Poster Presentation The Australasian Society for Immunology 2017 Annual Scientific Meeting

Gene expression profiling reveals the molecular signature of severe carbamazepine-induced hypersensitivity reactions (#319)

Nicole Mifsud 1 , Alison Anderson 2 3 , Patricia Illing 1 , Patrick Kwan 2 3 , Anthony Purcell 1
  1. Monash University, Clayton, VIC, Australia
  2. Royal Melbourne Hospital, Parkville, VIC, Australia
  3. University of Melbourne, Parkville, VIC, Australia

Antiepileptic drugs are a major cause of cutaneous adverse drug reactions (cADRs), ranging from mild maculopapular exanthema (MPE) to potentially fatal reactions, such as Stevens Johnson syndrome (SJS). Carbamazepine (CBZ), a first-line treatment drug for epilepsy and bipolar disorder, has been implicated in a spectrum of severe cADRs that are strongly associated with both HLA-B*15:02 and HLA-A*31:01 expression. This study investigated targeted transcriptomic analysis of peripheral blood mononuclear cells obtained from patients after resolution of CBZ-induced cADRs and controls using state-of-the-art digital molecular barcoding technology (NanoString). This count-based method is optimised for differential expression analyses with superior sensitivity (zeptamole [10-21 mole] of RNA) that provides enhanced performance for gene-level relative quantification. We evaluated changes in gene expression (upregulation and downregulation) between CBZ-SJS (n=7), CBZ-MPE (n=6) cases and CBZ-Tolerant controls (n=10) using a human nCounter® CodeSet of 579 immunology-related genes. Analyses of the gene expression data was performed using both nSolver™ software (NanoString) and EdgeR software (Bioconductor). Comparison of different patient groups demonstrated statistically significant (p<0.05) differential gene expression between (i) CBZ-SJS and CBZ-Tolerant groups: upregulated (i.e. IL-1A, IL-6, CCL3, TNF) and downregulated (i.e. CCL7, CCL2) genes, (ii) CBZ-MPE and CBZ-Tolerant groups: upregulated (i.e. PPBP, EGR1, TAL1) and downregulated (i.e. IL-1B, LILRA4, CCL20) genes and (iii) CBZ-SJS and CBZ-MPE: upregulated (i.e. IL-1A, IL-B, CCL20, CCL3, IL6) and downregulated (i.e. CCL7, CCL2, CCR1) genes. This study exploits the ground-breaking potential of NanoString technology for multiplexed, quantitative analysis of gene expression, stratifying cADR clinical pathologies based on disease severity and providing novel insights into basal immune gene expression that may influence susceptibility to cADRs.