Studies in the Pathogenesis of Systemic Capillary Leak Syndrome

National Institute Of Allergy And Infectious Diseases

Investigators

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Abstract

Immune dysregulation may contribute to the pathophysiologic features observed in SCLS. Monoclonal gammopathy of undetermined significance (MGUS), a premalignant precursor of multiple myeloma (MM), is characterized by a clonal plasma cell population that secretes monoclonal immunoglobulins (Ig, or paraproteins). MGUS is detectable in the majority of SCLS cases. Notably, several patients whose MGUS progressed to myeloma or plasma cell leukemia experienced fewer capillary leak episodes after receiving chemotherapy for their hematologic disorder. These findings suggest that the monoclonal paraprotein secreted by the dysregulated plasma cell clone may be a direct or indirect driver of the disease. Current studies are investigating whether SCLS immunoglobulins target a specific antigen, using high-throughput protein arrays. We are also analyzing the blood transcriptome and serum/plasma proteome, both before and after episodes, to identify biomarkers of acute attacks and potential etiologic factors. To date, we have evaluated more than 75 confirmed SCLS patients under this protocol over the past 12 years, making our center the primary U.S. referral site for SCLS. Circulating permeability factors—including vascular endothelial growth factor (VEGF), angiopoietin-2 (Angpt-2), CXCL10, CCL2, and interleukin-6 (IL-6)—were elevated in episodic compared with convalescent SCLS sera. These findings support a role for angiogenic and proinflammatory mediators in transient endothelial barrier dysfunction during acute flares. Transient episodes of hypotensive shock and anasarca in SCLS are believed to arise from reversible microvascular barrier failure. In vitro, episodic (but not remission) SCLS sera applied to human microvascular endothelial cells (ECs) induced internalization of vascular endothelial cadherin, junctional disruption, actin stress fiber formation, and increased permeability. These results indicate that EC contraction and weakening of adherens junctions contribute to the leakage of solutes and proteins into the extravascular space. Recent studies show that skin microvasculature and EC lines derived from SCLS patients are hyper-responsive to routine inflammatory mediators such as VEGF and histamine. Preliminary evidence suggests an underlying metabolic abnormality in SCLS ECs that renders them more susceptible to these signals. The role of genetic defects in SCLS remains uncertain. The disorder does not exhibit consistent familial aggregation, and whole-exome sequencing in unrelated SCLS adults and parent–child trios has not revealed a unifying etiology. However, the first genome-wide single nucleotide polymorphism (SNP) analysis using Affymetrix arrays (12 cases, 18 controls) identified 3p25.3 as the top candidate susceptibility locus (p = 10⁻⁶; odds ratio 41). These unusually high odds ratios (7–41) and significant p-values (10⁻⁴–10⁻⁶), despite small sample size, suggest the presence of a rare, highly penetrant risk allele. Whole-genome sequencing studies are ongoing to test the hypothesis that SCLS patients may have genetic variants that predispose them to exaggerated responses to otherwise routine inflammatory stressors. Building on prior work showing endothelial hyperresponsiveness to VEGF and Angpt-2, we conducted a phosphoproteomic screen in blood outgrowth endothelial cells (BOECs) derived from SCLS patients. Differential phosphorylation was found in proteins including endothelial nitric oxide synthase (eNOS), AMPK, and β-catenin. Increased eNOS activity appeared to drive much of the hyperresponsiveness. Inhibiting eNOS with N(γ)-nitro-l-arginine methyl ester (l-NAME) ameliorated vascular leakage in an SJL/J mouse model of SCLS challenged with histamine or VEGF. These findings highlight a mechanistic basis for microvascular barrier failure and identify eNOS as a potential therapeutic target. In FY25, in collaboration with PharmAbcine, Inc., we studied a novel agonistic monoclonal antibody, 4E2, which binds the Angpt1/2 receptor Tie2. Previously shown to stabilize leaky blood vessels in tumor models, 4E2 also activated Tie2 in SCLS-derived ECs and reduced both baseline and mediator-induced barrier dysfunction. In the SJL/J mouse model, 4E2 lowered mortality and vascular leakage triggered by histamine challenge or influenza infection. These results support the critical role of Tie2 dysregulation in SCLS and demonstrate Tie2 activation as a promising therapeutic avenue for this life-threatening disorder.