Allergenicity resulting from functional mimicry of the TLR complex

TLR 复合体的功能模仿导致过敏性

• 批准号: 8034306
• 负责人: Christopher L Karp
• 金额: $ 37.6万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8034306
• 关键词: Adjuvant; Adjuvanticity; Allergens; Allergic Disease; Antigen-Presenting Cells; Antigens; Asthma; Binding; Binding Proteins; Biochemical; Biological; Complex; Data; Dermatophagoides pteronyssinus antigen p 2; Development; Disease; Exhibits; Exposure to; Extrinsic asthma; Family; Family member; Goals; Histocompatibility Antigens Class II; House Dust Mite Allergens; Human; Hypersensitivity; Hypersensitivity skin testing; Immune response; Immune system; In Vitro; Inflammation; Knowledge; Link; Lipid Binding; Lipids; Lipopolysaccharides; Mites; Molecular; Morbidity - disease rate; Pathogenesis; Patients; Pattern recognition receptor; Play; Population; Prevalence; Prevention approach; Prevention therapy; Preventive; Property; Protein Family; Proteins; Pyroglyphidae; Receptor Activation; Receptor Signaling; Regulation; Research; Role; Sequence Homology; Severities; Signal Transduction; Source; Structure; TLR4 gene; Therapeutic; Toll-like receptors; airborne allergen; base; in vivo; member; microbial; mimicry; mortality; novel; novel strategies; novel therapeutic intervention; programs; protein complex; public health relevance; pyroglyphid; reconstitution

DESCRIPTION (provided by applicant): Allergy is thought to arise from maladaptive, Th2-polarized immune responses to ubiquitous, otherwise innocuous environmental proteins. While the proteins so targeted represent a tiny fraction of the proteins humans are exposed to, allergenicity is a quite public phenomenon-the same proteins typically behave as allergens across the human population. Why particular proteins tend to act as allergens in susceptible hosts is a fundamental mechanistic question that has remained largely unanswered. The major house dust mite allergen, Der p 2, has structural homology with MD-2, the lipopolysaccharide (LPS)-binding component of the TLR4 signaling complex. Our data indicate that: (a) Der p 2 has functional homology with MD-2 as well, facilitating signaling through direct interactions with the TLR4 complex, and reconstituting LPS-driven TLR4 signaling in the absence of MD-2; (b) Der p 2 facilitates LPS signaling in primary antigen presenting cells, with or without MD-2 being present; and (c) the in vivo allergenic activity of Der p 2 mirrors its in vitro functional and biochemical activity: Der p 2 efficiently drives airway Th2 inflammation in vivo in a TLR4- dependent manner, retaining this ability in the absence of MD-2. These data suggest that Der p 2 tends to be targeted by adaptive immune responses because of its auto-adjuvant properties. The fact that other members of the MD-2 lipid-binding domain family are major allergens and, more broadly, that more than 50% of defined major allergens are lipid-binding proteins, suggests that intrinsic adjuvant activity by such proteins and their accompanying lipid cargo may have some generality as a mechanism underlying the phenomenon of allergenicity. The fundamental hypothesis underlying this proposal is that biologically important functional mimicry of TLR complex proteins underlies the adjuvanticity and allergenicity of Der p 2 and related ML family proteins. The long-term goal of this research program is to use mechanistic knowledge about molecular pathogenesis to devise novel therapeutic approaches to allergic disease. The studies in this proposal will determine the molecular and cellular mechanisms, and biological consequences, of Der p 2-driven TLR4 signaling in experimental allergic asthma, define the molecular requirements for TLR4 activation by Der p 2, and determine whether other major allergens that are ML domain family members exhibit auto-adjuvanticity and allergenicity based on functional mimicry of the TLR complex. PUBLIC HEALTH RELEVANCE: The prevalence and severity of allergic diseases such as asthma have undergone dramatic increases in the developed world in recent decades. It is clear that novel approaches to prevention and therapy are desperately needed. The rational development of novel preventive and therapeutic approaches to allergic asthma will likely depend upon a better molecular understanding of disease pathogenesis. Why particular proteins tend to act as allergens in susceptible hosts is a fundamental question that has remained largely unanswered. Our data indicate that biologically important functional mimicry of a Toll-like receptor (TLR) complex protein underlies the adjuvanticity and allergenicity of Der p 2, a major house dust mite allergen. The fact that related proteins are major allergens and, more broadly, that more than 50% of defined major allergens are, like Der p 2, lipid-binding proteins, suggests that intrinsic adjuvant activity by such proteins and their accompanying lipid cargo may have some generality as a mechanism underlying the phenomenon of allergenicity. The long-term goal of this research program is to use mechanistic knowledge about molecular pathogenesis to devise novel therapeutic approaches to allergic disease. The studies in this proposal will determine the molecular and cellular mechanisms, and biological consequences, of Der p 2-driven TLR signaling in experimental allergic asthma, define the molecular requirements for TLR activation by Der p 2, and determine the generality of these findings for other allergens.

