Objective. 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. 

Methods. In this case-control study, we collected 124 blood samples from individuals with a variety of pathogenicPRNPmutations and 78 control individuals with a positive family history of genetic prion disease but lacking disease-associatedPRNPmutations. Antibody reactivity was measured using an indirect ELISA for the detection of human IgG_1-4 antibodies against wild-type human prion protein. Multivariate linear regression models were constructed to analyze differences in autoantibody reactivity between a) PRNPmutation carriers versus controls and b) asymptomatic versus symptomatic PRNPmutation carriers. Robustness of results was examined in matched cohorts.

Results. We found that antibody reactivity was present in a subset of both PRNPmutation carriers and controls. Autoantibody levels were not influenced by PRNP mutation status nor clinical manifestation of prion disease. Post hocanalyses showed anti-PrP^Cautoantibody titers to be independent of personal history of autoimmune disease and other immunological disorders, as well as PRNPcodon 129 polymorphism. 

Conclusions.Pathogenic PRNPvariants do not notably stimulate antibody-mediated anti-PrP^Cimmunity. Anti-PrP^CIgG autoantibodies are not associated with the onset of prion disease. The presence of anti-PrP^Cautoantibodies in the general population without any disease-specific association suggests that relatively high titers of naturally occurring antibodies are well tolerated. Clinicaltrials.gov identifier NCT02837705.