A role for B lymphocytes in anti-infective prion therapies?

Abstract

The deposition of proteins in the form of amyloid fibrils and plaques is the characteristic feature of a number of neurodegenerative conditions affecting the nervous system. These disorders include prion and Alzheimer's diseases and are of enormous importance for public health. It has become apparent over the last 20 years that specificity and application in prion diseases' diagnostic and therapeutic situations are the most important considerations in designing strategies for the generation of antiprion antibodies. Specific antiprion therapeutics have been suggested and the establishment of the 'proof-of-principle' that the use of epitope-specific antiprion antibodies leads to indefinite delay of disease onset, has increased momentum for its use, although caution should be exerted prior to the application of new therapeutic strategies in a clinical set up. Furthermore, in vivo stimulation of immune-competent cells to specifically recognize and neutralize the abnormally folded isoform should also be pursued.

A Camelid Anti-PrP Antibody Abrogates PrPSc Replication in Prion-Permissive Neuroblastoma Cell Lines

“…Prion disorders are associated with conversion of the normal cellular prion protein (PrP C ) into a disease-associated isoform, PrP Sc , that acquires increased β-sheet structure and detergent insolubility [2]. These diseases are characterised by the deposition and aggregation of proteins into highly stable, partially proteinase-resistant plaques and fibrils [3], leading to neuronal cell death and spongiform change of the brain parenchyma [4].…”

Detection of Protein Aggregates in Brain and Cerebrospinal Fluid Derived from Multiple Sclerosis Patients

“…We have also shown previously that immunization with amyloid component of native prions leads to T-independent B-cell immune response with chronic secretion of abnormally hyper mutated IgM (Tayebi and David, Personal communication). In prion disease, failure of classical immune protection to “neutralize” auto-antigens suggests a highly aggregated state of these proteins and their ability to resist low pH in the endosomal environment renders them unable to properly process such proteins in an MHC class II-restricted pathway that involves T-cell help ( 7 ). The failure to process these auto-antigens through classical pathways has perhaps led the immune system to use “alternative” pathways, namely the T-independent B-cell responses as is well recognized with so-called thymus-independent (TI)-1 and 2 antigens ( 6 ).…”

“…Proteinase K (PK)-sensitive oligomers are considered the toxic species in protein-misfolding diseases (PMDs) and have been demonstrated by many research groups ( 7 ). We wanted to confirm whether soluble oligomers immunodetected in MS displayed resistance to PK and behaved in a prion-like fashion.…”