Humoral Immunity by Anergic B cells

项目总结 并不是所有的自身反应性B细胞在发育过程中都受到中枢耐受的审查。因此， B细胞无能机制对于自身反应性B细胞的功能性沉默是必不可少的 在人类和小鼠身上都是外围的。然而，目前还不清楚为什么这个定义不清的过程 免疫耐受允许自身反应性B细胞暂时保留在外周， 在特定的遗传和环境设置下，这些细胞可以促进自身免疫。的确，无能 B细胞可以从其功能惰性状态中释放出来，但需要独特的环境(例如，强TLR 刺激和高度多聚体抗原)，推测可能发生在不受控制的感染期间。AS 因此，我们认为，自身反应性无能B细胞可能作为一种储备群体，能够对 不包含在初始免疫反应中的病原体，尤其是那些旨在逃避 通过分子模拟自身抗原的免疫反应。因此，我们实验室的工作最近 评估通常被免疫耐受抑制的自身反应性B细胞是否有助于保护性 交叉反应抗体反应。为了完成这一任务，我们使用了倾向于自身免疫的B6Sle123小鼠和 用Pristane治疗野生型小鼠，这种治疗的特点是削弱耐受性并促进自身抗体 制作。这些小鼠用HIV包膜蛋白(Env)免疫，免疫血清被发现 中和临床相关的HIV-1的二级基因亚型，一种被提议利用免疫耐受的病原体 以逃避免疫反应。此外，我们从这些小鼠身上分离出了环境特异性的中和 也识别H_2A组蛋白的单抗。因此，该提案的目标是使用 小鼠和人源化小鼠模型，以确定促进这种抗体的性质和机制 外周自身反应性B细胞的反应，并建立实验上违反耐受性的条件 并促进无能B细胞的交叉反应自身抗体反应。

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.