Humoral Immunity by Anergic B cells

项目摘要 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限制。因此，在本发明中， B细胞无反应性的机制对于自体反应性B细胞的功能性沉默是必需的，所述自体反应性B细胞存在于 人类和小鼠的外周。然而，目前还不清楚为什么这种定义不清的过程， 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条件下，这些细胞可以促进自身免疫。的确， B细胞可以从它们的功能惰性状态释放出来，但需要独特的环境（例如，强TLR 刺激物和高度多聚化的抗原），这可能发生在不受控制的感染期间。作为 因此，我们认为自身反应性无反应性B细胞可能作为一个储备群体，能够响应 初始免疫应答不包含的病原体，特别是旨在逃避免疫应答的病原体。 通过自身抗原的分子模拟的免疫应答。因此，我们实验室的工作最近 评估通常被免疫耐受沉默的自身反应性B细胞是否有助于保护性免疫耐受。 交叉反应性抗体应答。为了实现这一点，我们使用了自身免疫易感B6.Sle123小鼠和 用降植烷处理的野生型小鼠，降植烷是一种以损害耐受性和促进自身抗体为特征的治疗方法。 生产用HIV包膜蛋白（Env）免疫这些小鼠，发现免疫血清 中和临床相关HIV-1的二级遗传亚型，这是一种被提议利用免疫耐受的病原体 以逃避免疫反应此外，从这些小鼠中，我们分离了Env特异性中和抗体。 也识别H2 A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，以鉴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，并建立实验性破坏耐受性的条件 并促进无反应性B细胞的交叉反应性自身抗体应答。

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.