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，涉及肥大细胞激活和脱粒。荨麻疹根据其慢性性分类为急性和慢性形式。它可能是自发发生的，也可能是暴露于物理因素时。在后一种情况下，荨麻疹被归类为物理荨麻疹。物理荨麻疹可以通过机械和施加的压力，运动或暴露于冷，热，太阳，水或振动中引起。 一般来说，物理荨麻疹的病理基础尚不清楚，这些疾病的遗传基础尚未得到阐明。 该方案的目的是研究物理荨麻疹的肥大细胞依赖性致病机制，既可以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，成人和小儿患者接受标准挑战测试以验证其荨麻疹。 获得血液样本以研究疾病过程中涉及的分子和遗传途径。 临床诱导荨麻疹表现后，收集了其他血液样本，以确定参与发病机理的可溶性介质。在挑战测试期间进行摄影成像研究。皮肤活检是在分析生化和组织学标志物的挑战测试之前和之后进行的。 自2009年物理荨麻疹方案成立以来，我们已经招募了112多名患者和19名健康受试者。所有患者都根据其病史安全地进行了挑战测试。已经收集并存储了血液样本和皮肤活检，以用于生化，分子，并在适用的情况下进行遗传分析。通过皮肤活检证实了肥大细胞脱粒。大多数患者对冷诱导的，胆碱能，皮肤病学，太阳能或振动性荨麻疹的挑战是正面的。 与对照组相比，我们已经表征了七个冷诱导荨麻疹患者的肥大刺激后皮肤中肥大细胞依赖的血管反应。激光螺旋对比度成像，红外和极化的比色法被用来同时确定基线挑战后基线患者的温度，血流和颜色模式，同时用抗组胺药治疗。 通过升高血清组胺水平的升高和挑战后巡回巡回式活检中胰蛋白酶的局部释放来确定肥大细胞脱粒的证据。 我们发现伴随肥大细胞脱粒的血管反应是快速而广泛的。在组织水平上，它的特征是血液流动增加，热变暖，血管舒张和累积循环的募集。这些血管反应通过抗组胺药的给药来改变。我们得出的结论是，监测与肥大细胞脱粒有关的组织内的血管反应提供了对急性炎症反应的演变的更多见解，并提供了一种评估治疗干预效果的独特方法。 这些结果在PLOS One（2013）中发表在一项题为“肥大细胞依赖于肥大细胞的血管变化与对原发性接触荨麻疹中冷浸泡有关的急性反应相关的血管变化”。 最近，在对本研究中提到的物理荨麻疹挑战测试的76名受试者的一项前瞻性调查中，我们探讨了物理荨麻疹病史与挑战测试结果之间的一致性。总共对这些患者进行了294次挑战测试，其中大多数是在药物上进行的，并大大改变了其生活方式以避免反应。我们发现，在76名患者中，有38％的挑战是对诊断的负面挑战，发现28％的患者对所进行的所有挑战测试均为阴性。 这些发现通常使患者令人惊讶，并使在负面挑战组中的患者能够减少药物使用的使用，在某些情况下，通过适当的监测，停止药物并恢复正常活动。大多数患者（76例中的57例）在初步评估后一年重新评估，并且没有变化，并指出最初对挑战的19例患者中，所有患者均为阴性。 这些结果支持具有身体荨麻疹病史的患者挑战测试的巨大价值和可重复性。在最初对挑战测试呈阳性的38例患者中，有4例患者（11％）可以解决症状。这些发现突出了物体诱发荨麻疹病史的患者中客观测试的价值，以便准确评估疾病状态和治疗。 这项研究名为“在物理荨麻疹患者中的历史与挑战之间的分离”，在J Allergy Clin Immunol实践中。