Determinants of autoantibody induction by conjugated papillomavirus virus-like particles

Immunization of mice with self-Ag arrayed on the surface of papillomavirus-like particles induces long-lasting high-titer IgG production by autoreactive B cells. In contrast, immunization with disorganized self-Ag linked to foreign Th epitopes induces weak autoantibody responses that are predominantly of the IgM isotype. In this study, we evaluated the structural correlates of autoantibody induction to determine the basis of these disparate observations, using a system in which mice were vaccinated with a fusion protein containing self (TNF-alpha) and foreign (streptavidin) components, conjugated to biotinylated virus-like particles (VLPs). Similar titers of autoantibodies to TNF-alpha were elicited using conjugated polyomavirus VLPs and papillomavirus VLPs, indicating that acute activation of dendritic cells by the Ag is not required. Strong autoantibody responses were also induced by conjugated papillomavirus capsid pentamers, indicating that a higher order particulate structure is also not required. However, a reduction of self-Ag density on VLP surfaces dramatically reduced the efficiency of IgG autoantibody induction. In contrast, the negative effects of reductions in foreign Ag density were limited and could be overcome by dosage and adjuvant. These data suggest that the immune system has evolved to differentially recognize closely spaced repetitive Ags and that the signals generated upon interactions with high-density self-Ags can overwhelm the normal mechanisms for B cell tolerance.