Summary Transmissible spongiform encephalopathies (TSEs) are a group of subacute infectious neurodegenerative diseases that are characterized by the accumulation in affected tissues of PrPSc, an abnormal isoform of the host prion protein (PrPc). Following peripheral exposure, TSE infectivity and PrPSc usually accumulate in lymphoid tissues prior to neuroinvasion. Studies in mice have shown that exposure through scarified skin is an effective means of TSE transmission. Following inoculation via the skin, a functional immune system is critical for the transmission of TSEs to the brain, but until now, it has not been known which components of the immune system are required for efficient neuroinvasion. Temporary dedifferentiation of follicular dendritic cells (FDCs) by treatment with an inhibitor of the lymphotoxin‐β receptor signalling pathway (LTβR‐Ig) 3 days before or 14 days after inoculation via the skin, blocked the early accumulation of PrPSc and TSE infectivity within the draining lymph node. Furthermore, in the temporary absence of FDCs before inoculation, disease susceptibility was reduced and survival time significantly extended. Treatment with LTβR‐Ig 14 days after TSE inoculation also significantly extended the disease incubation period. However, treatment 42 days after inoculation did not affect disease susceptibility or survival time, suggesting that the infection may have already have spread to the nervous system. Together these data show that FDCs are essential for the accumulation of PrPSc and infectivity within lymphoid tissues and subsequent neuroinvasion following TSE exposure via the skin.
Summary The accumulation of the scrapie agent in lymphoid tissues following inoculation via the skin is critical for efficient neuroinvasion, but how the agent is initially transported from the skin to the draining lymph node is not known. Langerhans cells (LCs) are specialized antigen‐presenting cells that continually sample their microenvironment within the epidermis and transport captured antigens to draining lymph nodes. We considered LCs probable candidates to acquire and transport the scrapie agent after inoculation via the skin. XS106 cells are dendritic cells (DCs) isolated from mouse epidermis with characteristics of mature LC cells. To investigate the potential interaction of LCs with the scrapie agent XS106 cells were exposed to the scrapie agent in vitro. We show that XS106 cells rapidly acquire the scrapie agent following in vitro exposure. In addition, XS106 cells partially degrade the scrapie agent following extended cultivation. These data suggest that LCs might acquire and degrade the scrapie agent after inoculation via the skin, but data from additional experiments demonstrate that this ability could be lost in the presence of lipopolysaccharide or other immunostimulatory molecules. Our studies also imply that LCs would not undergo maturation following uptake of the scrapie agent in the skin, as the expression of surface antigens associated with LC maturation were unaltered following exposure. In conclusion, although LCs or DCs have the potential to acquire the scrapie agent within the epidermis our data suggest it is unlikely that they become activated and stimulated to transport the agent to the draining lymph node.
Many natural transmissible spongiform encephalopathy (TSE) infections are likely to be acquired peripherally, and studies in mice show that skin scarification is an effective means of scrapie transmission. After peripheral exposure, TSE agents usually accumulate in lymphoid tissues before spreading to the brain. The mechanisms of TSE transport to lymphoid tissues are not known. Langerhans cells (LCs) reside in the epidermis and migrate to the draining lymph node after encountering antigen. To investigate the potential role of LCs in scrapie transportation from the skin, we utilized mouse models in which their migration was blocked either due to CD40 ligand deficiency (CD40L ؊/؊ mice) or after caspase-1 inhibition. We show that the early accumulation of scrapie infectivity in the draining lymph node and subsequent neuroinvasion was not impaired in mice with blocked LC migration. Thus, LCs are not involved in TSE transport from the skin. After intracerebral inoculation with scrapie, wild-type mice and CD40L ؊/؊ mice develop clinical disease with similar incubation periods. However, after inoculation via skin scarification CD40L ؊/؊ mice develop disease significantly earlier than do wild-type mice. The shorter incubation period in CD40L ؊/؊ mice is unexpected and suggests that a CD40L-dependent mechanism is involved in impeding scrapie pathogenesis. In vitro studies demonstrated that LCs have the potential to acquire and degrade protease-resistant prion protein, which is thought to be a component of the infectious agent. Taken together, these data suggest that LCs are not involved in scrapie transport to draining lymphoid tissues but might have the potential to degrade scrapie in the skin.
IntroductionEpstein-Barr virus (EBV) is a ␥-herpes virus with a widespread distribution in human populations. 1 EBV infects and immortalizes B cells and persists in the vast majority of individuals as a lifelong latent infection of the resting memory B-cell pool. 2 EBV is implicated in the etiology of a diverse range of malignancies, including Burkitt lymphoma, Hodgkin disease, and lymphomas that arise in immunosuppressed individuals. In addition, EBV is implicated in the development of a number of autoimmune diseases, including systemic lupus erythematosus. 3 EBNA2, together with EBNA-leader protein (LP), is the first viral gene expressed following infection and is absolutely required for B-cell transformation by initiating and maintaining proliferation. EBNA2 is a transcription factor with a potent transactivator domain, but without intrinsic DNA binding activity. EBNA2 is tethered to responsive viral and cellular promoters through host DNA-binding proteins, including CBF1 (also called RBP-J), 4-7 PU.1, 8 and hnRNP D. 9 EBNA2 initiates the transcription of a cascade of primary and secondary target genes that ultimately govern B-cell transformation. The relatively small group of proposed direct cellular target genes of EBNA2 includes CD23, 10 CD21, 11-13 C-MYC, 14 CCR7, 15 AML-2, 16 BATF, 17 and HES-1. 18 Of these, only CD23, AML-2, and C-MYC were conclusively demonstrated to be direct targets of EBNA2, as these genes did not require new protein synthesis for induction. Using a CBF1-deficient cell line, CD21 and CCR7 have recently been shown to strictly depend on CBF1 for induction by EBNA2. 19 AML-2, c-myc, BATF, and Hes-1 are all transcription factors, indicating there are likely to be numerous indirect targets of EBNA2. Indeed, among other genes, EBNA2 induces the tumor necrosis factor-␣ (TNF-a), cyclin D2, and interleukin-18 (IL-18) receptor genes indirectly. 20,21 In contrast, EBNA2 suppresses the transcription of the immunoglobulin (Ig) gene via CBF1-independent mechanisms. 19,22 EBNA2 is considered a viral analog of the cellular protein Notch. Accordingly, EBNA2 can functionally replace activated Notch. 23 All 4 Notch proteins interact with CBF1, and similarly to EBNA2 function by masking the transcriptional repressor domain of CBF1. [23][24][25] Not surprisingly, the target genes of EBNA2, at least partially, overlap with those of activated Notch. 17,26,27 Fc-receptor homolog (FcRH; also called immunoglobulin superfamily receptor translocation associated [IRTA]) comprises a family of 5 recently identified genes contiguously encoded on human chromosome 1q21. [28][29][30] Three mouse FcRHs have subsequently been identified, but there is considerable divergence from the human genes. 31 FcRH5 has no mouse homolog. The human FcRH genes are differentially expressed by specific B-cell subpopulations. 32,33 These genes encode transmembrane proteins with 3 to 9 Ig-like extracellular domains. All FcRH contain immunoreceptor tyrosine-based inhibitory motif (ITIM) and/or immunoreceptor tyrosine-based activation mot...
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