A CRUCIAL ROLE FOR B-CELLS IN NEUROINVASIVE SCRAPIE

Although prion proteins are most efficiently propagated through intrac erebral inoculation, peripheral administration has caused the diseases kuru, iatrogenic Creutzfeldt-Jakob disease (CJD), bovine spongiform e ncephalopathy (BSE) and new-variant CJD(1,2). The development of neuro logical disease after peripheral inoculation depends on prion expansio n within cells of the lymphoreticular system(3,4). Here we investigate the identity of these cells by using a panel of immune-deficient mice inoculated with prions intraperitoneally: we found that defects affec ting only T lymphocytes had no apparent effect, but that all mutations that disrupted the differentiation and response of B lymphocytes prev ented the development of clinical scrapie. As an absence of B cells an d of antibodies correlates with severe defects in follicular dendritic cells, a lack of any of these three components may prevent the develo pment of clinical scrapie. However, we found that scrapie developed af ter peripheral inoculation in mice expressing immunoglobulins that wer e exclusively of the M subclass and without detectable specificity for the normal form of the prion PrPc, and in mice which had differentiat ed B cells but no functional follicular dendritic cells. We conclude t hat differentiated B cells are crucial for neuroinvasion by scrapie, r egardless of the specificity of their receptors.