This biological activity was linked to particular Ab glycosylation profiles, which, when replicated with monoclonal IC immunization, resulted in enhanced IC capture by noncognate B cells, accelerated IC deposition within B cell follicles, and elevated Ab titers and avidity Ab production in a complement-dependent manner. Moreover, immunization with ICs generated with polyclonal Abs from neutralizers induced higher HIV-specific Ab responses after vaccination. Using “systems serology” ( 33), we observed significant differences in the Fc profiles of HIV-specific Abs in individuals who developed neutralizing breadth (neutralizers) compared with those who did not (non-neutralizers). We speculated that qualitative changes in the Fc domain track with the development of bNAbs during HIV infection and point to the mechanism by which the Fc domain of the Ab may be leveraged to drive the evolution of highly affinity-matured bNab responses. 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. 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. 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. We sought to define whether IC-FcR or CR interactions differ among individuals who develop bNAb responses to HIV. 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. However, why a fraction of infected individuals are able to successfully drive more effective affinity maturation is unclear. Structural features of bNAbs indicate that they originate from extensive germinal center (GC) selection, which relies on persistent GC activity. HIV-specific broadly neutralizing antibodies (bNAbs) confer protection after passive immunization, but the immunological mechanisms that drive their development are poorly understood.
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