Pathogenesis and Treatment of Atopic Dermatitis

特应性皮炎的发病机制和治疗

• 批准号: 9566708
• 负责人: Joshua Milner
• 金额: $ 65.49万
• 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/9566708
• 关键词: Acute; Affect; Aftercare; Allergic; Allergic inflammation; Anaphylaxis; Atopic Dermatitis; Biological Assay; Biological Markers; Biopsy; Collaborations; Comorbidity; Defect; Dermatitis; Development; Disease; Disease susceptibility; Eczema; Enrollment; Failure; Family; Food Hypersensitivity; GATA3 gene; Genetic; Glutamine; Goals; Hereditary Disease; Human; Hypersensitivity skin testing; IgE; Immune; Immunologic Deficiency Syndromes; In Vitro; Individual; Infection; Instruction; Journals; Knockout Mice; Measurement; Measures; Morphine; Mus; Mutation; NF-kappa B; Nature; Pathogenesis; Pathway interactions; Patients; Phenotype; Protocols documentation; Publishing; Recruitment Activity; Regulatory T-Lymphocyte; Role; STAT3 gene; Series; Signal Transduction; Skin; Snow; Specificity; Supplementation; Syndrome; T-Lymphocyte; Time; Wiskott-Aldrich Syndrome; Work; atopy; clinical investigation; cohort; mast cell; medical schools; microbiome; prevent; response; screening; transcription factor

The main protocol for this project is in active recruitment and accrual stages now. We continue to enroll a cohort of patients with severe atopic dermatitis (AD) alone, and those with AD in the context of immune deficiency. We have a substantial cohort of patients with genetic disorders, which include atopy as a part of the syndrome (now numbering over 400 patients total). The main findings that have occurred in this project within the past year are described in detail below. Finding 1: Severe atopic dermatitis in the absence of other syndromic features can be difficult to explain pathophysiologically. In collaboration with Erwin Gelfand, NJH, Andy Snow, USUHS and others, we identified heterozygous, hypomorphic, dominant interfering CARD11 mutations in four unrelated families with severe atopic dermatitis, with and without comorbid conditions including infection. Furthermore, we found that the mutations affected the NFKB pathway, as expected, but also the mTORC1 pathway, whose control is critical for preventing Th2 responses. Furthermore, addition of glutamine, thought to be critical for mTORC1 activation and reliant upon CARD11 for import, appeared to partially rescue a number of cellular phenotypes. The results suggest that there could be a monogenic cause for severe atopic dermatitis, and that this pathway may be a modifiable cause. A trial of glutamine supplementation in these patients is now in development. These findings were published in Nature Genetics Finding 2: Wiskott-Aldrich Syndrome (WAS) is known to be associated with atopic dermatitis and high IgE, but atopic disease had not been quantified in WAS. Further, the mechanistic work contributing to this allergic diathesis had not been performed at any detailed level. In collaboration with Scott Snapper and Edda Fiebiger, Harvard Medical School, we found that WAS patients have a marked increase in food allergy, on top of their eczema. Their rates of allergic sensitization were even higher. Despite that, anaphylaxis was not seen, and, similar to STAT3LOF patients, morphine skin testing of these patients suggested a blunted response, consistent with a failure of normal mast cell activation-- which had been demonstrated in WASP null mice previously. Consistent with that, we found that deletion of WASP in Tregs alone was sufficient to induce the allergic phenotype, in fact more severe than the systemic loss of WASP, likely due to the fact that mast cells were able to fully exert their effect function. We showed that the Treg defect was recapitulated in humans, in that GATA3 expression-- a key Th2 transcription factor usually suppressed in Tregs, was elevated in both mouse and human Tregs. These findings were published in the Journal of Clinical Investigation.

该项目的主要协议是现在积极招聘和应计阶段。我们将继续仅招募一群患有严重特应性皮炎（AD）的患者，而在免疫缺陷的背景下患有AD的患者。我们有大量的遗传疾病患者队列，其中包括特应性是综合征的一部分（现在总计400例患者）。在过去一年中，该项目中发生的主要发现将在下面进行详细描述。 发现1：在没有其他综合征特征的情况下，严重的特应性皮炎可能很难在病理生理上解释。在与Erwin Gelfand，NJH，Andy Snow，Usuhs等人的合作中，我们确定了四个不相关的严重特征性性感性皮炎，有和没有合并症的杂合，造型，主要的干扰Card11突变，包括感染包括感染。此外，我们发现突变会如预期的那样影响NFKB途径，也影响了MTORC1途径，其控制对于防止TH2响应至关重要。此外，添加谷氨酰胺，被认为对MTORC1激活至关重要，并且依靠Card11进口，似乎部分营救了许多细胞表型。结果表明，可能会导致严重特应性皮炎的原因，并且该途径可能是可修改的原因。这些患者中补充谷氨酰胺的试验正在发育中。这些发现在自然遗传学中发表 查找2： 已知Wiskott-Aldrich综合征（WAS）与特应性皮炎和高IgE有关，但尚未量化特应性疾病。此外，尚未在任何详细的水平上进行促成这种过敏性素质的机械工作。与哈佛医学院的Scott Snapper和Edda Fiebiger合作，我们发现患者在湿疹之外的食物过敏显着增加。他们的过敏敏化率甚至更高。尽管如此，没有看到过敏反应，并且与Stat3LOF患者相似，这些患者的吗啡皮肤测试表明，钝化反应，与正常肥大细胞激活的失败一致 - 先前已经在黄蜂无效的小鼠中证明了这一点。与此一致，我们发现单独的Treg中的黄蜂的缺失足以诱导过敏表型，实际上比WASP的全身性损失更为严重，这可能是由于肥大细胞能够完全发挥其作用功能。我们表明，在人类中概括了Treg缺陷，因为GATA3表达 - 在小鼠和人treg中，通常抑制了Tregs中通常抑制的关键Th2转录因子。这些发现发表在《临床研究杂志》上。