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

• 批准号: 8336293
• 负责人: Kirk m Druey
• 金额: $ 33.18万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 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/8336293
• 关键词: Actins; Acute; Address; Anaphylaxis; Angiogenic Factor; Angioneurotic Edema; Angiopoietin-2; Antigen Targeting; Apoptosis; B-Lymphocytes; Binding; Biological Markers; Blood Vessels; Blood capillaries; Blood specimen; CD8-Positive T-Lymphocytes; Capillary Leak Syndrome; Case Series; Cells; Clinical; Clinical Protocols; Development; Disease; Disease remission; Edema; Endothelial Cells; Etiology; Event; Extravasation; Goals; Growth and Development function; Hematopoietic; Hypotension; Hypovolemia; IL2RA gene; Immune; Immunoglobulin G; Immunoglobulins; In Vitro; Infiltration; Link; Liquid substance; Mediator of activation protein; Modeling; Molecular; Monoclonal gammopathy of uncertain significance; Morbidity - disease rate; Multiple Myeloma; Nature; Nomenclature; Oliguria; Paraproteins; Pathogenesis; Pathology; Pathway interactions; Patients; Peripheral; Permeability; Phase; Plasma Cells; Plasmacytic Leukemia; Population; Premalignant; Process; Proteome; Protocols documentation; Regimen; Reporting; Research; Sepsis; Serum; Shock; Signs and Symptoms; Skin; Source; Stress Fibers; Symptoms; Syndrome; T-Lymphocyte; Testing; Tissues; United States National Institutes of Health; Vascular Endothelial Growth Factors; Vascular Permeabilities; angiogenesis; cadherin 5; capillary; cell type; chemotherapy; experience; macromolecule; mortality; novel therapeutic intervention; therapeutic target

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. Likewise, increased numbers of circulating CD25+ T cells and peri-capillary infiltration of CD8+ lymphocytes in skin have been noted during acute SCLS attacks. Finally, several patients with SCLS in whom MGUS evolved into frank myeloma or plasma cell leukemia experienced fewer capillary leak episodes after chemotherapy for the hematopoietic disorder. Considered together, 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, possibly through activation of T lymphocytes. 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 proteome of SCLS serum, both pre- and post-attack, to determine whether specific biomarkers of acute symptoms can be identified. We have now evaluated 23 patients to the NIH clinical center under this protocol in the last 2 years. We are now the primary worldwide referral center for research on SCLS. Although the nomenclature of this disorder implies a pathogenic increase in vascular permeability, this hypothesis has not been formally tested, in part due to the rarity of the condition. We performed mechanistic studies using blood samples from 21 patients, the largest SCLS case series to date and found evidence for the pathogenic contribution of circulating angiogenic factors to the clinical symptoms of SCLS. Application of episodic SCLS sera to microvascular endothelial cells caused vascular endothelial cadherin (VE-cadherin) internalization, disruption of cell-cell addherens junctions, and actin stress fiber formation without endothelial apoptosis whereas the sera from the same subjects obtained during remission had no such effects. Levels of permeability mediators vascular endothelial growth factor (VEGF) and Angiopoietin 2 (Ang2) were significantly elevated in SCLS sera during acute episodes but not in asymptomatic periods or healthy control subjects. In a single patient experiencing a severe SCLS crisis, VEGF levels spiked at the beginning of the vascular leak phase followed by a slower rise in Ang2. Both returned to baseline as peripheral edema resolved. Our results support a model of SCLS pathogenesis in which circulating permeability mediators transiently activate endothelial retraction pathways, providing potential therapeutic targets (Ang2 and VEGF) for this highly lethal disorder.

多项证据表明，免疫失调可能导致 SCLS 的病理生理学结果。首先，大多数 SCLS 病例中都存在意义不明的单克隆丙种球蛋白病 (MGUS)。 MGUS 是多发性骨髓瘤 (MM) 的癌前前兆，其中克隆浆细胞群分泌大量可在患者血清中检测到的单克隆免疫球蛋白（Ig，也称为副蛋白）。 同样，在急性 SCLS 发作期间，我们注意到皮肤中循环 CD25+ T 细胞数量增加和 CD8+ 淋巴细胞毛细血管周围浸润。最后，几位 MGUS 演变为骨髓瘤或浆细胞白血病的 SCLS 患者在接受造血障碍化疗后毛细血管渗漏事件减少。 综合考虑，这些发现表明来自失调的浆细胞群的单克隆副蛋白可能是所观察到的病理生理学结果的直接或间接来源，可能是通过 T 淋巴细胞的激活。我们正在通过体外检查单克隆 Ig 在血管病理学发展中的功能来探索 SCLS 的分子机制。使用 SCLS 患者的单克隆 Ig，我们将确定它是否与特定细胞类型、靶抗原（如果有）结合，以及对内皮细胞产生的影响（直接或间接）。我们还对攻击前和攻击后 SCLS 血清的蛋白质组进行了表征，以确定是否可以识别急性症状的特定生物标志物。过去 2 年里，我们已根据该方案对 NIH 临床中心的 23 名患者进行了评估。我们现在是全球主要的 SCLS 研究转诊中心。 尽管这种疾病的命名意味着血管通透性的致病性增加，但这一假设尚未得到正式检验，部分原因是这种情况很罕见。我们使用 21 名患者的血液样本进行了机制研究，这是迄今为止最大的 SCLS 病例系列，并找到了循环血管生成因子对 SCLS 临床症状致病作用的证据。将间歇性 SCLS 血清应用于微血管内皮细胞会引起血管内皮钙粘蛋白 (VE-钙粘蛋白) 内化、细胞-细胞粘附连接破坏和肌动蛋白应力纤维形成，但不会导致内皮细胞凋亡，而在缓解期间获得的同一受试者的血清则没有这种效果。 SCLS 血清中的通透性介质血管内皮生长因子 (VEGF) 和血管生成素 2 (Ang2) 水平在急性发作期间显着升高，但在无症状期或健康对照受试者中没有显着升高。在一名经历严重 SCLS 危机的患者中，VEGF 水平在血管渗漏阶段开始时飙升，随后 Ang2 缓慢上升。随着外周水肿消退，两者均恢复到基线。我们的结果支持 SCLS 发病机制模型，其中循环通透性介质短暂激活内皮回缩通路，为这种高度致命的疾病提供潜在的治疗靶点（Ang2 和 VEGF）。