Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
About the Speaker: Program in Emerging Infectious Diseases (EID) “HLA-association with disease is illuminated by drugs” By Professor James McCluskey Deputy Vice Chancellor Research The University of Melbourne Abstract : Human Leukocyte Antigens (HLA) are highly polymorphic proteins that initiate immunity by presenting pathogen-derived peptides to T cells. HLA polymorphisms mostly map to the antigen (Ag)-binding cleft, thereby diversifying the repertoire of self- and pathogenderived peptide Ags selected by different HLA allotypes. A growing number of immunologically-based drug reactions, including abacavir hypersensitivity syndrome (AHS) and carbamazepineinduced Steven-Johnson’s syndrome (SJS), are associated with specific HLA alleles. However, little is known about the underlying mechanisms of these associations, including AHS, a prototypical HLA-associated drug reaction occurring exclusively in individuals with the common histocompatibility molecule, HLA-B*57:01, and with a relative risk of >1000. We show that unmodified abacavir binds non-covalently to HLA-B*57:01, lying across the bottom of the Ag-binding cleft and reaching into the F-pocket where a C-terminal tryptophan typically anchors peptides bound to HLA-B*57:01. Abacavir binds with exquisite specificity to HLA-B*57:01, changing the shape and chemistry of the Ag-binding cleft, thereby altering the repertoire of endogenous peptides that can bind HLA-B*57:01. In this way, abacavir guides selection of new endogenous peptides, inducing a dramatic alteration in ‘immunological self’. The resultant peptide-centric ‘altered self’ activates abacavir-specific T-cells, thereby driving polyclonal CD8+ T cell activation and a systemic reaction manifesting as AHS. We also show that carbamazepine, a widely used anti-epileptic drug associated with hypersensitivity reactions in HLA-B*15:02 individuals, binds to this allotype, producing alterations in the repertoire of presented self-peptides. These findings simultaneously highlight the importance of HLA polymorphism in the evolution of pharmacogenomics, perhaps providing a general mechanism for some of the growing number of HLA-linked hypersensitivities that involve small molecule drugs, but also suggesting novel pathway for induction of autoimmunity. Date : January 15, 2013 (Tuesday) Time : 3.00 – 4.00 pm Host : Professor Linfa (Lin-Fa) WANG, PhD FTSE Program Director Program in Emerging Infectious Diseases Venue : Duke-NUS, Amphitheatre, 2nd Floor Dr James McCluskey trained in Perth as a physician and pathologist before working at the National Institutes of Health (USA). Stints at Monash University, Flinders University and the Australian Red Cross Blood Service preceded a Chair in Microbiology and Immunology at the University of Melbourne where he is now Deputy Vice Chancellor research. He has published more than 250 scientific articles on how genes control immunity. He received the Parr Prize from the Australian Rheumatism Association and the Rose Payne Medal from the American Society for Histocompatibility and Immunogenetics. He is a member of several Boards of Directors of medical research institutes and has consulted for the Australian Red Cross Blood Service for more than 20 years. He is Editor-in-Chief Tissue Antigens and Past President of the Australasian Society for Immunology and International Histocompatibility Workshop Group. He has recently led the development of the $210M Peter Doherty Institute for Infection and Immunity in Melbourne Australia. Duke-NUS Graduate Medical School, 8 College Road, S169857. For more information, please visit our website www.duke-nus.edu.sg