IGG CLASS AND FUNCTION OF ANTIPOLYSACCHARIDE ANTIBODIES

描述：抗多糖(PS)抗体(Ab)对宿主至关重要 对被包裹的细菌的防御。抗PS抗体的功能包括 补体结合和调理细菌摄取和杀死 吞噬细胞。哺乳动物的免疫球蛋白抗PS抗体反应延迟了个体发育和 最初的同型限制(小鼠为IgG3，人为IgG2)。这些抗体 类-如果PS与蛋白质偶联，则主要切换为IgG1 无论是老鼠还是人。也定义了这种同种类型限制的原因 作为不同免疫球蛋白亚类的抗PS抗体的相对功能 对于更好地理解对PS包裹的细菌和 人类疾病的发病机制，如免疫球蛋白亚类缺陷。精确 此外，还评价了亚类对抗PS抗体功能的影响 提高疫苗接种后免疫学相关血清学指标的重要性 使用PS和PS结合疫苗。不同亚型抗PS抗体的功能 免疫球蛋白亚类仍不清楚，因为之前的研究已经使用了 多克隆亲和纯化抗体暴露于改变Fc的杂交剂 功能。此外，使用具有不同抗原性的单抗 特异性，以及缺乏免疫球蛋白亚类缺陷的动物模型 限制了对亚类特异性抗体的理解。在当前 建议研究人员将准确定义免疫球蛋白亚类在 抗PS抗体的效应器功能，并确定其作用的恒定区 免疫优势抗PS-Ig G亚类基因及类基因 当PS与蛋白质结合时发生的转换。首先，使用 四种人的可变区完全相同的鼠/人嵌合抗体 抗铜绿假单胞菌(PA)LPSO侧链亚类，调查者 将确定抗体在动物模型中的保护效果的差异 PA感染，然后确定观察到的功能机制 不同之处。其次，他将制造人鼠嵌合体并对其进行表征 肺炎球菌衣壳蛋白抗体更好地确定免疫球蛋白的作用 预防肺炎球菌亚类，以改善血清学 保护的相关性并确定抗PS亚类是否起作用 差异是特定于表位的。第三，为了确定体内的 主要的抗PS免疫球蛋白亚类的重要性和确定 重链基因在抗PS类转换中的重要性 研究人员和他的合作者成功地研制出一种免疫球蛋白 3基因打靶的3缺陷基因敲除小鼠及其同源基因 重组。 现在将评估这些小鼠的免疫学能力 对PS、PS-蛋白结合物和包裹的细菌感染作出反应。 这些研究将确定哪种抗PS免疫球蛋白亚类的作用最强 有效地对抗PS包衣细菌，更好地定义了 免疫球蛋白亚类之间的功能差异及其相关性探讨 活体内的这些差异。这些数据将使我们能够采取更理性的策略 对PS包被细菌的主动免疫和被动免疫的改进 治疗免疫球蛋白亚类缺陷。

DESCRIPTION: Anti-polysaccharide (PS) antibodies (Ab) are critical to host defense against encapsulated bacteria. The function of anti-PS Ab includes complement fixation and opsonization of bacteria for uptake and killing by phagocytes. The mammalian IgG anti-PS Ab response has delayed ontogeny and isotype restriction initially (IgG3 in mice, IgG2 in man). These antibodies class-switch predominately to IgG1 if the PS is conjugated to protein in both mouse and man. Defining the causes of this isotype restriction as well as the relative function of anti-PS antibodies of different IgG subclasses is crucial to better understanding immunity to PS-encapsulated bacteria and pathogenesis of human diseases such as IgG subclass deficiency. Precise evaluation of the effect of subclass on anti-PS antibody function is also important to improve serological correlates of immunity after vaccination with PS and PS-conjugate vaccines. The function of anti-PS Ab of different IgG subclasses remains unclear because to previous studies have used polyclonal affinity purified Ab exposed to chaotropic agents that alter Fc function. In addition, the use of monoclonal Ab with different antigenic specificities, and the lack of animal models of IgG subclass deficiency have limited the understanding of subclass-specific antibodies. In the current proposal the investigator will precisely define the role of IgG subclass in anti-PS Ab effector function, and determine the role of the constant region gene for the dominant anti-PS IgG subclass in immunity and in class switching that occurs when PS are conjugated to proteins. First, using variable region identical mouse/human chimeric Ab of all four human subclasses against P. aeruginosa (PA) LPS O-side chain, the investigator will determine differences in protective efficacy of Ab in animal models of PA infection and then define the mechanism of the observed functional differences. Second, he will make and characterize mouse/human chimeric antibodies against pneumococcal capsular PS to better define the role of IgG subclass in protection against pneumococcus, to improve serological correlates of protection and to determine if anti-PS subclass functional differences are epitope specific. Third, in order to determine the in vivo importance of the predominant anti-PS IgG subclass and to determine the importance of the heavy chain gene in anti-PS class switching, the investigator and his collaborators have successfully developed an IgG 3-deficient knockout mouse via 3 gene targeting and homologous recombination. These mice will now be evaluated for their ability to immunologically respond to PS, PS-protein conjugates, and encapsulated bacterial infections. These studies will determine which anti-PS IgG subclass functions most efficiently against PS-coated bacteria, better define the mechanism of functional differences between IgG subclasses and explore the relevance of these differences in vivo. These data will allow more rational strategies of active and passive immunization against PS-coated bacteria and improved treatment of IgG subclass deficiencies.