The immune system seems to be a firm ally of prions. Not only do these infectious, modified proteins rely on the immune architecture for invasion and dispersal within their host, but also immunological tolerance to the cellular version of the prion protein (PrPc) presents a important formidable obstacle to vaccination against the antigenically indistinguishable disease-associated prion protein (PrPSc). Heppner and colleagues now report, in Science, that antibodies to PrP, produced in the host by a 'genetic trick', can protect against prion disease.
Scrapie infection in mice provides a useful model of prion diseases. In this study, a high-affinity, PrP-specific immunogolulin heavy-chain V region, derived from a PrP-immunized Prnp -deficient mouse, was used to create a transgenic mouse. The transgenic μ-chain can pair with any of the endogenous light chains, resulting in a repertoire enriched in anti-PrP specificities of various affinities.
On a Prnp-deficient background, the transgenic mice spontaneously produce anti-PrP IgM antibodies, despite an absence of specific antigen. Transgenic mice on a Prnp-sufficient background, also spontaneously produce anti-PrP antibody, but initially at lower levels and, crucially, there is no evidence of autoimmune disease.
But can these low levels of anti-PrP antibodies protect against infection? To test this, transgenic Prnp+/o mice were innoculated with scrapie prions and protection was assessed in three ways. First, the abundance of prions in the spleen was measured by an in vivo bioassay, which showed a complete absence of infective prions. Second, western blots showed no trace of PrPsc in the spleens — normally a principal prion reservoir. Third, no scrapie deposits were found in the brains of these mice, indicating that prion transport to the central nervous system had been blocked.
Are the specific antibodies really responsible for this protection? An absence of follicular dendritic cells (FDCs), which depend on B cells for their development, is known to prevent scrapie pathogenesis. Could intrinsic immune defects in the transgenic mice account for their immunity to scrapie? The authors showed that the mice can produce normal levels of anti-viral antibody and also have normal clusters of FDCs in the spleen, implying that immune function is intact.
Importantly, this is the first indication that specific anti-PrP antibodies can protect against prion neuroinvasion. As no autoimmune disease occurred, passive transfer of anti-PrP immunity, either directly by antibodies or by gene therapy, might be a successful strategy against prion disease.
ORIGINAL RESEARCH PAPER
Heppner, F. L. et al. Prevention of scrapie pathogenesis by transgenic expression of anti-prion protein antibodies. Science 6 September [e-pub ahead of print] (2001)
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Bell, J. Friend or foe?. Nat Rev Immunol 1, 7 (2001). https://doi.org/10.1038/35095537