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。荨麻疹是根据其慢性分为急性和慢性形式。它可以自发发生或暴露于物理因素。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压力，运动，或暴露于冷，热，阳光，水，或振动引起的。 物理性荨麻疹的病理基础一般仍不清楚，这些疾病的遗传基础尚未阐明。 本方案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的挑战测试，以验证他们的荨麻疹。 获得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，收集额外的血液样品以确定参与发病机制的可溶性介质。在挑战试验期间进行摄影成像研究。在激发试验之前和之后获得皮肤活检，分析其生化和组织学标志物。 自2009年物理荨麻疹方案开始以来，我们已招募了超过112名患者和19名健康受试者。根据病史，所有患者均安全接受了激发试验。已收集并储存了血液样本和皮肤活组织检查，以进行生物化学、分子分析，并在适用时进行遗传分析。肥大细胞脱颗粒通过皮肤活检证实。大多数患者对冷诱导的、胆碱能的、皮肤划痕症、日光性或振动性荨麻疹均呈激发阳性。 我们的特点是肥大细胞依赖的血管反应在皮肤后的冷刺激7例冷诱导荨麻疹与对照组相比。激光散斑对比成像，红外和偏振光比色法被用来同时确定温度，血流和颜色模式的患者在基线后冷挑战，而与抗组胺药治疗。 通过激发后荨麻疹活检中血清组胺水平升高和类胰蛋白酶的局部释放证实了肥大细胞脱粒的证据。 我们发现伴随肥大细胞脱颗粒的血管反应是迅速和广泛的。在组织水平上，其特征在于血流量增加、温度升高、血管舒张和侧支循环募集的均匀模式。这些血管反应可通过服用抗组胺药来改变。我们的结论是，监测与肥大细胞脱颗粒相关的组织内的血管反应提供了对急性炎症反应演变的额外见解，并提供了评估治疗干预有效性的独特方法。 这些结果发表在PLOS One（2013）的一项研究中，标题为“与原发性接触性荨麻疹冷浸急性反应相关的肥大细胞依赖性血管变化”。" 最近，在一项前瞻性调查的76名受试者提到物理性荨麻疹激发试验本研究中，我们探讨了物理性荨麻疹的历史和激发试验结果之间的一致性。共对这些患者进行了294次激发试验，其中大多数患者正在接受药物治疗，并已显著改变了生活方式以避免反应。我们发现，76例患者中有38%的患者对当前诊断呈挑战阴性，28%的患者对所有挑战试验均呈阴性。 这些发现通常令患者感到非常惊讶，并使阴性激发组的患者能够减少药物使用，在某些情况下，在适当的监测下，停止药物并恢复正常活动。大多数患者（76例中的57例）在初次评估后一年进行了重新评估，结果没有变化，注意到在最初对攻毒呈阴性的19例患者中，所有患者均保持阴性。 这些结果支持在有物理性荨麻疹病史的患者中进行激发试验的巨大价值和可重复性。在38名最初对激发试验呈阳性的患者中，4名患者（11%）症状消退。这些发现突出了客观测试的价值，在患者的历史，物理诱导荨麻疹，以准确地评估疾病状态和治疗。 这项研究，题为“分离的历史和挑战之间的一个子集的患者与物理性荨麻疹”，是在新闻杂志过敏临床免疫实践。