RT Journal Article ID 0fe5f8f4225863b6 A1 Aoki, K. Roger A1 Smith, Leonard A. A1 Atassi, M. Zouhair T1 Mode of Action of Botulinum Neurotoxins: Current Vaccination Strategies and Molecular Immune Recognition JF Critical Reviews™ in Immunology JO CRI YR 2010 FD 2010-04-02 VO 30 IS 2 SP 167 OP 187 K1 Antigenic sites K1 antibodies K1 botulinum neurotoxin K1 cervical dystonia K1 epitopes K1 immunoresistance K1 mechanism of action K1 subunit K1 synthetic peptides K1 vaccines AB The action of a botulinum neurotoxin (BoNT) commences by binding at the nerve terminal via its H- (heavy) chain to a cell-surface receptor, which consists of a ganglioside and a cell-surface protein. Binding enables the L-chain, a Zn2+-dependent endopeptidase, to be internalized and act intracellularly, cleaving one or more SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins required for vesicle docking and fusion, which results in reduced neurotransmitter release. Sprouts emerge at motor-nerve terminals that reestablish synaptic contact and lead to restoration of exocytosis. As the terminals recover, sprouts retreat and synaptic function is fully re-established. Neutralizing antibodies (Abs) induced by vaccination can prevent the neuronal changes produced by BoNT. Until recently, vaccines against BoNT have been based on toxins inactivated by treatment with formaldehyde (toxoids) and contain either one (monovalent) or five (pentavalent) toxoids, but formalin-based toxoids have many undesirable side effects. Availability of the gene sequences of BoNT serotypes enabled design of recombinant subunit vaccines that have included the C-terminal domain of the H chain (HC, its subdomains (HC-N and HC-C), the L- (catalytic) chain, and the L-chain expressed with the translocation domain (LCHN). Of these, the HC displays the highest protective ability. Recent vaccines have used whole toxins inactivated by three key mutations at the enzyme active site, which have been found to be very effective in mice against the correlated toxin. Immune responses to BoNTs A and B epitopes are under the host’s MHC (major histocompatibility complex) control. Anti-BoNT/A blocking Abs bind at sites that coincide or overlap with those that bind synaptosomes and to BoNT/B at sites that overlap with synaptotagmin-II and ganglioside-binding sites. Therefore, locations occupied by blocking Abs preclude the respective toxin from binding to its receptor and thus from binding to cell surface. Information on BoNT epitopes for blocking Abs, sites for binding to cell surface receptors, and T-cell epitopes that provide help to B cells making blocking Abs afford a prospect for rational design of stable synthetic vaccines. These constructs should be clinically useful for epitope-selective modulation of Ab responses to restore effective BoNT treatment in immunoresistant patients. PB Begell House LK https://www.dl.begellhouse.com/journals/2ff21abf44b19838,5603dbb41ca52347,0fe5f8f4225863b6.html