Allergenicity resulting from functional mimicry of the TLR complex

描述(由申请人提供)：过敏被认为是由于对无处不在的，否则无害的环境蛋白的不适应，Th2极化的免疫反应引起的。虽然如此靶向的蛋白质只占人类接触的蛋白质的一小部分，但过敏性是一种相当常见的现象--相同的蛋白质通常在整个人类群体中表现为过敏原。为什么特定的蛋白质倾向于在易感宿主中作为过敏原，这是一个基本的机制问题，在很大程度上仍然没有答案。屋尘螨的主要变应原Der p 2与TLR4信号复合体的脂多糖结合组分MD-2具有结构上的同源性。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TLR4复合体的直接相互作用促进信号传递，并在没有MD-2的情况下重组内毒素驱动的TLR4信号；(B)Der p 2促进初级抗原提呈细胞中的LPS信号转导，无论是否存在MD-2；以及(C)Der p 2的体内致敏活性反映了其体外功能和生化活性：Der p 2以TLR4依赖的方式有效地推动体内的气道Th2炎症，并在没有MD-2的情况下保持这一能力。这些数据表明，由于其自身的佐剂特性，Der p 2往往是适应性免疫反应的靶点。MD-2脂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%的已定义主要过敏原是脂结合蛋白，这一事实表明，这些蛋白及其伴随的脂类的内在佐剂活性可能具有一些共性，作为过敏性现象的基础机制。支持这一建议的基本假设是，TLR复合体蛋白在生物学上的重要功能模仿是Der p 2及其相关ML家族蛋白的佐剂和过敏性的基础。这项研究计划的长期目标是利用分子发病机制方面的知识来设计治疗过敏性疾病的新方法。该方案中的研究将确定实验性过敏性哮喘中Der p 2驱动的TLR4信号的分子和细胞机制以及生物学后果，确定Der p 2激活TLR4的分子要求，并基于TLR复合体的功能模仿确定作为ML结构域家族成员的其他主要变应原是否表现出自佐剂和过敏性。 与公共卫生的相关性：近几十年来，发达国家哮喘等过敏性疾病的患病率和严重程度急剧增加。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发展很可能取决于对疾病发病机制的更好的分子理解。为什么特定的蛋白质倾向于在易感宿主中作为过敏原，这是一个基本的问题，在很大程度上仍然没有答案。我们的数据表明，Toll样受体(TLR)复合体蛋白在生物学上具有重要的功能模拟作用，这是Der p 2的佐剂性和过敏性的基础，Der p 2是一种主要的屋尘变应原。相关蛋白是主要过敏原，更广泛地说，超过50%的已定义主要过敏原是脂结合蛋白，这一事实表明，这些蛋白及其伴随的脂类物质的内在佐剂活性可能具有一些共性，作为过敏性现象的基础机制。这项研究计划的长期目标是利用分子发病机制方面的知识来设计治疗过敏性疾病的新方法。该方案中的研究将确定实验性过敏性哮喘中Der p 2驱动的TLR信号的分子和细胞机制以及生物学后果，确定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。

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.