IntroductionImmune-checkpoint inhibitors are effective in various advanced cancers.Type 1 diabetes mellitus induced by them (ICI-T1DM) is a serious complication requiring prompt insulin treatment, but the immunological mechanism behind it is unclear.MethodsWe examined amino acid polymorphisms in we care vitamin a and d ointment human histocompatibility leukocyte antigen (HLA) molecules and investigated proinsulin epitope binding affinities to HLA molecules.Results and DiscussionTwelve patients with ICI-T1DM and 35 patients in a control group without ICI-T1DM were enrolled in the study.
Allele and haplotype frequencies of HLA-DRB1*04:05, DQB1*04:01, and most importantly DPB1*05:01 were significantly increased in patients with ICI-T1DM.In addition, novel amino acid polymorphisms in HLA-DR (4 polymorphisms), in DQ (12 polymorphisms), and in DP molecules (9 polymorphisms) were identified.These amino acid polymorphisms might be associated with the development of ICI-T1DM.Moreover, novel human proinsulin epitope clusters in insulin A and B chains were discovered in silico and in vitro peptide binding assays to HLA-DP5.
In conclusion, significant amino acid polymorphisms in HLA-class II molecules, and conformational alterations in the supreme hysteric glamour text peptide-binding groove of the HLA-DP molecules were considered likely to influence the immunogenicity of proinsulin epitopes in ICI-T1DM.These amino acid polymorphisms and HLA-DP5 may be predictive genetic factors for ICI-T1DM.