Studies in the Pathogenesis of Systemic Capillary Leak Syndrome

几条线索的证据表明，免疫失调可能有助于在scs中看到的病理生理结果。首先，在大多数scs病例中存在一种未知意义的单克隆γ病（MGUS）。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大量单克隆免疫球蛋白（Ig，也称为副蛋白），可在患者血清中检测到。此外，在一些患者的急性scs发作期间，循环CD25+ T细胞数量增加，皮肤中CD8+淋巴细胞浸润。最后，一些MGUS演变为直率骨髓瘤或浆细胞白血病的scs患者在造血系统疾病化疗后毛细血管泄漏事件较少。综合考虑，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，可能通过T淋巴细胞的激活。我们正在通过检测单克隆Ig在体外血管病理发展中的功能来探索SCLS的分子机制。使用来自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（如果有的话）结合，以及对内皮细胞的直接或间接影响。我们还对发作前和发作后scs血清/血浆的血细胞RNA转录组和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。在过去的三年里，我们已经在NIH临床中心评估了32名与该方案相关的患者。我们是scs研究的主要全球转诊中心。

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. Additionally, increased numbers of circulating CD25+ T cells and peri-capillary infiltration of CD8+ lymphocytes in skin have been noted during acute SCLS attacks in a few patients. 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 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 32 patients at the NIH clinical center in association with this protocol in the last 3 years. We are 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. While the high prevalence of MGUS in SCLS suggests a pathogenic contribution of endogenous Igs, the mechanisms of vascular hyperpermeability remain obscure. We compiled clinical parameters and studied biomaterial from 23 subjects, the largest SCLS case series to date. Application of episodic SCLS sera, but neither the purified Ig fraction nor sera obtained from subjects during remission, to human microvascular endothelial cells caused vascular endothelial cadherin (VE-cadherin) internalization, disruption of inter-endothelial junctions, actin stress fiber formation, and increased permeability in complementary functional assays without inducing endothelial apoptosis. IVIG, one promising therapy for SCLS, mitigated the permeability effects of episodic sera directly. Consistent with the presence of endogenous, non-Ig, circulating permeability factor(s) constrained to SCLS episodes, we found that two such proteins, vascular endothelial growth factor (VEGF) and angiopoietin 2 (Ang2), were elevated in episodic SCLS sera but not in remission sera. Antibody-based inhibition of Ang2 counteracted permeability induced by episodic SCLS sera. Comparable experiments with anti-VEGF antibody (bevacizumab) yielded less interpretable results, likely due to endothelial toxicity of VEGF withdrawal.