Studies in the Pathogenesis of Systemic Capillary Leak Syndrome

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications, trials & patents

Abstract

Immune dysregulation may contribute to the pathophysiologic findings seen in SCLS. A MGUS, a premalignant precursor to multiple myeloma (MM), is a condition characterized by a clonal plasma cell population that secretes monoclonal immunoglobulins (Ig, also referred to as a paraprotein). MGUS is detectable 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. Current studies are focused on identifying the target antigen of SCLS monoclonal Ig, if any, using high-throughput protein arrays. 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 SCLS symptoms and/or etiological factors can be identified. We have now evaluated more than 75 patients with a confirmed diagnosis of SCLS under this protocol in the last 12 years. We are the primary referral center in the U.S. for SCLS. 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. These findings suggest that angiogenic proteins and proinflammatory cytokines that induce endothelial cell (EC) hyper-permeability may contribute to transient EC barrier dysfunction around SCLS flares. 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 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. In fiscal year 21, we continued to study mechanisms underlying the discovery that the skin microvasculature and endothelial cell lines from SCLS patients are hyper-responsive to routine inflammatory mediators such as VEGF and histamine. Preliminary data suggest that SCLS cells have a primary metabolic abnormality that renders them more susceptible to these mediators. The role of specific gene defects in SCLS, if any, is unknown; e.g. whether the endothelium is genetically programmed for hyper-responsiveness to routine stimuli. There are no consistent familial aggregations in SCLS, and whole exome sequencing of unrelated adults with SCLS and several parent-child trios failed to reveal a uniform exotic etiology. 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. Currently, we are performing whole genome sequencing of DNA from patients to test the hypothesis that they are prone to exaggerated responses to otherwise mundane inflammatory stressors due to underlying genetic defect(s). In FY21, we described clinical flares of SCLS in association with COVID-19. One patient carried an established diagnosis of SCLS and the other sought treatment for new-onset hypotensive shock, hemoconcentration, and anasarca, classic symptoms indicative of an SCLS flare. Both patients had only mild-to-moderate symptoms of COVID-19. This clinical picture suggests that these patients succumbed to complications of SCLS induced by infection with severe acute respiratory syndrome coronavirus 2. Persons with known or suspected SCLS may be at increased risk for developing a disease flare in the setting of mild-to-moderate COVID-19 infection. Second, we described 3 patients who had severe flares of SCLS immediately after receiving standard doses of the COVID-19 vaccines that have emergency use authorization from the U.S. Food and Drug Administration. We believe these patients identify SCLS as a risk factor for the development of serious adverse reactions after COVID-19 vaccination. SCLS is a rare disease, and persons without a diagnosis of SCLS or a history suggestive of SCLS are unlikely to develop a flare after COVID-19 vaccination. However, some persons with unexplained episodes of hypotension and edema may have undiagnosed SCLS. In addition, none of the 3 patients we describe were receiving IVIG prophylaxis when they were vaccinated, and we have received no reports of SCLS flares after COVID-19 (or other antiviral) vaccinations among our 78 patients with SCLS, most of whom are receiving IVIG prophylaxis. Based on these findings, we recommended that patients with a diagnosis or a suspected diagnosis of SCLS should receive IVIG prophylaxis before vaccination. Finally, we entered into a collaboration with PharmAbcine, Inc. to study a monoclonal antibody, PMC-403, which targets the Angpt2 receptor, Tie2. PMC-403 is a novel agonistic antibody that binds to human-Tie2 receptor and promotes stabilization of leaky blood vessels in tumor models in mice. The key findings were presented recently at the American Association of Cancer Research (AACR) meeting 2020, and PMC-403 is expected to enter a phase I clinical trial in 2022. We are investigating PMC-403 in the preclinical mouse model of SCLS and its effects on SCLS ECs to inflammatory mediators in vitro.