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Studies in the Pathogenesis of Systemic Capillary Leak Syndrome

全身毛细血管渗漏综合征发病机制的研究

基本信息

批准号：
8946466
负责人：
Kirk m Druey
金额：
$ 61.43万
依托单位：
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8946466
关键词：
2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole 3p25.3 Actins Acute Address Anaphylaxis Angioneurotic Edema Angiopoietin-2 Antigen Targeting Antihypertensive Agents B-Cell Neoplasm Binding Biological Assay Biological Markers Blood Blood Cells Blood Vessels Blood capillaries Bradykinin Candidate Disease Gene Capillary Leak Syndrome Chromosomes, Human, Pair 6 Clinical Clinical Protocols Data Development Disease Disease remission Edema Endothelial Cells Etiology Event Extravasation Functional disorder Gene Expression Profile Generations Genetic Genomic DNA Goals Growth and Development function Hematopoietic Histamine Human Hypersensitivity Hypotension Hypovolemia IL8 gene Immune Immunoglobulin G Immunoglobulins In Vitro Inbred Strains Mice Intravenous Immunoglobulins Link Liquid substance Maps Mass Spectrum Analysis Mediating Mediator of activation protein Molecular Monoclonal gammopathy of uncertain significance Morbidity - disease rate Multiple Myeloma Mus Nature Oliguria Paraproteins Pathogenesis Pathology Patients Permeability Phase Phenotype Plasma Plasma Cells Plasmacytic Leukemia Polymorphism Analysis Population Predisposition Premalignant Process Property Proteins Proteome Protocols documentation RNA Reporting Research Resistance SJL Mouse Sepsis Serotonin Serum Shock Signs and Symptoms Single Nucleotide Polymorphism Source Stress Fibers Symptoms Syndrome Tissues Tumor Necrosis Factor-alpha Two-Dimensional Gel Electrophoresis United States National Institutes of Health Ursidae Family Validation Vascular Endothelial Growth Factors Xenograft Model anasarca angiogenesis base cadherin 5 capillary cell type chemotherapy cohort cytokine exome experience genetic association genome sequencing genome-wide human TNF protein macromolecule mortality novel therapeutic intervention response

项目摘要

Immune dysregulation may contribute to the pathophysiologic findings seen in SCLS. A monoclonal gammopathy of unknown significance (MGUS, which is 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 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. Using 2D gel electrophoresis and mass spectrometry, we have identified proteins that appear to bind to IgG from subjects with SCLS, but not healthy controls. Confirmatory studies of potential paraprotein targets are underway. 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 nearly 40 patients at the NIH clinical center under this protocol in the last 5 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. Application of episodic SCLS sera, but neither the purified immunoglobulin fraction nor sera obtained from patients during remission, to normal human microvascular endothelial cells caused vascular endothelial cadherin internalization, disruption of interendothelial junctions, actin stress fiber formation, and increased permeability in complementary functional assays. Circulating permeability factors, vascular endothelial growth factor (VEGF) and angiopoietin 2 (Ang2), were elevated in episodic SCLS sera but not in remission sera. These results suggest that humoral factors such as VEGF and Ang2 contribute to transient endothelial contraction in SCLS, suggesting a molecular mechanism for this highly lethal disorder. Current studies are aimed at examined responses of endothelial cells derived from subjects with SCLS and controls to permeability mediators. In FY 2014, we characterized a subject with atypical disease features using detailed mechanistic studies. Microvascular barrier function assays corroborated our atypical patient's clinical resistance to IVIG and suggested that his episodes were driven by acute phase cytokines IL-8 and TNF-alpha. Thus, our data suggest that SCLS may have clinically varying forms of presentation and that within the group of patients with SCLS, different cytokines may mediate capillary leak. In FY 2014, 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. Exome capture sequencing was performed on genomic DNA from nine of these patients as validation for the SNP-chip discoveries and de novo data generation. We identified candidate susceptibility loci for SCLS. 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.

免疫失调可能导致scs的病理生理表现。未知意义单克隆γ病变（MGUS）是多发性骨髓瘤（MM）的恶性前体细胞，其中克隆浆细胞群分泌单克隆免疫球蛋白（Ig，也称为副蛋白），在患者血清中可检测到，存在于大多数scs病例中。一些MGUS演变为直率骨髓瘤或浆细胞白血病的scs患者在化疗后的毛细血管泄漏事件较少。这些发现表明，来自失调浆细胞群的单克隆副蛋白可能是观察到的病理生理结果的直接或间接来源。