Oral Presentation The 13th International Congress of the Immunology of Diabetes Society 2013

Immune self-reactivity triggered by drug-modified Human Leukocyte Antigen-peptide repertoire (#2)

Patricia T Illing 1 2 , Julian P Vivian 3 , Nadine L Dudek 2 , Lyudmila Kostenko 1 , Zhenjun Chen 1 , Mandvi Bharadwaj 1 , John J Miles 4 , Lars Kjer-Nielsen 1 , Stephanie Gras 3 , Nicholas A Williamson 3 , Scott R Burrows 4 , Anthony W Purcell (Joint corresponding author) 3 , Jamie Rossjohn (Joint corresponding author) 3 5 , James McCluskey 1
  1. Department of Microbiology & Immunology, University of Melbourne, Parkville, VIC 3010, Australia
  2. Department of Biochemistry and Molecular Biology and Bio21 Molecular Science and Biotechnology Institute, Metabolomics Australia, University of Melbourne, Parkville, VIC 3010, Australia
  3. Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, VIC 3800, Australia
  4. Queensland Institute of Medical Research and Australian Centre for Vaccine Development, Brisbane, Australia
  5. Department of Infection, Immunity and Biochemistry, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, Wales, UK

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 pathogen-derived peptide Ags selected by different HLA allotypes. A growing number of immunologically-based drug reactions, including abacavir hypersensitivity syndrome (AHS) and carbamazepine-induced 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.