Pathogenesis of Physical Urticaria Syndromes

荨麻疹是一种常见的皮肤病，涉及肥大细胞的激活和脱颗粒。荨麻疹根据其慢性化程度分为急性和慢性两种。它可能是自发发生的，也可能是暴露在身体因素下发生的。在后一种情况下，荨麻疹被归类为物理性荨麻疹。机械性和外加性压力、运动或暴露在寒冷、高温、阳光、水或振动下都可能导致生理性的荨麻疹。一般情况下，生理性荨麻疹的病理基础尚不清楚，这些疾病的遗传学基础尚未阐明。 该方案的目的是为了更好地了解如何控制荨麻疹炎症，并探索肥大细胞脱颗粒在人体组织中的后果，从而研究肥大细胞依赖的物理性荨麻疹的致病机制。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。采集血液样本用于研究疾病过程中涉及的分子和遗传途径。在临床上出现麻风症状后，采集更多的血液样本，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。皮肤活检是在挑战测试之前和之后获得的，这些测试被分析为生化和组织学标记。 自2009年开始治疗体理性荨麻疹以来，我们已经招募了超过112名患者和19名健康受试者。所有患者都根据他们的病史安全地接受了挑战测试。已收集和储存血液样本和皮肤活检，以便进行生化、分子和适当情况下的遗传分析。皮肤活检证实肥大细胞脱颗粒。大多数患者对寒性、胆碱能、皮肤刺激性、日光性或振动性荨麻疹呈激发阳性。 与对照受试者相比，我们研究了7名寒性荨麻疹患者在冷刺激后皮肤中肥大细胞依赖性血管反应的特征。采用激光散斑对比成像、红外和偏振光比色法同时测定冷激发后和抗组胺治疗后患者基线时的温度、血流和颜色变化。肥大细胞脱颗粒的证据是通过血清组胺水平的升高和挑战后荨麻疹活检组织中类胰蛋白酶的局部释放而建立的。我们发现伴随肥大细胞脱颗粒的血管反应迅速而广泛。在组织水平上，它的特点是血流增加，体温升高，血管扩张，侧支循环恢复。这些血管反应可以通过给予抗组胺药物来改变。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可以进一步深入了解急性炎症反应的演变，并为评估治疗干预的有效性提供了一种独特的方法。这些结果发表在《公共科学图书馆·综合》(PLOS One)(2013)上，发表在一项题为《初级接触性荨麻疹患者对冷浸泡的急性反应与肥大细胞依赖性血管改变相关的研究》中。 最近，在一项前瞻性调查中，我们对76名在这项研究中被推荐进行体理性荨麻疹挑战测试的受试者进行了调查，探讨了体理性荨麻疹病史和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，其中大多数都在服药，并显著改变了他们的生活方式，以避免反应。我们发现，在76名患者中，38%的患者对目前的诊断是挑战阴性，28%的患者对所有进行的挑战测试都是阴性的。这些发现通常令患者相当惊讶，并使阴性挑战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，停止药物治疗并恢复正常活动。大多数患者(76名患者中的57名)在最初评估一年后进行了重新评估，并保持不变。他们指出，在最初对挑战呈阴性的19名患者中，所有患者都保持阴性。这些结果支持了在有物理风疹病史的患者中进行激发试验的巨大价值和可重复性。在最初挑战试验呈阳性的38名患者中，4名患者(11%)症状得到缓解。这些发现突出了对有物理诱导性荨麻疹病史的患者进行客观检测的价值，以准确评估疾病状况和治疗。这项题为“一组生理性荨麻疹患者的病史与挑战之间的关系”的研究，发表在“J过敏性临床免疫实践”杂志上。

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.