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普遍存在的、无害的环境蛋白质的不适应的、th2极化的免疫反应引起的。虽然如此靶向的蛋白质只代表了人类接触到的蛋白质的一小部分，但过敏原性是一个相当普遍的现象——同样的蛋白质通常在人群中表现为过敏原。为什么特定的蛋白质倾向于在易感宿主中充当过敏原，这是一个基本的机制问题，在很大程度上仍未得到解答。主要的屋尘螨过敏原derp2与TLR4信号复合物的脂多糖（LPS）结合成分MD-2具有结构同源性。我们的数据表明：(a) Der p2与MD-2也具有功能同源性，通过与TLR4复合物的直接相互作用促进信号传导，并在MD-2缺失的情况下重建lps驱动的TLR4信号传导；(b)无论MD-2是否存在，Der p2促进初级抗原呈递细胞中的LPS信号传导；(c) Der p2的体内致敏活性反映了其体外功能和生化活性：Der p2在体内以TLR4依赖的方式有效驱动气道Th2炎症，在缺乏MD-2的情况下保持这种能力。这些数据表明，由于其自身佐剂特性，Der p2容易成为适应性免疫反应的靶标。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%的已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，是致敏性现象的基础机制。这一提议的基本假设是，TLR复合物蛋白的生物学上重要的功能模仿是Der p2和相关ML家族蛋白的佐剂性和致敏性的基础。这项研究计划的长期目标是利用分子发病机制的知识来设计新的治疗方法来治疗过敏性疾病。本研究将确定实验性过敏性哮喘中Der p2驱动的TLR4信号的分子和细胞机制以及生物学后果，确定Der p2激活TLR4的分子要求，并确定ML结构域家族成员中的其他主要过敏原是否表现出基于TLR复合物功能模仿的自佐剂性和致敏性。

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.