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. Several patients with SCLS in whom MGUS evolved into frank myeloma or plasma cell leukemia experienced fewer capillary leak episodes after chemotherapy for their hematopoietic disorder. 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. 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 35 patients at the NIH clinical center in association with this protocol in the last 4 years. We are the primary worldwide referral center for research on SCLS. The transient episodes of hypotensive shock and anasarca in SCLS are thought to arise from reversible microvascular barrier dysfunction. Our principal findings were that application of episodic SCLS sera, but neither the purified immunoglobulin fraction nor sera obtained from patients during remission, to human microvascular endothelial cells caused vascular endothelial cadherin internalization, disruption of interendothelial junctions, actin stress fiber formation, and increased permeability in complementary functional assays without inducing endothelial apoptosis. Intravenous immunoglobulin, one promising therapy for SCLS, mitigated the permeability effects of episodic sera. Consistent with the presence of endogenous, nonimmunoglobulin, circulating permeability factor(s) constrained to SCLS episodes, we found that vascular endothelial growth factor (VEGF) and angiopoietin 2 (Ang2), were elevated in episodic SCLS sera but not in remission sera. Ab-based inhibition of Ang2 counteracted permeability induced by episodic SCLS sera. Our results support a model of SCLS pathogenesis in which nonimmunoglobulin humoral factors such as VEGF and Ang2 contribute to transient endothelial contraction, suggesting a molecular mechanism for this highly lethal disorder. Due to the lack of specific biomarkers, the diagnosis of SCLS is made clinically. We searched for radiographic modalities that could aid in identifying active SCLS. Diffuse myocardial fibrosis, and to a lesser extent global myocardial edema, are difficult to assess or quantify with cardiovascular magnetic resonance (CMR) using conventional late gadolinium enhancement (LGE) or T1-mapping. Measurement of the myocardial extracellular volume fraction (ECV) circumvents factors that confound T1-weighted images or T1-maps. We hypothesized that quantitative assessment of myocardial ECV would be clinically useful for detecting both focal and diffuse myocardial abnormalities in a variety of common and uncommon heart diseases. We found that the mean ECV of 62 normal individuals was 25.4, 2.5% (m, SD), normal range 20.4%-30.4%. Abnormally elevated ECV was identified in 4 of 16 patients with non-ischemic dilated cardiomyopathy (38.1, 1.9%;p<0.001 vs normal). Mean ECV values in other disease entities ranged 32-60% for cardiac amyloidosis (N=4), 40-41% for systemic capillary leak syndrome (N=2), and 39-56% within abnormal regions affected by myocarditis (N=7). This study suggests that ECV mapping appears promising to complement LGE imaging in cases of more homogenously diffuse disease.

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Sek, Albert C; Xie, Zhihui; Terai, Kaoru et al. (2015) Endothelial Expression of Endothelin Receptor A in the Systemic Capillary Leak Syndrome. PLoS One 10:e0133266
Xie, Zhihui; Chan, Eunice C; Long, Lauren M et al. (2015) High-dose intravenous immunoglobulin therapy for systemic capillary leak syndrome (Clarkson disease). Am J Med 128:91-5
Ertel, Andrew; Pratt, Drew; Kellman, Peter et al. (2015) Increased myocardial extracellular volume in active idiopathic systemic capillary leak syndrome. J Cardiovasc Magn Reson 17:76
Hsu, Peter; Xie, Zhihui; Frith, Katie et al. (2015) Idiopathic systemic capillary leak syndrome in children. Pediatrics 135:e730-5
Xie, Zhihui; Ghosh, Chandra C; Parikh, Samir M et al. (2014) Mechanistic classification of the systemic capillary leak syndrome: Clarkson disease. Am J Respir Crit Care Med 189:1145-7
Xie, Zhihui; Chan, Eunice; Yin, Yuzhi et al. (2014) Inflammatory Markers of the Systemic Capillary Leak Syndrome (Clarkson Disease). J Clin Cell Immunol 5:1000213
Xie, Zhihui; Nagarajan, Vijayaraj; Sturdevant, Daniel E et al. (2013) Genome-wide SNP analysis of the Systemic Capillary Leak Syndrome (Clarkson disease). Rare Dis 1:
Kellman, Peter; Wilson, Joel R; Xue, Hui et al. (2012) Extracellular volume fraction mapping in the myocardium, part 2: initial clinical experience. J Cardiovasc Magn Reson 14:64
Xie, Zhihui; Ghosh, Chandra C; Patel, Roshni et al. (2012) Vascular endothelial hyperpermeability induces the clinical symptoms of Clarkson disease (the systemic capillary leak syndrome). Blood 119:4321-32
Druey, Kirk M; Greipp, Philip R (2010) Narrative review: the systemic capillary leak syndrome. Ann Intern Med 153:90-8