Immune dysregulation may contribute to the pathophysiologic findings seen in SCLS. A monoclonal gammopathy of unknown significance (MGUS, a premalignant precursor to multiple myeloma (MM), in which a clonal plasma cell population secretes monoclonal immunoglobulin (Ig, also referred to as a paraprotein) detectable in patient sera, is present in a majority of SCLS cases. Several patients with SCLS in whom MGUS evolved into 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 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 and/or etiological factors can be identified. We have now evaluated 58 patients with a confirmed diagnosis of SCLS under this protocol in the last 7 years. We are the primary referral center in the U.S. for SCLS. The transient episodes of hypotensive shock and anasarca in SCLS are thought to arise from reversible microvascular barrier dysfunction. Application of episodic but not convalescent SCLS sera to human microvascular endothelial cells (ECs) caused vascular endothelial cadherin internalization, disruption of interendothelial junctions, actin stress fiber formation, and increased permeability in complementary functional assays. EC contraction and temporary attenuation of adherens junctions may thus permit leakage of solutes and proteins into the extravascular space during acute episodes. Circulating permeability factors, vascular endothelial growth factor (VEGF), angiopoietin 2 (Angpt-2), CXCL10, CCL2, and IL-6, were elevated in episodic SCLS sera compared to remission sera. Thus, angiogenic proteins and proinflammatory cytokines that induce EC hyper-permeability may contribute to transient EC barrier dysfunction around SCLS flares. To test the possible contribution of the Angpt2 pathway and/or other permeability inducers to SCLS, we have expanded blood-outgrowth ECs (BOECs) from circulating precursors obtained by venipuncture. These cells possess structural and molecular characteristics of mature ECs. Preliminary results suggest abnormal gene expression patterns in SCLS BOECs compared to those from healthy controls. Current studies are aimed at examined responses of ECs derived from subjects with SCLS and controls to various mediators of permeability to test the hypothesis that the SCLS endothelium is prone to exaggerated responses to otherwise mundane inflammatory stressors. The role of specific gene defects in SCLS, if any, is also unknown; e.g. whether the endothelium is genetically programmed for hyper-responsiveness to routine stimuli. There are no consistent familial aggregations in SCLS. Using Affymetrix Single Nucleotide Polymorphism (SNP) microarrays, we performed the first genome-wide SNP analysis of SCLS in a cohort of 12 disease subjects and 18 controls. From unbiased high-density mapping of single-nucleotide polymorphisms (SNPs), a small genetic interval, 3p25.3, was identified as the highest-ranking candidate susceptibility locus (p 10-6) with an odds ratio of 41. Odds ratios (7-41) and p values (10-4 and 10-6) for the top SCLS-associated variants were outsized for such a small sample size. These results imply high penetrance for a rare disease allele that remains to be identified. An inbred mouse strain was identified (SJL/J), whose phenotype bears similarity to SCLS, including spontaneous vascular hypersensitivity to a variety of permeability factors including histamine (HA), serotonin, and bradykinin, important mediators of endothelial hyperpermeability in humans, and B cell neoplasms characterized by the presence of serum paraproteins. A recessive locus in SJL mice controlling systemic vascular hypersensitivity to HA (Shs) was mapped to an interval on mouse chromosome 6 syntenic with human 3p25.3, which harbors the primary genetic association with SCLS in humans. This interval contains several gene candidates, which will be analyzed in the SCLS cohort and various mouse strains.
| 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 |
| Xie, Zhihui; Chen, Wei-Sheng; Yin, Yuzhi et al. (2018) Adrenomedullin surges are linked to acute episodes of the systemic capillary leak syndrome (Clarkson disease). J Leukoc Biol 103:749-759 |
| Druey, Kirk M; Parikh, Samir M (2017) Idiopathic systemic capillary leak syndrome (Clarkson disease). J Allergy Clin Immunol 140:663-670 |
| Hsu, Peter; Xie, Zhihui; Frith, Katie et al. (2015) Idiopathic systemic capillary leak syndrome in children. Pediatrics 135:e730-5 |
| 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 |
| 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; 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 |
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