**5. Pathogenesis of CWD: the interaction of prions and immune system**

The unique features of prions as infectious agents are also blatant when considering its interaction with the host's immune system. As stated previously, PrPc is involved in important neurologic functions; however, the depletion of neuronal PrPc in experimental models, such as mice, cows, and goats, did not result in altered phenotypes [11]. This suggests the existence of redundant mechanisms that compensate the absence of PrPc , albeit its ubiquitous cellular expression. Pertaining the immune system, PrPc is expressed in lymphocytes, granulocytes, and stromal cells. This abundant expression may explain why PrPsc does not elicit specific immune responses despite its accumulation in high levels within the host's secondary lymphoid tissues (SLT) in the initial phases of the infection. In particular, gut-associated lymphoid tissues (GALT), such as the Peyer's patches in the small intestine, seem to be pivotal for the infection and disease process. As in most natural occurring prion diseases, CWD of cervids is acquired peripherally, mainly after oral exposure, after which prions replicate in GALT. The importance of GALT in the pathogenesis of prion diseases is well documented by several studies that revealed impaired neuroinvasion in the absence of Peyer's patches [137–140].

#### **5.1** *M* **cells**

Within GALT, studies suggest that prions depend on host *M* cells to enter the organism, as they seem to be involved in the initial transfer of the prion agent across the gut epithelium. These are specialized epithelial cells widely spread among the follicle-associated epithelium, which are involved in the transcytosis of particulate antigens and microorganisms from the gut lumen into the GALT [141]. *M* cells are essential to the gut immune system being fundamental to antigen recognition and presentation of pathogens or commensal microflora. As such, factors that increase *M*-cell density in the gut epithelium (coinfections or miscellaneous inflammatory conditions) may also increase susceptibility to orally acquired prion infections. A study by Wyckoff et al. [142] mentions the binding of prions to certain types of soil particles that may result in an increased uptake of prions from the gut lumen, but it is not yet clear if this uptake is mediated by *M* cells. Host infection by

**117**

with CWD [173].

*TSE Monitoring in Wildlife Epidemiology, Transmission, Diagnosis, Genetics and Control*

**5.2 Follicular dendritic cells (FDC) and B and T lymphocytes**

*M*-cell-independent mechanisms cannot be disregarded, namely, those involving directly enterocytes from the follicle-associated epithelium [143] or other *M*-cell-

Several studies show that in prion-infected hosts, high accumulations of disease-specific PrP are detectable within the B-cell follicles of the SLT [145–149]. After internalization, evidence suggests that prions accumulate and replicate in the follicular dendritic cells (FDC) that lie in the B-cell follicles and germinal centers of SLT [150–156]. FDC possess multiple slender and long dendritic processes, differentiate from ubiquitous perivascular precursor cells (pericytes), and are a distinct lineage from bone marrow-derived conventional dendritic cells (DC) [157, 158]. FDC extend throughout the B-cell follicle being able to trap and retain large amounts of native antigens upon their surfaces in the form of immune complexes composed by antigen–antibody and/or opsonizing complement components. Apparently, prions can be bound by opsonizing complement components [152–155], internalized, and replicated within FDC, as it was demonstrated that

mice, sheep with natural scrapie, cervids with CWD, and patients with vCJD [145–149]. Subsequently, immunohistochemistry studies identified FDC as the first sites of prion conversion and replication in experimentally infected mice, in which increased prion labeling was observed on the plasma membranes of FDC in the Peyer's patch germinal centers [143]. Furthermore, evidence suggests that FDC maturation and regression cycle are impaired by disease-associated prion protein, thus affecting immune function [159]. Despite this, some prion strains can establish infection within SLT regardless of FDC, as it was demonstrated by experimental studies in mice, where infection occurred associated to the high endothelial venules

The role of B and T cells in prion disease pathogenesis remains uncertain. Experimental studies showed that mice lacking mature B and T cells were not susceptible to peripheral infection with prions [145, 161–163], despite prion disease pathogenesis being unaffected in T-deficient mice [162, 164, 165]; however, it seems that prions are not capable of replicating within B and T cells [166, 167]. These cells appear to be intermediary actors in prion diseases, by providing physical and humoral support to other cells, thus contributing to the homeostatic state of the immune system. However, B cells, in particular, seem to play a more active role during prion infection. The ability of secreting tumor necrosis factor-α (TNF-α) and lymphotoxins (LT) turns B cells pivotal in keeping FDC in their differentiated state, since in the absence of stimulation from these cytokines, FDC rapidly dedifferentiate [168]. In Peyer's patches, B cells migrate to the mesenteric lymph nodes and then return to the circulation [169]. It is this constant rotation between Peyer's patches and SLT that may help B cells to disseminate prions acquired from FDC as they both migrate together through the germinal centers [170, 171]. Additionally, the accumulation of prions in the spleen and subsequent neuroinvasion are significantly decreased in the specific absence of B cells [162]. It is also noteworthy that prions were detected in B cells from the blood of sheep with scrapie [172] and deer

As it was already mentioned, FDC in the Peyer's patches are major sites of early prion replication in orally infected animals, both experimentally [137–140, 174] and in the natural forms of the disease. The study of natural scrapie cases in sheep showed that GALT of the upper gastrointestinal tract exhibited early accumulation


*DOI: http://dx.doi.org/10.5772/intechopen.85797*

independent pathways [144].

they accumulate upon PrPc

in the lymph nodes [160].

*M*-cell-independent mechanisms cannot be disregarded, namely, those involving directly enterocytes from the follicle-associated epithelium [143] or other *M*-cellindependent pathways [144].
