Several lines of evidence suggest that immune dysregulation may contribute to the pathophysiologic findings seen in SCLS. First, a monoclonal gammopathy of unknown significance (MGUS) is present in a majority of SCLS cases. MGUS is a premalignant precursor to multiple myeloma (MM), in which a clonal plasma cell population secretes large amounts of monoclonal immunoglobulin (Ig, also referred to as a paraprotein) detectable in patient sera. Additionally, increased numbers of circulating CD25+ T cells and peri-capillary infiltration of CD8+ lymphocytes in skin have been noted during acute SCLS attacks in a few patients. Finally, several patients with SCLS in whom MGUS evolved into frank myeloma or plasma cell leukemia experienced fewer capillary leak episodes after chemotherapy for the hematopoietic disorder. Considered together, these findings suggest that the monoclonal paraprotein from the dysregulated plasma cell population may be the direct or indirect source of the pathophysiologic findings observed, possibly through activation of T lymphocytes. We are exploring the molecular mechanisms of SCLS by examining the function of the monoclonal Ig in the development of vascular pathology in vitro. Using monoclonal Ig from SCLS patients, we will determine whether it binds to a specific cell type, target antigen (if any), and resulting effect (direct or indirect) on endothelial cells. We are also characterizing the transcriptome of blood cell RNA and the proteome of SCLS serum/plasma, both pre- and post-attack, to determine whether specific biomarkers of acute symptoms can be identified. We have now evaluated 32 patients at the NIH clinical center in association with this protocol in the last 3 years. We are the primary worldwide referral center for research on SCLS. Although the nomenclature of this disorder implies a pathogenic increase in vascular permeability, this hypothesis has not been formally tested, in part due to the rarity of the condition. While the high prevalence of MGUS in SCLS suggests a pathogenic contribution of endogenous Igs, the mechanisms of vascular hyperpermeability remain obscure. We compiled clinical parameters and studied biomaterial from 23 subjects, the largest SCLS case series to date. Application of episodic SCLS sera, but neither the purified Ig fraction nor sera obtained from subjects during remission, to human microvascular endothelial cells caused vascular endothelial cadherin (VE-cadherin) internalization, disruption of inter-endothelial junctions, actin stress fiber formation, and increased permeability in complementary functional assays without inducing endothelial apoptosis. IVIG, one promising therapy for SCLS, mitigated the permeability effects of episodic sera directly. Consistent with the presence of endogenous, non-Ig, circulating permeability factor(s) constrained to SCLS episodes, we found that two such proteins, vascular endothelial growth factor (VEGF) and angiopoietin 2 (Ang2), were elevated in episodic SCLS sera but not in remission sera. Antibody-based inhibition of Ang2 counteracted permeability induced by episodic SCLS sera. Comparable experiments with anti-VEGF antibody (bevacizumab) yielded less interpretable results, likely due to endothelial toxicity of VEGF withdrawal.

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