RECEPTOR DIVERSITY IN RECOGNITION OF INFLUENZA HA

这项提案的目的是分析流感病毒是如何 A/PR/8/34血凝素(PR8 HA)被认为是一种确定的自身抗原 在HA转基因(HA-TG)小鼠中。HA TG小鼠将被免疫或感染 用定义的含有氨基酸替换的突变的PR8病毒 HA、T和B细胞决定簇。在HA中可以诱导的反应 Tg小鼠将与非Tg小鼠诱导的反应进行比较 Balb/c小鼠，以及相关的丰富信息，描述了 HA被认为是一种外来抗原。特异度和遗传性 T细胞对HA耐受性的基础将通过以下方式系统分析 HA、TG和BALB/c小鼠对辅助物类似物反应的比较 表现出不同程度交叉反应的测试细胞决定簇 PR8 HA。HATG小鼠是否感染变异病毒 含有这些类似物可以诱导T细胞与 还将检查作为已定义自身抗原的PR8 HA。B的范围 HATG小鼠的细胞耐受性将通过免疫来评估 B区含有氨基酸替换的抗原性变异病毒 细胞抗原性部位。对PR8 HA的耐受性是否集中在 HA-TG小鼠对含氨基表位的抗体应答 将对酸取代进行分析。此外，HA TG小鼠是否使用 与BALB/c小鼠相同的显著H链和L链识别 房委会将接受检查。转基因透明质酸的表达模式 影响其作为自身抗原的识别也将被评估。 不同的HA TG谱系将被比较组织位置， 表达水平，以及HA所处的发育阶段 表达。不同的表达方式是否会导致不同的 自我容忍的表现形式将通过分析 不同血统HA-TG小鼠对免疫应答的研究 感染PR8病毒。总而言之，这些分析将提供独特的 以及对人类免疫缺陷的特殊性和遗传基础的基本见解 对HA的耐受性是一种明确的自身抗原。此外，‘分子’ 自身免疫的模仿模型，该模型认为一种免疫反应 可以诱导淋巴细胞与微生物抗原发生交叉反应 将直接对自身抗原进行评估。

The objective of this proposal is to analyze how the influenza virus A/PR/8/34 hemagglutinin (PR8 HA) is recognized as a defined self antigen in HA transgenic (HA Tg) mice. HA Tg mice will be immunized or infected with mutant PR8 viruses that contain amino acid substitutions in defined HA T and B cell determinants. The responses that can be induced in HA Tg mice will be compared to the responses that are induced in non-Tg BALB/c mice, and related to the wealth of information describing how the HA is recognized as a foreign antigen. The specificity and genetic basis of T cell tolerance to the HA will be systematically analyzed by comparing the responses of HA Tg and BALB/c mice to analogs of a helper T cell determinant that display varying degrees of cross-reactivity with the PR8 HA. Whether infection of HA Tg mice with mutant viruses containing these analogs can induce T cells that cross-react with the PR8 HA as a defined self antigen will also be examined. The extent of B cell tolerance in HA Tg mice will be assessed by immunization with antigenic variant viruses that contain amino acid substitutions in B cell antigenic sites. Whether tolerance to the PR8 HA focuses the antibody response of HA Tg mice toward epitopes that contain the amino acid substitution will be analyzed. In addition, whether HA Tg mice use the same prominent H and L chains that BALB/c mice use to recognize the HA will be examined. How the pattern of expression of the transgenic HA influences its recognition as a self antigen will also be assessed. Different HA Tg lineages will be compared for the tissue location, the level of expression, and the developmental stage at which the HA is expressed. Whether different patterns of expression lead to distinct manifestations of self tolerance will be examined by analyzing the responsiveness of HA Tg mice from different lineages to immunization or infection with PR8 virus. Together, these analyses will provide unique and fundamental insights into the specificity and genetic basis of tolerance to the HA as a defined self antigen. In addition, 'molecular mimicry' models of autoimmunity, which propose that an immune response to a microbial antigen can induce lymphocytes that cross-react with a self antigen will be directly evaluated.