The influence of IgA on B Cell Homeostasis

描述(申请人提供)：粘膜组织是抵御大多数感染性物质的第一道防线，含有大量的IgA抗体，可迅速中和毒素和病原体，同时防止炎症。因此，预计免疫球蛋白A水平的紊乱将严重影响粘膜组织的免疫防御和动态平衡。令人惊讶的是，我们发现IgA缺陷小鼠(IgA-/-小鼠)对多糖疫苗不能产生类别转换的抗体反应，但对蛋白质疫苗却有正常的反应。可能与此有关，IgA-/-小鼠黏膜B细胞数量显著减少，腹膜B1-a细胞水平也降低。因此，我们假设，IgA的表达对于B细胞在粘膜组织中的正确运输和保留至关重要。我们将通过1)确定IgA-/-小鼠粘膜B细胞缺陷的具体性质和2)建立IgA影响粘膜B细胞运输和维持的机制来研究IgA对B细胞动态平衡的影响，尤其是对B1-a细胞的影响。这些研究将促进我们对免疫球蛋白A、B细胞和环境之间动态相互作用的理解，这是一个相对未被探索的领域，与人类健康密切相关。 相关：免疫球蛋白缺乏症是人类最常见的原发免疫缺陷。这项建议旨在确定在许多此类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。通过利用一种独特的IgA免疫缺陷小鼠模型，我们的结果最终将允许设计新的疗法和佐剂，以提高疫苗在这一人群中的效力。

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.