Suscripción a Biblioteca: Guest
Portal Digitalde Biblioteca Digital eLibros Revistas Referencias y Libros de Ponencias Colecciones
Critical Reviews™ in Immunology
Factor de Impacto: 1.404 Factor de Impacto de 5 años: 3.347 SJR: 0.706 SNIP: 0.55 CiteScore™: 2.19

ISSN Imprimir: 1040-8401
ISSN En Línea: 2162-6472

Volumes:
Volumen 40, 2020 Volumen 39, 2019 Volumen 38, 2018 Volumen 37, 2017 Volumen 36, 2016 Volumen 35, 2015 Volumen 34, 2014 Volumen 33, 2013 Volumen 32, 2012 Volumen 31, 2011 Volumen 30, 2010 Volumen 29, 2009 Volumen 28, 2008 Volumen 27, 2007 Volumen 26, 2006 Volumen 25, 2005 Volumen 24, 2004 Volumen 23, 2003 Volumen 22, 2002 Volumen 21, 2001 Volumen 20, 2000 Volumen 19, 1999 Volumen 18, 1998 Volumen 17, 1997 Volumen 16, 1996 Volumen 15, 1995 Volumen 14, 1994

Critical Reviews™ in Immunology

DOI: 10.1615/CritRevImmunol.v30.i2.50
pages 167-187

Mode of Action of Botulinum Neurotoxins: Current Vaccination Strategies and Molecular Immune Recognition

K. Roger Aoki
Ailergan, Inc., 2525 DuPont Drive, Irvine, CA 92612, USA
Leonard A. Smith
Integrated Toxicology Division, US Army Medical Research Institute of Infectious Diseases; Fort Detrick, MD 21702-5011, USA
M. Zouhair Atassi
Baylor College of Medicine Houston, TX 77030

SINOPSIS

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.


Articles with similar content:

The Role of Tissue Factor in Cancer-Related Hypercoagulability, Tumor Growth, Angiogenesis and Metastasis and Future Therapeutic Strategies
Critical Reviews™ in Oncogenesis, Vol.22, 2017, issue 3-4
Grigoris T. Gerotziafas, Ιsmail Εlalamy, Patrick Van Dreden
Structure, Activity, and Immune (T and B Cell) Recognition of Botulinum Neurotoxins
Critical Reviews™ in Immunology, Vol.19, 1999, issue 3
Minako Oshima, M. Zouhair Atassi
DNA Vaccines
Critical Reviews™ in Immunology, Vol.18, 1998, issue 5
Wayne C. Lai, Michael Bennett
The Mucosal Adjuvant Activities of ADP-Ribosylating Bacterial Enterotoxins
Critical Reviews™ in Immunology, Vol.15, 1995, issue 3-4
Denis P. Snider
Antigen-Specific B-Lymphocyte Activation
Critical Reviews™ in Immunology, Vol.23, 2003, issue 3
Gail A. Bishop, Sokol A. Haxhinasto, Bruce S. Hostager, Laura L. Stunz