Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA.
Department of Immunology and Biotechnology, Tropical Medicine Research Institute, Khartoum, Sudan.
Sci Immunol. 2018 Aug 17;3(26). doi: 10.1126/sciimmunol.aat7796.
HIV-specific broadly neutralizing antibodies (bNAbs) confer protection after passive immunization, but the immunological mechanisms that drive their development are poorly understood. Structural features of bNAbs indicate that they originate from extensive germinal center (GC) selection, which relies on persistent GC activity. However, why a fraction of infected individuals are able to successfully drive more effective affinity maturation is unclear. Delivery of antigens in the form of antibody-immune complexes (ICs), which bind to complement receptors (CRs) or Fc receptors (FcRs) on follicular dendritic cells, represents an effective mechanism for antigen delivery to the GC. We sought to define whether IC-FcR or CR interactions differ among individuals who develop bNAb responses to HIV. Enhanced Fc effector functions and FcR/CR interactions, via altered Fc glycosylation profiles, were observed among individuals with neutralizing antibody responses to HIV compared with those without neutralizing antibody activity. Moreover, both polyclonal neutralizer ICs and monoclonal IC mimics of neutralizer antibodies induced higher antibody titers, higher-avidity antibodies, and expanded GC B cell reactions after immunization of mice via accelerated antigen deposition within B cell follicles in a complement-dependent manner. Thus, these data point to a direct role for altered Fc profile/complement interactions in shaping the maturation of the humoral immune response, providing insights into how GC activity may be enhanced to drive affinity maturation in next-generation vaccine approaches.
HIV 特异性广泛中和抗体（bNAb）在被动免疫后提供保护，但驱动其产生的免疫机制仍知之甚少。bNAb 的结构特征表明，它们源自广泛的生发中心（GC）选择，这依赖于持续的 GC 活性。然而，为什么一部分感染者能够成功地驱动更有效的亲和力成熟尚不清楚。以抗体免疫复合物（IC）的形式递呈抗原，这些复合物结合滤泡树突状细胞上的补体受体（CR）或 Fc 受体（FcR），代表了将抗原递呈给 GC 的有效机制。我们试图确定在产生 HIV bNAb 反应的个体中，IC-FcR 或 CR 相互作用是否存在差异。与没有中和抗体活性的个体相比，对 HIV 产生中和抗体反应的个体中观察到增强的 Fc 效应子功能和 FcR/CR 相互作用，这是通过改变 Fc 糖基化谱实现的。此外，多克隆中和性 IC 以及中和性抗体的单克隆 IC 模拟物在通过补体依赖性方式加速 B 细胞滤泡内的抗原沉积来免疫小鼠后，诱导更高的抗体滴度、更高亲和力的抗体和扩大 GC B 细胞反应。因此，这些数据表明，改变的 Fc 谱/补体相互作用在塑造体液免疫反应的成熟中具有直接作用，为了解 GC 活性如何增强以驱动下一代疫苗方法中的亲和力成熟提供了线索。
