A crucial role for B cells in neuroinvasive scrapie

Abstract

Although prion proteins are most efficiently propagated through intracerebral inoculation, peripheral administration has caused the diseases kuru, iatrogenic Creutzfeldt-Jakob disease (CJD), bovine spongiform encephalopathy (BSE) and new-variant CJD. The development of neurological disease after peripheral inoculation depends on prion expansion within cells of the lymphoreticular system. Here we investigate the identity of these cells by using a panel of immune-deficient mice inoculated with prions intraperitoneally: we found that defects affecting only T lymphocytes had no apparent effect, but that all mutations that disrupted the differentiation and response of B lymphocytes prevented the development of clinical scrapie. As an absence of B cells and of antibodies correlates with severe defects in follicular dendritic cells, a lack of any of these three components may prevent the development of clinical scrapie. However, we found that scrapie developed after peripheral inoculation in mice expressing immunoglobulins that were exclusively of the M subclass and without detectable specificity for the normal form of the prion PrPC, and in mice which had differentiated B cells but no functional follicular dendritic cells. We conclude that differentiated B cells are crucial for neuroinvasion by scrapie, regardless of the specificity of their receptors.

Immunologically Induced, Complement-Dependent Up-Regulation of the Prion Protein in the Mouse Spleen: Follicular Dendritic Cells Versus Capsule and Trabeculae

“…Rag-1 Ϫ/Ϫ mice do not harbor mature lymphocytes or develop germinal centers in the secondary lymphoid organs (21). Intriguingly, in a previous study the prion pathogen was found not to replicate in spleens of Rag-1-deficient mice (22). Our immunohistochemical staining of Rag-1 Ϫ/Ϫ spleens showed that PrP is abundantly and exclusively expressed in the capsule and trabecuale (Fig.…”

“…Yet, the relative ease of immunohistochemical detection of the accumulating pathological form makes its ignorance in the abundant capsular and trabecular structures unlikely. Second, spleens of mice deficient in Rag-1 do not propagate the prion agent (22), however, we report that their capsule and trabeculae abundantly harbor PrP. Thus, trabeculocapsular PrP does not appear to be sufficient for splenic prion propagation.…”

Peripheral prion pursuit

“…While the very first step, the passage through the GI mucosal barrier, has not yet been studied in much detail, it has become clear that prions exploit various components of the immune system to move around the body. Both lymphoinvasion and neuroinvasion depend on the presence of B lymphocytes (4). Because expression of the cellular prion protein by B cells is not required for neuroinvasion (5), it has been proposed that their main function is to enable maintenance of follicular dendritic cells (FDCs) by providing lymphotoxin-β to spleen and lymph nodes.…”

Five Questions on Prion Diseases

“…1), where they colocalize with follicular dendritic cells (FDCs). The maintenance of FDCs depend on B cell-derived lymphotoxins (LTs) and tumor necrosis factor (TNF); accordingly, B cell–deficient mice (μMT, Rag1 −/− , Rag2 −/− ) that lack mature FDCs are resistant to extraneural prion challenge [7]. However, the expression of PrP C in B cells is dispensable, and transgenic expression of PrP C restricted to B cells cannot restore prion replication or neuroinvasion in Prnp knockout mice.…”