The influence of IgA on B Cell Homeostasis

IgA 对 B 细胞稳态的影响

• 批准号: 7714319
• 负责人: DENNIS W METZGER
• 金额: $ 23.55万
• 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 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7714319
• 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）：粘膜组织是针对大多数传染剂的第一道防线，其中包含大量的IGA抗体，可在预防炎症的同时迅速中和毒素和病原体。因此，IgA水平的扰动可以预期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缺乏小鼠（IgA - / - 小鼠）特异性地无法安装对多糖疫苗的类切换抗体反应，但对蛋白质疫苗的正常方式反应。也许与此相关的是，IgA - / - 小鼠中粘膜B细胞的数量急剧减少，并且腹膜B1-A细胞的水平也降低了。因此，我们假设IgA表达对于粘膜组织中B细胞的适当运输和保留至关重要。我们将通过1）确定IgA - / - 小鼠中粘膜B细胞缺损的特异性，研究IgA对B细胞稳态的影响，并特别关注B1-A细胞，以及2）确定IgA会影响粘膜B细胞运输和维持的机制。这些研究将提高我们对IgA，B细胞和环境之间动态相互作用的理解，IgA，B细胞和环境是一个相对未开发的区域，与人类健康相关。 相关性：IgA缺乏是人类原发性免疫缺陷的最常见形式。该提案旨在确定复发性呼吸道感染的原因和对多糖疫苗的反应性差，这在许多患者中都观察到。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治疗剂和辅助药，以提高疫苗在该人群中的功效。