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.

项目摘要并非所有自动反应性B细胞在发育过程中都会受到中央耐受性的审查。因此， B细胞消除机制对于存在于自动反应性B细胞的功能沉默至关重要人类和小鼠的外围。但是，尚不清楚为什么这个定义不明的过程免疫耐受性允许在周围暂时保留自动反应性B细胞，因为这是因为在某些遗传和环境环境下，这些细胞可以导致自身免疫性。确实，厌食症 B细胞可以从其功能惰性状态中释放出来，但需要独特的情况（例如，强的TLR 刺激和高度多层抗原），可能在不受控制的感染过程中发生。作为这样，我们建议自动反应性的Anergic B细胞可以用作能够应对的储备金人群初始免疫反应所包含的病原体，尤其是针对逃避的病原体通过自我抗原的分子模仿来免疫反应。因此，我们实验室的工作最近有评估通常会被免疫耐受沉默的自动反应性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，我们同时使用了自身免疫性俯卧b6.sle123小鼠和用pristane处理的野生型小鼠，这种治疗的特征是损害耐受性和促进自身抗体生产。这些小鼠用HIV包膜蛋白（ENV）免疫，并发现免疫血清中和临床上相关的HIV-1的第2层遗传亚型，该病原体提议利用免疫耐受性为了逃避免疫反应。此外，从这些小鼠中，我们隔离了ENV特异性中和也识别H2A组蛋白的单克隆抗体。因此，该提议的目的是使用小鼠和人源化的小鼠模型，以识别促进该抗体的性质和机制外周自动反应性B细胞的响应，并建立实验违反耐受性的条件并促进通过厌食B细胞的交叉反应自身抗体反应。