Identification of a critical CYP2E1 epitope in patients with drug-induced liver injury from anesthetics (93.16)

• Published in: The Journal of immunology (1950) 2010-04, Vol.184 (1_Supplement), p.93-93.16
• Main Authors: Njoku, Dolores, Li, Zhaoxia, Li, Haiyan, Ligons, Davinna, Rose, Noel
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.184.Supp.93.16

Susceptible individuals develop immune-mediated drug-induced liver injury (DILI) after receiving halogenated anesthetics, anti-seizure medications, antibiotics or non-steroidal anti-inflammatory drugs. In anesthetic DILI, serum cytochrome P4502E1 (CYP2E1) autoantibodies and diminished CYP2E1 activity assist in confirming the diagnosis, while responsible epitopes are unknown. We hypothesize that anesthetic DILI is initiated by pathogenic CYP2E1 epitopes centered on the Ser129 active site and presented by MHC II molecules in susceptible haplotypes. To test our hypothesis, we identified 15 mer human CYP2E1 candidate epitopes centered on Ser129 that bind to mouse MHC II using competitive inhibition of OVA323 - 329 in I-Ad DO11.10 T cell hybridomas + LS102.9 activation. Next we measured splenocyte T cell proliferation to candidate epitopes using our model of anesthetic DILI in BALB/c mice two weeks following TFA-S100 immunizations. Two CYP2E1 epitopes were detected by competitive inhibition; however, only one epitope Gly113 - Leu135 was recognized by proliferation and human sera ELISA assays. SYFPEITHI prediction of the probability of binding confirmed H2-Ad and H2-Ed haplotypes in BALB/c mice and identified 6 human MHC II haplotypes that could bind this epitope: HLA-DRB1*0101, HLA-DRB1*0301 HLA-DRB1*0401, HLA-DRB1*0701 HLADRB*1101 and HLADRB1*1501. This is the first demonstration of a CYP2E1 epitope and MHC II haplotypes that may increase the risk of developing anesthetic DILI.