The influence of IgA on B Cell Homeostasis

描述（由申请人提供）：粘液组织是抵抗大多数感染因子的第一道防线，含有大量伊加抗体，可快速中和毒素和病原体，同时预防炎症。因此，伊加水平的扰动可能会严重影响粘膜组织的免疫防御和体内平衡。令人惊讶的是，我们已经发现伊加缺陷型小鼠（伊加-/-小鼠）特异性地不能对多糖疫苗产生类别转换的抗体应答，但以正常方式对蛋白质疫苗产生应答。可能与此相关，伊加-/-小鼠中粘膜B细胞的数量显著减少，腹膜B1-a细胞的水平也降低。因此，我们假设伊加表达对于B细胞在粘膜组织中的适当运输和保留至关重要。我们将研究伊加对B细胞稳态的影响，特别关注B1-a细胞，通过1）确定伊加-/-小鼠中粘膜B细胞缺陷的特定性质和2）建立伊加影响粘膜B细胞运输和维持的机制。这些研究将促进我们对伊加、B细胞和环境之间动态相互作用的理解，这是一个相对未开发的领域，与人类健康有着重要的相关性。 相关性：伊加缺乏症是人类原发性免疫缺陷最常见的形式。该提案旨在确定在许多患者中观察到的反复呼吸道感染和对多糖疫苗反应性差的原因。通过利用独特的伊加免疫缺陷小鼠模型，我们的研究结果将最终允许设计新的治疗方法和佐剂，以提高疫苗在这一人群中的疗效。

DESCRIPTION (provided by applicant): Mucosal tissue, the first line of defense against the majority of infectious agents, contains large amounts of IgA antibody, which serves to rapidly neutralize toxins and pathogens, while preventing inflammation. Perturbations in IgA levels can thus be expected to severely affect immune defenses and homeostasis at mucosal tissues. Surprisingly, we have found that IgA deficient mice (IgA-/- mice) specifically fail to mount class-switched antibody responses to polysaccharide vaccines but respond in a normal fashion to protein vaccines. Perhaps related to this, there is a dramatic reduction in the numbers of mucosal B cells in IgA-/- mice and the levels of peritoneal B1-a cells are also decreased. Thus, we hypothesize that IgA expression is critical for the proper trafficking and retention of B cells in mucosal tissues. We will investigate the influence of IgA on B cell homeostasis with a particular focus on B1-a cells by 1) determining the specific nature of the mucosal B cell defect in IgA-/- mice and 2) establishing the mechanism by which IgA influences trafficking and maintenance of mucosal B cells. These studies will advance our understanding of the dynamic interactions between IgA, B cells, and the environment, a relatively unexplored area with significant relevance to human health. RELEVANCE: IgA deficiency is the most frequent form of primary immunodeficiency in humans. This proposal seeks to determine the reason for recurrent respiratory infections and poor responsiveness to polysaccharide vaccines that is observed in many of these patients. By exploiting a unique IgA immunodeficient mouse model, our results will ultimately allow design of new therapeutics and adjuvants to improve the efficacy of vaccines in this population.