The influence of IgA on B Cell Homeostasis

IgA 对 B 细胞稳态的影响

• 批准号: 7866605
• 负责人: DENNIS W METZGER
• 金额: $ 19.43万
• 依托单位: ALBANY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7866605
• 关键词: Adjuvant; Adoptive Cell Transfers; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Antibody Formation; Antigens; Area; B-Lymphocyte Subsets; B-Lymphocytes; Bone Marrow; Cell physiology; Cells; Cellular biology; Chimera organism; Data; Death Rate; Defect; Environment; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Health; Homeostasis; Human; IgA Deficiency; Immune; Immune response; Immune system; Immunoglobulin A; Immunoglobulin Class Switching; Immunoglobulins; Immunohistochemistry; Immunologic Deficiency Syndromes; Inbred BALB C Mice; Infectious Agent; Inflammation; Maintenance; Mucous Membrane; Mus; Nature; Patients; Peritoneal; Play; Polysaccharides; Population; Positioning Attribute; Proteins; Recurrence; Regulation; Respiratory Tract Infections; Reverse Transcriptase Polymerase Chain Reaction; Role; Surface; Syndrome; Toxin; Vaccine Design; Vaccines; Western Blotting; chemokine; congenic; cytokine; design; immunodeficient mouse model; improved; in vivo; insight; neutralizing antibody; novel therapeutics; pathogen; prevent; response; trafficking; vaccine efficacy

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.

描述（由申请人提供）：粘膜组织是抵御大多数传染源的第一道防线，含有大量 IgA 抗体，可快速中和毒素和病原体，同时预防炎症。因此，IgA 水平的扰动预计会严重影响粘膜组织的免疫防御和稳态。令人惊讶的是，我们发现IgA缺陷小鼠（IgA-/-小鼠）特别不能对多糖疫苗产生类别转换抗体反应，但对蛋白质疫苗以正常方式反应。也许与此相关，IgA-/-小鼠的粘膜B细胞数量急剧减少，腹膜B1-a细胞的水平也降低。因此，我们假设 IgA 表达对于 B 细胞在粘膜组织中的正常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以及 2) 建立 IgA 影响运输的机制来研究 IgA 对 B 细胞稳态的影响，特别关注 B1-a 细胞和维持粘膜B细胞。这些研究将增进我们对 IgA、B 细胞和环境之间动态相互作用的理解，这是一个相对未经探索的领域，与人类健康密切相关。 相关性：IgA 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不佳的原因。通过利用独特的 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，以提高疫苗在该人群中的功效。