Pathogenesis of Physical Urticaria Syndromes

物理性荨麻疹综合征的发病机制

• 批准号: 8946474
• 负责人: Dean D Metcalfe
• 金额: $ 44.26万
• 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/8946474
• 关键词: Acute; Adult; Amino Acid Sequence; Antihistamines; Ascaridil; Biochemical; Biopsy; Blood Vessels; Blood flow; Blood specimen; Cell Degranulation; Childhood; Chronic; Clinical; Collateral Circulation; Color; Colorimetry; Diagnosis; Disease; Dissociation; Enrollment; Evolution; Exercise; Exposure to; Gene Expression; Genetic; Genetic Polymorphism; Heating; Histamine; Hypersensitivity; Image; Immersion Investigative Technique; Inflammation; Inflammatory Response; Intervention; Investigation; Lasers; Life Style; Mechanics; Mediator of activation protein; Medicine; Molecular; Molecular Genetics; Monitor; Mutation; Pathogenesis; Pathologic; Pathway interactions; Patients; Pattern; Peptide Sequence Determination; Pharmaceutical Preparations; Process; Protocols documentation; Publishing; Reaction; Recording of previous events; Reproducibility; Resolution; Role; Sampling; Serum; Skin; Stimulus; Surveys; Symptoms; Syndrome; Temperature; Testing; The Sun; Tissue Sample; Tissues; Treatment Effectiveness; Tryptase; Urticaria; Vasodilation; Water; base; cholinergic; cytokine; genetic analysis; human tissue; insight; mast cell; polarized light; pressure; prospective; research clinical testing; response; screening; skin disorder; vibration

Urticaria is a common skin disorder involving mast cell activation and degranulation. Urticaria is classified according to its chronicity into acute and chronic forms. It may occur spontaneously or on exposure to a physical factor. In the latter case, the urticaria is classified as a physical urticaria. Physical urticaria may be induced by mechanical and applied pressure, exercise, or exposure to cold, heat, sun, water, or vibration. The pathologic basis of physicial urticarias in general remains unclear and a genetic basis for these disorders has not been elucidated. The purpose of this protocol is to investigate the mast cell dependent pathogenic mechanisms of physical urticaria, both to better understand how to manage urticarial inflammation and to explore the consequences of mast cell degranulation in human tissues. In these studies, adult and pediatric patients undergo standard challenge testing to verify their urticaria. Blood samples are obtained for the investigation of molecular and genetic pathways involved in the disease process. Following the clinical induction of urticarial manifestations, additional blood samples are collected to determine soluble mediators involved in pathogenesis. Photographic imaging studies are performed during challenge testing. Skin biopsies are obtained prior to and following challenge testing that are analyzed for biochemical and histological markers. Since the inception of the physical urticaria protocol in 2009, we have enrolled over 112 patients and 19 healthy subjects. All patients safely underwent challenge testing based on their history. Blood samples and skin biopsies have been collected and stored for biochemical, molecular and, when applicable, genetic analysis. Mast cell degranulation was verified by skin biopsy. The majority of the patients were challenge positive to either cold-induced, cholinergic, dermatographism, solar or vibratory urticaria. We have characterized the mast cell dependent vascular response in skin following a cold stimulus in seven patients with cold-induced urticaria in comparison to control subjects. Laser-speckle contrast imaging, infrared and polarized-light colorimetry were used to simultaneously determine the temperature, blood flow and color patterns in patients at baseline after cold challenge and while treated with antihistamine. Evidence for mast cell degranulation was established by elevation of serum histamine levels and the localized release of tryptase in post-challenge urticarial biopsies. We found that the vascular response accompanying mast cell degranulation is rapid and extensive. At the tissue level, it is characterized by a uniform pattern of increased blood flow, thermal warming, vasodilation, and recruitment of collateral circulation. These vascular responses are modified by the administration of an antihistamine. We concluded that monitoring the vascular responses within tissues that are associated with mast cell degranulation provides additional insight into the evolution of the acute inflammatory response and offers a unique approach to assess the effectiveness of treatment intervention. These results were published in PLOS One (2013) in a study entitled, "Mast cell dependent vascular changes associated with an acute response to cold immersion in primary contact urticaria." Recently, in a prospective survey of 76 subjects referred for physical urticaria challenge testing on this study, we explored the consistency between a history of physical urticaria and results of challenge testing. A total of 294 challenge tests were performed on these patients, most of which were on medications and had altered their life style significantly to avoid reactions. We found that 38% of the 76 patients were challenge negative to the presenting diagnosis and 28% were found to be negative to all challenge testing performed. These findings were generally quite surprising to the patients and enabled those in the negative challenge group to decrease medication use and in some cases, with proper monitoring, to stop medicine and resume normal activities. Most patients (57 of 76) were reevaluated one year after their initial assessment and were unchanged, noting that of the 19 patients that were initially negative to challenge, all remained negative. These results support the great value and reproducibility of challenge testing in patients with a history of a physical urticaria. Of the 38 patients that were initially positive to challenge testing, 4 patients (11%) had resolution of symptoms. These findings highlight the value of objective testing in patients with a history of a physically induced urticaria in order to accurately assess disease status and therapy. This study, entitled "Dissociation Between History and Challenge in a Subset of Patients with Physical Urticarias", is in press in J Allergy Clin Immunol Pract.

