etiology are extremely limited due to the rarity of clinical cases. Immune dysregulation may have a function in disease pathogenesis. Although one postmortem examination of SCLS skin identified basement membrane thickening and infiltration of CD8+CD25+ lymphocytes surrounding endothelial cells in the dermis, skin biopsies taken from several other SCLS patients were histologically normal by light and electron microscopy. Most serum analytes are within the normal range in SCLS patients including complement and C1 esterase inhibitor levels. Nonetheless, a circulating factor could play a role in eliciting attacks. In 1960, Clarkson reported that infusion of plasma from an SCLS patient taken during an episode induced hypotension in rats. However, in a subsequent study done in 1977, injection of patient serum or plasma obtained either during remission or from an acute episode into guinea pig skin or the patients own skin failed to evoke capillary permeability.Whether the monoclonal paraproteins present in SCLS contribute directly to disease pathogenesis is also unclear. Indirect immunofluoresence performed on a skin biopsy from several patients did not reveal IgG complexes on endothelial basement membranes. In a subsequent study, purified monoclonal paraprotein from 4 SCLS patients failed to bind cultured endothelial cells or induce cytotoxicity. Most recently, it was shown that exposure of healthy control cultured microvascular endothelial cells to SCLS serum induced apoptosis, which was associated with increased quantities of reactive oxygen species. There is no clearly effective therapy for acute episodes of SCLS. Corticosteroids, intravenous immunoglobulin (IV Ig), plasmapheresis, and other immunosuppressive agents have been used with variable success. Nor is there efficacious maintenance therapy to prevent leak episodes from occurring. Anecdotal and small case series reports suggest that phosphodiesterase inhibitors such as theophylline in combination with beta-adrenergic agonists (terbutaline) may reduce episode frequency and severity in some patients. However, the chronic use of these drugs may be limited by sympathomimetic side effects. Interestingly, several patients with SCLS in which the MGUS evolved into multiple myeloma saw abatement of their leak symptoms after treatment of the plasma cell malignancy, suggesting a role of the plasma cell dyscrasia in disease pathogenesis. We are investigating the possibility that the monoclonal paraprotein triggers acute capillary leak by an immune (autoimmune or anti-idiotypic) mechanism. Anti-idiotype responses are common in MGUS. One possibility is that the paraprotein may activate lymphocytes or other cells to secrete permeability factors such as VEGF or angiopoietin 2. High plasma VEGF levels are thought to contribute to pathology in another MGUS-related disorder (POEMS), and high circulating levels of Ang2 have been linked to cytokine-induced vascular leak. Alternatively, the source of permeability-inducing factor(s) may be the acquired clonal population of plasma cells or B cells. These hypotheses will be tested initially by purification of the monoclonal paraprotein and stimulation of peripheral blood mononuclear cells. We will initially examine proliferation, expression of surface markers by flow cytometry, and cytokine production or gene expression. To further characterize potential genetic abnormalities associated with SCLS, we will first perform cytogenetics and SNP microarray analysis. These arrays will determine whether macroscopic genetic abnormalities or genomic hot spots are present by searching for entities such as loss of heterozygosity (LOH) and copy number variation. Once we accumulate samples from several SCLS patients, we will also perform gene expression microarrays using peripheral blood mononuclear cell RNA. Baseline patient samples will be compared to specimens obtained during an SCLS attack and to healthy, age-matched controls. Finally, we will determine how blood vessel growth and mature endothelial cell function compare in SCLS patients and healthy controls. Two distinct populations of circulating endothelial cells (CECs) can be detected in peripheral blood by surface marker analysis: 1) mature endothelial cells sloughed from microvasculature (CD34+/−CD133−CD31+VEGFR2+) and 2) bone marrow-derived endothelial progenitor cells (EPCs) (CD34+CD133+VEGFR2+). In collaboration with Dr. Dudek, we will enumerate EPCs in peripheral blood from SCLS patients and evaluate the function of the more differentiated cells by deriving blood-outgrowth endothelial cells (BOEC) from EPCs. We will assess their proliferative capacity and measure permeability and apoptotic responses to serum and/or specific factors. We will also use these cells to evaluate how endothelial signaling pathways and gene expression patterns differ in SCLS and healthy patients. Eventually, such studies may identify new therapeutic targets for SCLS, and BOEC will provide a platform to test the ability of various compounds to prevent endothelial barrier dysfunction.

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Druey, Kirk M; Arai, Andrew E; Parikh, Samir M (2018) Reply. J Allergy Clin Immunol 141:1540-1541
Bøe, Ole Wilhelm; Sveen, Kjell; Børset, Magne et al. (2018) Raised Serum Levels of Syndecan-1 (CD138), in a Case of Acute Idiopathic Systemic Capillary Leak Syndrome (SCLS) (Clarkson's Disease). Am J Case Rep 19:176-182
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