描述（由申请人提供）：过敏被认为是由对普遍存在的、否则无害的环境蛋白质的适应不良、Th 2极化免疫应答引起的。虽然这些蛋白质只占人类接触的蛋白质的一小部分，但过敏性是一个相当普遍的现象--在整个人类群体中，同样的蛋白质通常表现为过敏原。为什么特定的蛋白质倾向于在易感宿主中作为过敏原是一个基本的机制问题，在很大程度上仍然没有答案。主要的屋尘螨过敏原Der p 2与MD-2（TLR 4信号传导复合物的脂多糖（LPS）结合组分）具有结构同源性。我们的数据表明：（a）Der p 2也与MD-2具有功能同源性，通过与TLR 4复合物的直接相互作用促进信号传导，并在MD-2不存在的情况下重建LPS驱动的TLR 4信号传导;（B）Der p 2促进原代抗原呈递细胞中的LPS信号传导，存在或不存在MD-2;和（c）Der p 2的体内变应原活性反映了其体外功能和生物化学活性：Der p 2以TLR 4依赖性方式在体内有效地驱动气道Th 2炎症，在MD-2不存在时保持这种能力。这些数据表明，Der p 2由于其自身佐剂性质而倾向于被适应性免疫应答靶向。MD-2脂质结合结构域家族的其他成员是主要过敏原，更广泛地说，超过50%的定义的主要过敏原是脂质结合蛋白，这一事实表明，这些蛋白质及其伴随的脂质货物的内在佐剂活性可能具有一定的普遍性，作为过敏性现象的基础机制。该提议的基本假设是TLR复合物蛋白的生物学重要功能模拟是Der p 2和相关ML家族蛋白的佐剂性和变应原性的基础。这项研究计划的长期目标是利用分子发病机制的知识，设计新的治疗方法过敏性疾病。本提案中的研究将确定Der p 2驱动的TLR 4信号传导在实验性过敏性哮喘中的分子和细胞机制以及生物学后果，定义Der p 2激活TLR 4的分子要求，并确定作为ML结构域家族成员的其他主要过敏原是否基于TLR复合物的功能模拟表现出自佐剂性和过敏原性。 公共卫生相关性：近几十年来，过敏性疾病如哮喘的患病率和严重程度在发达国家急剧增加。显然，迫切需要新的预防和治疗方法。过敏性哮喘新的预防和治疗方法的合理开发将可能依赖于对疾病发病机制的更好分子理解。为什么特定的蛋白质倾向于在易感宿主中作为过敏原是一个基本的问题，在很大程度上仍然没有答案。我们的数据表明，Toll样受体（TLR）复合物蛋白的生物学重要功能模拟是Der p 2（一种主要的屋尘螨过敏原）的佐剂性和过敏原性的基础。相关蛋白是主要变应原，更广泛地说，超过50%的确定的主要变应原是脂质结合蛋白，如Der p 2，这一事实表明，这些蛋白及其伴随的脂质货物的内在佐剂活性可能具有一定的普遍性，作为变应原性现象的基础机制。这项研究计划的长期目标是利用分子发病机制的知识，设计新的治疗方法过敏性疾病。本提案中的研究将确定实验性过敏性哮喘中Der p 2驱动的TLR信号传导的分子和细胞机制以及生物学后果，定义Der p 2激活TLR的分子要求，并确定这些发现对其他过敏原的普遍性。