荨麻疹是一种常见的皮肤病，涉及肥大细胞活化和脱颗粒。荨麻疹根据其慢性程度分为急性和慢性两种。它可能会自发发生或在暴露于物理因素时发生。在后一种情况下，荨麻疹被归类为物理性荨麻疹。物理性荨麻疹可能是由机械和施加的压力、运动或暴露于冷、热、阳光、水或振动引起的。 一般而言，物理性荨麻疹的病理学基础仍不清楚，这些疾病的遗传基础也尚未阐明。 该协议的目的是研究物理性荨麻疹的肥大细胞依赖性致病机制，以便更好地了解如何管理荨麻疹炎症并探索人体组织中肥大细胞脱粒的后果。 在这些研究中，成人和儿童患者接受标准激发测试来验证他们的荨麻疹。 获取血液样本用于研究疾病过程中涉及的分子和遗传途径。 在临床诱导荨麻疹表现后，收集额外的血样以确定参与发病机制的可溶性介质。在挑战测试期间进行摄影成像研究。在攻击测试之前和之后获得皮肤活检，并分析生化和组织学标记。 自 2009 年物理性荨麻疹方案启动以来，我们已招募了超过 112 名患者和 19 名健康受试者。所有患者根据其病史安全地接受了挑战测试。已收集并储存血液样本和皮肤活组织检查，以进行生化、分子分析以及（适用时）遗传分析。通过皮肤活检证实肥大细胞脱颗粒。大多数患者对寒冷诱发的荨麻疹、胆碱能荨麻疹、皮肤病、日光性荨麻疹或振动性荨麻疹呈挑战阳性。 我们对七名寒冷诱发荨麻疹患者与对照受试者进行寒冷刺激后皮肤中肥大细胞依赖性血管反应的特征进行了比较。使用激光散斑对比成像、红外和偏振光比色法同时测定冷刺激后和接受抗组胺药治疗时患者基线时的体温、血流和颜色模式。 肥大细胞脱颗粒的证据是通过血清组胺水平升高和攻击后荨麻疹活检中类胰蛋白酶的局部释放来确定的。 我们发现伴随肥大细胞脱粒的血管反应是快速且广泛的。在组织水平上，其特征是血流量增加、温度升高、血管舒张和侧支循环募集的统一模式。这些血管反应可以通过服用抗组胺药来改变。我们的结论是，监测与肥大细胞脱粒相关的组织内血管反应可以进一步了解急性炎症反应的演变，并提供一种独特的方法来评估治疗干预的有效性。 这些结果发表在 PLOS One (2013) 的一项研究中，题为“肥大细胞依赖性血管变化与原发性接触性荨麻疹对冷浸的急性反应相关”。 最近，在一项针对本研究中接受物理性荨麻疹激发试验的 76 名受试者的前瞻性调查中，我们探讨了物理性荨麻疹病史与激发试验结果之间的一致性。对这些患者总共进行了 294 次挑战测试，其中大多数患者正在服用药物，并显着改变了生活方式以避免反应。我们发现，76 名患者中有 38% 的诊断结果呈激发阴性，28% 的所有激发测试均呈阴性。 这些发现通常让患者感到非常惊讶，并使阴性攻击组的患者能够减少药物使用，在某些情况下，通过适当的监测，可以停止用药并恢复正常活动。大多数患者（76 名中的 57 名）在初次评估一年后进行了重新评估，结果没有变化，并指出，最初对攻击呈阴性的 19 名患者中，全部仍为阴性。 这些结果支持了对有身体荨麻疹病史的患者进行激发试验的巨大价值和可重复性。在最初挑战测试呈阳性的 38 名患者中，4 名患者 (11%) 症状得到缓解。这些发现强调了对有物理性荨麻疹病史的患者进行客观测试的价值，以便准确评估疾病状态和治疗。 这项研究题为“身体性荨麻疹患者子集的病史与挑战之间的分离”，发表在《J Allergy Clin Immunol Pract》杂志上。