Prion diseases are well known for their tropism toward the central nervous system (CNS) in which they cause irremediable and fatal neurodegenerescence. Prions are misfolded proteins that can target almost every mammals, in which their endogenous PrPC is highly conserved and serves as a substrate for conversion into a pathologic form when in contact with the infectious form of PrP (PrPSc). The endogenous PrPC is expressed in almost every organ of the body, in particular in the lymphoid system. Follicular dendritic cells (FDCs) are cornerstones for development, architecture and function of the secondary and tertiary lymphoid organs. In addition, they have been shown to play essential role in the extraneural replication of prions. Our experimental models could not determine whether these cells are also responsible for lymphofollicular competency of some prion strains, however our experimental data clearly show that the endogenous expression level of PrPC is critical for selection of mutant prion strains that preexist in the initial inoculum. Why some strictly neuronal prion strains could not be found in the lymphoid system of the host regardless the incubation time remains to be questioned.