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.

一些证据表明，免疫失调可能有助于在SCLS中观察到的病理生理学结果。首先，意义不明的单克隆丙种球蛋白病（MGUS）存在于大多数SCLS病例中。 MGUS是多发性骨髓瘤（MM）的癌前前病变，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）。 几名MGUS演变为明显骨髓瘤或浆细胞白血病的SCLS患者在化疗后发生的毛细血管渗漏事件较少。 这些结果表明，从失调的浆细胞群的单克隆副蛋白可能是直接或间接的来源观察到的病理生理学结果。我们正在通过检测单克隆IG在体外血管病理学发展中的作用来探索SCLS的分子机制。使用SCLS患者的单克隆IG，我们将确定其是否与特定细胞类型、靶抗原（如果有）结合，以及对内皮细胞的影响（直接或间接）。我们还表征了血细胞RNA的转录组和SCLS血清/血浆的蛋白质组，包括发作前和发作后，以确定是否可以识别急性症状的特定生物标志物。在过去的4年里，我们已经在NIH临床中心评估了35例与该方案相关的患者。我们是SCLS研究的主要全球转诊中心。 SCLS中短暂发作的水肿性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。我们的主要研究结果是，在不诱导内皮细胞凋亡的情况下，将发作性SCLS血清应用于人微血管内皮细胞引起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和渗透性增加。静脉注射免疫球蛋白，SCLS的一个有前途的治疗，减轻了发作性血清的渗透性影响。与SCLS发作中存在的内源性、非免疫球蛋白、循环通透性因子一致，我们发现血管内皮生长因子（VEGF）和血管生成素2（Ang 2）在SCLS发作血清中升高，但在缓解血清中不升高。基于Ab的Ang 2抑制抵消了由偶发性SCLS血清诱导的渗透性。我们的研究结果支持SCLS发病机制的模型，其中非免疫球蛋白体液因子，如VEGF和Ang 2有助于短暂的内皮收缩，这表明这种高致死性疾病的分子机制。 由于缺乏特异性生物标志物，SCLS的诊断是临床上做出的。我们寻找有助于识别活动性SCLS的影像学方法。弥漫性心肌纤维化，以及较小程度的整体心肌水肿，难以使用常规晚期钆增强（LGE）或T1标测进行心血管磁共振（CMR）评估或量化。心肌细胞外容积分数（ECV）的测量避免了混淆T1加权图像或T1图的因素。我们假设，心肌ECV的定量评估将是临床上有用的检测局灶性和弥漫性心肌异常的各种常见和不常见的心脏病。62例正常人ECV平均值为25.4，2.5%（m，SD），正常范围20.4%~ 30.4%。16例非缺血性扩张型心肌病患者中有4例ECV异常升高（38.1，1.9%; p<0.001 vs正常）。其他疾病实体的平均ECV值范围为：心脏淀粉样变性32-60%（N=4），全身毛细血管渗漏综合征40-41%（N=2），心肌炎影响的异常区域39-56%（N=7）。这项研究表明，ECV映射似乎有希望补充LGE成像的情况下，更均匀的弥漫性疾病。