The Role of CD32 in the Basophil Response to Specific Immunotherapy

描述(由申请人提供)：嗜碱性粒细胞分泌介质是过敏反应的重要组成部分。这两个低亲和力的免疫球蛋白受体(CD32a和CD32b)是如何调节这种分泌的，这是本提案的重点。特异性免疫疗法(SIT)是治疗变态反应性疾病的主要方法。虽然有几个强有力的假设为这种治疗方法的成功(或缺乏)提供了解释，但这些假设中的大多数都没有在人类身上进行完全的检验。长期以来的观察之一是，SIT诱导产生特异性的免疫球蛋白抗体，但这些抗体对SIT疗效的作用机制尚不清楚。这项建议将检验阻断免疫球蛋白通过细胞表面CD32b(FcgRIIb)影响人嗜碱细胞反应的假设。现有的有限文献验证这一假说是相互矛盾的，但有新的信息可能有助于探索这一点 提出问题并说明SIT临床研究中可能出现的潜在生物变异。本实验室的研究表明，CD32a和CD32b的相对比例可以随着细胞因子的暴露而改变。这项建议的第一个目的是扩大我们对CD32表达调控的了解，特别强调是否存在允许CD32a介导的分泌的CD32a和CD32b基因型以及免疫球蛋白G亚类。其中一些知识将被用来进一步改进临床研究的设计和解释。 这是在提案的第二个目标中提出的。临床研究的目的是为患者提供探索所提出的假说所需要的，但我们将把体外嗜碱性细胞功能测试的结果与实验性鼻变应原挑战所衡量的SIT的临床结果结合起来。第三个目的探索了一个独特的新观察结果，即CD32b调节嗜碱性粒细胞IgE介导的分泌允许抑制介质的释放，但维持下调过程，如SYK表达的丧失。这一情况可能为SYK在普通人群中的重要可变表达提供了解释，目前已知这种变异与至少一种新的哮喘治疗药物奥马珠单抗的疗效有关。第三个目标将确定CD32b是否能调节IgE介导的从CD34+祖细胞成熟的嗜碱性粒细胞SYK表达的下调，并检查这一过程的基础。

DESCRIPTION (provided by applicant): Secretion of mediators from basophils is an important component of the allergic response. How this secretion is regulated by two low affinity IgG receptors (CD32a and CD32b) is the focus of this proposal. Specific immunotherapy (SIT) is a mainstay approach in the treatment of allergic diseases. While there are several strong hypotheses that provide an explanation for the success (or lack thereof) of this therapeutic approach, most of these hypotheses are incompletely examined in humans. One of the longstanding observations is that SIT induces enhanced production of specific IgG antibodies but the mechanism by which these antibodies may contribute to the efficacy of SIT is not well understood. This proposal will test the hypothesis that blocking IgG exerts an influence on the human basophil response through cell surface CD32b (FcgRIIb). The limited existing literature testing this hypothesis is contradictory but there is new information that may help to explore this question and account for potential biological variation that may occur in a clinical study of SIT. Studies in this laboratory demonstrate that the relative proportion of CD32a and CD32b can be altered with cytokine exposure. The first aim of this proposal is to expand our knowledge of the regulation of CD32 expression, with a particular emphasis on whether there are genotypes of CD32a and CD32b and IgG subclass profiles that allow for CD32a-mediated secretion. Some of this knowledge will be used to further improve on the design and interpretation of a clinical study of SIT that is proposed in the second aim of the proposal. The purpose of the clinical study is to provide the patients needed to explore the proposed hypothesis but we will couple the results from the in vitro testing of basophil function to the clinical outcomes of SIT as measured by experimental nasal allergen challenges. The third aim explores a unique new observation that regulation of IgE-mediated secretion from basophils by CD32b allows for suppression of mediator release but maintenance of down-regulatory processes such as the loss in the expression of syk. This circumstance may provide an explanation for the important variable expression of syk seen in the general population, variation that is now known to be linked to the efficacy of at least one new asthma therapeutic, omalizumab. The third aim will determine whether CD32b can modulate the IgE-mediated down-regulation of syk expression in basophils maturing from their CD34+ progenitors and examine the basis for this process.