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: 8745514
• 负责人: Kirk m Druey
• 金额: $ 78.6万
• 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/8745514
• 关键词: 2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole; Actins; Acute; Address; Affect; Amyloidosis; Anaphylaxis; Angioneurotic Edema; Angiopoietin-2; Antigen Targeting; Antihypertensive Agents; Apoptosis; Binding; Biological Assay; Biological Markers; Blood; Blood Cells; Blood Vessels; Blood capillaries; Capillary Leak Syndrome; Cardiac; Cardiovascular system; Clinical; Clinical Protocols; Complement; Development; Diagnosis; Diffuse; Dilated Cardiomyopathy; Disease; Disease remission; Edema; Endothelial Cells; Etiology; Event; Extravasation; Fibrosis; Functional disorder; Gadolinium; Gene Expression Profile; Genetic; Goals; Growth and Development function; Heart Diseases; Hematopoietic; Human; Hypotension; Hypovolemia; Image; Image Enhancement; Immune; Immunoglobulin G; Immunoglobulins; In Vitro; Individual; Intravenous Immunoglobulins; Link; Liquid substance; Magnetic Resonance; Maps; Measurement; Mediator of activation protein; Modality; Modeling; Molecular; Monoclonal gammopathy of uncertain significance; Morbidity - disease rate; Multiple Myeloma; Myocardial; Myocarditis; Nature; Normal Range; Oliguria; Paraproteins; Pathogenesis; Pathology; Patients; Permeability; Plasma; Plasma Cells; Plasmacytic Leukemia; Population; Premalignant; Process; Property; Proteome; Protocols documentation; RNA; Reporting; Research; Sepsis; Serum; Shock; Signs and Symptoms; Source; Stress Fibers; Symptoms; Syndrome; Tissues; United States National Institutes of Health; Vascular Endothelial Growth Factors; Weight; anasarca; angiogenesis; base; cadherin 5; capillary; cell type; chemotherapy; experience; extracellular; gadolinium oxide; genome sequencing; macromolecule; mortality; novel therapeutic intervention

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. 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. 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 35 patients at the NIH clinical center in association with this protocol in the last 4 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. Our principal findings were that application of episodic SCLS sera, but neither the purified immunoglobulin fraction nor sera obtained from patients during remission, to human microvascular endothelial cells caused vascular endothelial cadherin internalization, disruption of interendothelial junctions, actin stress fiber formation, and increased permeability in complementary functional assays without inducing endothelial apoptosis. Intravenous immunoglobulin, one promising therapy for SCLS, mitigated the permeability effects of episodic sera. Consistent with the presence of endogenous, nonimmunoglobulin, circulating permeability factor(s) constrained to SCLS episodes, we found that vascular endothelial growth factor (VEGF) and angiopoietin 2 (Ang2), were elevated in episodic SCLS sera but not in remission sera. Ab-based inhibition of Ang2 counteracted permeability induced by episodic SCLS sera. Our results support a model of SCLS pathogenesis in which nonimmunoglobulin humoral factors such as VEGF and Ang2 contribute to transient endothelial contraction, suggesting a molecular mechanism for this highly lethal disorder. Due to the lack of specific biomarkers, the diagnosis of SCLS is made clinically. We searched for radiographic modalities that could aid in identifying active SCLS. Diffuse myocardial fibrosis, and to a lesser extent global myocardial edema, are difficult to assess or quantify with cardiovascular magnetic resonance (CMR) using conventional late gadolinium enhancement (LGE) or T1-mapping. Measurement of the myocardial extracellular volume fraction (ECV) circumvents factors that confound T1-weighted images or T1-maps. We hypothesized that quantitative assessment of myocardial ECV would be clinically useful for detecting both focal and diffuse myocardial abnormalities in a variety of common and uncommon heart diseases. We found that the mean ECV of 62 normal individuals was 25.4, 2.5% (m, SD), normal range 20.4%-30.4%. Abnormally elevated ECV was identified in 4 of 16 patients with non-ischemic dilated cardiomyopathy (38.1, 1.9%; p<0.001 vs normal). Mean ECV values in other disease entities ranged 32-60% for cardiac amyloidosis (N=4), 40-41% for systemic capillary leak syndrome (N=2), and 39-56% within abnormal regions affected by myocarditis (N=7). This study suggests that ECV mapping appears promising to complement LGE imaging in cases of more homogenously diffuse disease.

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）。 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。 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观察到的病理生理学结果的直接或间接来源。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的血细胞 RNA 转录组和 SCLS 血清/血浆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。在过去 4 年里，我们已经根据该方案对 NIH 临床中心的 35 名患者进行了评估。我们是全球主要的 SCLS 研究转诊中心。 SCLS 中短暂的低血压休克和全身水肿被认为是由可逆性微血管屏障功能障碍引起的。我们的主要发现是，将间歇性 SCLS 血清（但不是纯化的免疫球蛋白组分或从缓解期间患者获得的血清）应用于人微血管内皮细胞，会导致血管内皮钙粘蛋白内化、内皮间连接破坏、肌动蛋白应力纤维形成以及补充功能测定中通透性增加，而不诱导内皮细胞凋亡。静脉注射免疫球蛋白是一种有前途的 SCLS 疗法，可减轻偶发性血清的通透性影响。与 SCLS 发作受限的内源性非免疫球蛋白循环渗透因子的存在相一致，我们发现血管内皮生长因子 (VEGF) 和血管生成素 2 (Ang2) 在发作性 SCLS 血清中升高，但在缓解血清中没有升高。基于抗体的 Ang2 抑制抵消了偶发性 SCLS 血清诱导的通透性。我们的结果支持 SCLS 发病机制模型，其中 VEGF 和 Ang2 等非免疫球蛋白体液因子有助于短暂的内皮收缩，提示了这种高度致命性疾病的分子机制。 由于缺乏特异性的生物标志物，SCLS的诊断是在临床上进行的。我们寻找有助于识别活动性 SCLS 的放射照相方式。弥漫性心肌纤维化以及较小程度的整体心肌水肿很难使用传统的晚期钆增强 (LGE) 或 T1 映射通过心血管磁共振 (CMR) 进行评估或量化。心肌细胞外体积分数 (ECV) 的测量避免了混淆 T1 加权图像或 T1 地图的因素。我们假设心肌 ECV 的定量评估在临床上可用于检测各种常见和不常见心脏病中的局灶性和弥漫性心肌异常。我们发现62名正常人的平均ECV为25.4，2.5%（m，SD），正常范围20.4%-30.4%。 16 名非缺血性扩张型心肌病患者中，有 4 名患者的 ECV 异常升高（38.1，1.9%；与正常相比，p<0.001）。其他疾病实体的平均 ECV 值范围为：心脏淀粉样变性 (N=4) 为 32-60%，全身性毛细血管渗漏综合征 (N=2) 为 40-41%，受心肌炎影响的异常区域为 39-56% (N=7)。这项研究表明，在更均匀弥散性疾病的情况下，ECV 映射似乎有望补充 LGE 成像。