Autoantibodies against the prion protein in individuals with <i>PRNP</i> mutations.

Abstract

To determine whether naturally occurring autoantibodies against the prion protein are present in individuals with genetic prion disease mutations and controls, and if so, whether they are protective against prion disease. In this case-control study, we collected 124 blood samples from individuals with a variety of pathogenic <i>PRNP</i> mutations and 78 control individuals with a positive family history of genetic prion disease but lacking disease-associated <i>PRNP</i> mutations. Antibody reactivity was measured using an indirect ELISA for the detection of human immunoglobulin G_1-4 antibodies against wild-type human prion protein. Multivariate linear regression models were constructed to analyze differences in autoantibody reactivity between (1) <i>PRNP</i> mutation carriers vs controls and (2) asymptomatic vs symptomatic <i>PRNP</i> mutation carriers. Robustness of results was examined in matched cohorts. We found that antibody reactivity was present in a subset of both <i>PRNP</i> mutation carriers and controls. Autoantibody levels were not influenced by <i>PRNP</i> mutation status or clinical manifestation of prion disease. Post hoc analyses showed anti-PrP^C autoantibody titers to be independent of personal history of autoimmune disease and other immunologic disorders, as well as <i>PRNP</i> codon 129 polymorphism. Pathogenic <i>PRNP</i> variants do not notably stimulate antibody-mediated anti-PrP^C immunity. Anti-PrP^C immunoglobulin G autoantibodies are not associated with the onset of prion disease. The presence of anti-PrP^C autoantibodies in the general population without any disease-specific association suggests that relatively high titers of naturally occurring antibodies are well-tolerated. NCT02837705.