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.

几条证据表明，免疫失调可能有助于SCL中看到的病理生理发现。首先，在大多数SCLS病例中存在一个未知意义（MGU）的单克隆性腔（MGU）。 MGUS是多发性骨髓瘤（MM）的前体前体，其中克隆等离子体细胞种群分泌大量的单克隆免疫球蛋白（IG，也称为患者血清中的副蛋白）。 几名患有MGUS的SCL患者在弗兰克（Frank）骨髓瘤或血浆细胞白血病中演变为造血疾病后化学疗法后的毛细血管泄漏事件较少。 这些发现表明，来自失调的血浆细胞群中的单克隆副蛋白可能是观察到的病理生理发现的直接或间接来源。我们正在通过检查单克隆Ig在体外血管病理发展中的功能来探索SCL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结合，靶抗原（如果有）以及对内皮细胞的产生影响（直接或间接）。我们还表征了血细胞RNA的转录组和攻击前和攻击后SCLS血清/血浆的蛋白质组，以确定是否可以鉴定出急性症状的特定生物标志物。在过去的四年中，我们与该方案有关，在NIH临床中心评估了35例患者。我们是SCLS研究的主要全球转诊中心。 SCL中降压冲击和Anasarca的短暂发作被认为是由可逆的微血管屏障功能障碍引起的。我们的主要发现是发作性SCLS血清的应用，但是在缓解期间从患者那里获得的纯净免疫球蛋白部分或从患者那里获得的血清均未引起人体微血管内皮细胞，导致血管内皮钙粘着蛋白内在化，破坏骨质压力纤维纤维形成和录音量的互联网均具有供应量的互联液，并在不弥补的情况下进行了互动式竞争。静脉注射免疫球蛋白是一种有希望的SCL疗法，可降低情节性血清的渗透性作用。与内源性非免疫球蛋白的存在一致，循环的渗透性因子约束在SCLS发作中，我们发现血管内皮生长因子（VEGF）和Angiopoietin 2（Ang2）在情节性SCLS Sera中升高，但在Sera中的缓解率升高。基于AB的抑制ANG2抑制了情节性SCLS血清引起的渗透性。我们的结果支持SCLS发病机理的模型，其中非免疫球蛋白体液因素（例如VEGF和ANG2）有助于短暂的内皮收缩，这表明这种高度致命的疾病具有分子机制。 由于缺乏特定的生物标志物，因此在临床上进行了SCL的诊断。我们搜索了可以帮助识别活跃SCL的放射学方式。弥漫性心肌纤维化，在较小程度上，使用常规的Gadolinium增强（LGE）或T1映射，难以通过心血管磁共振（CMR）评估或量化。心肌外体积分数（ECV）的测量规定了将T1加权图像或T1-MAPS混淆的因素。我们假设对心肌ECV的定量评估对于检测各种常见和罕见心脏病中的局灶性和弥漫性心肌异常在临床上是有用的。我们发现，62个正常人的平均ECV为25.4，2.5％（M，SD），正常范围为20.4％-30.4％。在16例非缺血性扩张性心肌病（38.1，1.9％; p <0.001 vs normal）中，有16例患者中有4例鉴定出异常升高的ECV。其他疾病实体的平均ECV值范围为32-60％（n = 4），全身毛细血管泄漏综合征（n = 2）为40-41％，在受心肌炎影响的异常区域内为39-56％（n = 7）。这项研究表明，在更均匀弥漫性疾病的情况下，ECV映射似乎有望补充LGE成像。