Humoral Immunity by Anergic B cells

无能 B 细胞的体液免疫

基本信息

批准号：
10460932
负责人：
Raul Martin Torres
金额：
$ 51.06万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-03 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10460932
关键词：
Adult Affinity Antibodies Antibody Formation Antibody Response Antigen Receptors Antigens Autoantibodies Autoantigens Autoimmune Autoimmune Diseases Autoimmunity B-Lymphocytes Bone Marrow CD4 Positive T Lymphocytes Cells Development Disease Etiology Genes Genetic Goals HIV HIV envelope protein HIV-1 Histone H2A Human Humoral Immunities Hydralazine Immune Evasion Immune Sera Immune Tolerance Immune response Immune system Immunity Immunization Immunize Immunoglobulin Somatic Hypermutation Impairment In Vitro Individual Infection Memory Modeling Molecular Mimicry Mus Nature Pathway interactions Peripheral Pharmaceutical Preparations Physiological Population Pristane Process Production Proteins Spleen Stimulus Time Viral Virus Wild Type Mouse Work anergy autoreactive B cell autoreactivity base central tolerance clinical subtypes clinically relevant cross reactivity env Gene Products experimental study hazard humanized mouse in vivo insight mimicry mouse model neutralizing antibody neutralizing monoclonal antibodies novel pathogen peripheral lymphoid organ peripheral tolerance prevent response restraint transcriptome

项目摘要

PROJECT SUMMARY Not all autoreactive B cells are censored by central tolerance during their development. Thus, mechanisms of B cell anergy are essential for the functional silencing of autoreactive B cells that exist in the periphery in both humans and mice. However, it remains unclear why this poorly defined process of immunological tolerance allows for the temporary retention of autoreactive B cells in the periphery given that, under certain genetic and environmental settings, these cells can contribute to autoimmunity. Indeed, anergic B cells can be released from their functionally inert state but requires unique circumstances (e.g., strong TLR stimulus and highly multimerized antigen), which could presumably occur during an uncontrolled infection. As such, we propose that autoreactive anergic B cells may serve as a reserve population able to respond to pathogens not contained by an initial immune response and particularly for pathogens that aim to evade the immune response through molecular mimicry of self-antigens. Accordingly, work from our lab has recently evaluated if autoreactive B cells that are normally silenced by immune tolerance can contribute to a protective cross-reactive antibody response. To accomplish this we used both autoimmune prone B6.Sle123 mice and wild-type mice treated with pristane, a treatment characterized to impair tolerance and promote autoantibody production. These mice were immunized with HIV envelope protein (Env) and immune sera was found to neutralize tier 2 genetic subtypes of clinically relevant HIV-1, a pathogen proposed to exploit immune tolerance in order to evade the immune response. Furthermore, from these mice we isolated Env-specific neutralizing monoclonal antibodies that also recognize the H2A histone protein. Thus, the goal of this proposal is to use mouse and humanized mouse models to identify the nature and mechanisms that facilitate this antibody response by peripheral autoreactive B cells and to establish conditions that experimentally breach tolerance and promote cross-reactive autoantibody responses by anergic B cells.

项目概要并非所有自身反应性 B 细胞在发育过程中都会受到中央耐受性的审查。因此， B 细胞无反应性机制对于存在于体内的自身反应性 B 细胞的功能性沉默至关重要。人类和小鼠的外围。然而，目前尚不清楚为什么这个定义不明确的过程免疫耐受允许自身反应性 B 细胞暂时保留在外周，因为：在某些遗传和环境条件下，这些细胞可以促进自身免疫。确实，无活力 B 细胞可以从功能惰性状态中释放出来，但需要独特的环境（例如，强 TLR 刺激和高度多聚化抗原），这可能发生在不受控制的感染期间。作为因此，我们建议自身反应性无能 B 细胞可以作为能够响应的储备群体初始免疫反应未包含的病原体，特别是旨在逃避免疫反应的病原体通过自身抗原的分子模拟产生免疫反应。因此，我们实验室的工作最近评估通常因免疫耐受而沉默的自身反应性 B 细胞是否有助于保护性交叉反应抗体反应。为了实现这一目标，我们使用了具有自身免疫倾向的 B6.Sle123 小鼠和用降植烷治疗的野生型小鼠，这种治疗的特点是损害耐受性并促进自身抗体产生生产。这些小鼠接受了 HIV 包膜蛋白 (Env) 免疫，并且发现免疫血清可以中和临床相关 HIV-1 的 2 级遗传亚型，这是一种利用免疫耐受的病原体以逃避免疫反应。此外，我们从这些小鼠中分离出 Env 特异性中和剂也可识别 H2A 组蛋白的单克隆抗体。因此，本提案的目标是使用小鼠和人源化小鼠模型，以确定促进该抗体的性质和机制外周自身反应性 B 细胞的反应并建立实验上突破耐受性的条件并促进无能 B 细胞的交叉反应性自身抗体反应。