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Laboratory of Cellular Oncology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
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-
) and foreign (streptavidin) components, conjugated to
biotinylated virus-like particles (VLPs). Similar titers of
autoantibodies to TNF- 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.
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