Autoantibodies against the prion protein in individuals with PRNP mutations

<p><span><span><span><span><span><span><span><span><span><span><span><i>Objective. </i>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. </span></span></span></span></span></span></span></span></span></span></span></p> <p><span><span><span><span><span><span><span><span><span><span><span><i>Methods. </i>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 IgG_1-4antibodies against wild-type human prion protein. Multivariate linear regression models were constructed to analyze differences in autoantibody reactivity between a) <i>PRNP</i>mutation carriers versus controls and b) asymptomatic versus symptomatic <i>PRNP</i>mutation carriers. Robustness of results was examined in matched cohorts.</span></span></span></span></span></span></span></span></span></span></span></p> <p><span><span><span><span><span><span><span><span><span><span><span><i>Results. </i>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 nor clinical manifestation of prion disease. <i>Post hoc</i>analyses showed anti-PrP^Cautoantibody titers to be independent of personal history of autoimmune disease and other immunological disorders, as well as <i>PRNP</i>codon 129 polymorphism. </span></span></span></span></span></span></span></span></span></span></span></p> <p><span><span><span><span><span><span><span><span><span><span><span><i>Conclusions.</i>Pathogenic <i>PRNP</i>variants 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. </span></span></span></span></span></span></span></span></span></span></span></p>