Etiology and Transmission Routes
Prion diseases arise from two main etiologic causes: a mutation in the endogenous gene encoding the normal prion protein (causing hereditary forms), or the entry of an exogenous infectious prion into the organism.
From an epidemiological perspective, several transmission routes for infectious forms are distinguished:
- Alimentary (dietary) route. Infection occurs by consuming animal products contaminated with prions, as well as food supplements manufactured from raw cattle organs.
- Artificially induced (iatrogenic) route. This involves transmission associated with medical interventions. It can occur via blood transfusion, organ and tissue transplantation, and instrumental procedures. Inadequately sterilized surgical and dental instruments can serve as vectors due to the high resistance of prions to standard sterilization.
- Medication-related route. This is a specific instance of iatrogenic transmission occurring through the administration of animal- or human-derived immunobiological products contaminated with prions. A classic example is the development of Creutzfeldt-Jakob disease in children who received human pituitary somatotropic hormone for dwarfism treatment. Transmission via other hormones, myelopeptides, and enzymes has also been described. In veterinary medicine, a mass outbreak among sheep was documented following the use of brain formalin vaccine.
Pathogenesis and the Role of the Lymphoid System
It was previously hypothesized that prions exclusively affect the central nervous system. However, modern evidence proves that pathogenesis is a staged process in which lymphoid tissue plays a critical role.
Following alimentary infection, the pathological protein undergoes the following stages:
- Initial stage. Pathological prions enter the intestinal lumen, from where they are transported into the blood and lymphatic system.
- Peripheral replication. Primary replication of the agent occurs not in the brain, but in peripheral lymphoid organs (tonsils, appendix, spleen). Follicular dendritic cells (FDCs), which specialize in trapping immune complexes, play a key role here. The membrane of FDCs expresses an abundance of normal prion protein. The pathological prion adsorbs onto the cell via complement receptors (upon opsonization) or through direct contact with the normal protein. The accumulation of prions in the spleen directly correlates with the number and activity of FDCs.
- Neuroinvasion. Following a period of accumulation in lymphoid organs (incubation), prions are transported to the CNS. The primary entry route into the brain is via peripheral nerves. An alternative route—direct crossing of the blood-brain barrier (BBB)—also exists.
Pathomorphological Changes and Clinical Presentation
High concentrations of pathological prions accumulating in the brain lead to extensive and irreversible tissue changes known as transmissible spongiform encephalopathies.
Morphologically, the process is characterized by the following features:
- Spongiform transformation. Vacuoles form within neurons, giving the nervous tissue a sponge-like appearance.
- Astrocytosis. Active proliferation of astrocytic neuroglia occurs with hyperproduction of glial fibers.
- Amyloidosis. Extracellular dysproteinosis develops, resulting in the formation of protein aggregates, fibrils, and amyloid deposits.
- Atrophy and sclerosis. Nervous tissue undergoes atrophy followed by subsequent sclerosis.
- These severe organic CNS lesions determine the clinical manifestations of the disease. Affected individuals exhibit profound behavioral changes, severe motor coordination deficits, and progressive dementia. The outcome is uniformly fatal, culminating in profound wasting. A critical feature of prion infections is that, despite severe systemic damage, no specific immune response against the agent is generated.