Author:
Yamamoto Hironori,Miyashita Yohei,Minamiguchi Hitoshi,Hosomichi Kazuyoshi,Yoshida Shohei,Kioka Hidetaka,Shinomiya Haruki,Nagata Haruno,Onoue Kenji,Kawasaki Masato,Kuramoto Yuki,Nomura Akihiro,Toma Yuichiro,Watanabe Tetsuya,Yamada Takahisa,Ishihara Yasuki,Nagata Miho,Kato Hisakazu,Hakui Hideyuki,Saito Yoshihiko,Asano Yoshihiro,Sakata Yasushi
Abstract
AbstractCardiac sarcoidosis (CS) is the scarring of heart muscles by autoimmunity, leading to heart abnormalities and patients with sarcoidosis with cardiac involvements have poor prognoses. Due to the small number of patients, it is difficult to stratify all patients of CS by human leukocyte antigen (HLA) analysis. We focused on the structure of antigen-recognizing pockets in heterodimeric HLA-class II, in addition to DNA sequences, and extracted high-affinity combinations of antigenic epitopes from candidate autoantigen proteins and HLA. Four HLA heterodimer-haplotypes (DQA1*05:03/05:05/05:06/05:08-DQB1*03:01) were identified in 10 of 68 cases. Nine of the 10 patients had low left ventricular ejection fraction (< 50%). Fourteen amino-acid sequences constituting four HLA anchor pockets encoded by the HLA haplotypes were all common, suggesting DQA1*05:0X-DQB1*03:01 exhibit one group of heterodimeric haplotypes. The heterodimeric haplotypes recognized eight epitopes from different proteins. Assuming that autoimmune mechanisms might be activated by molecular mimicry, we searched for bacterial species having peptide sequences homologous to the eight epitopes. Within the peptide epitopes form the SLC25A4 and DSG2, high-homology sequences were found in Cutibacterium acnes and Mycobacterium tuberculosis, respectively. In this study, we detected the risk heterodimeric haplotypes of ventricular dysfunction in CS by searching for high-affinity HLA-class II and antigenic epitopes from candidate cardiac proteins.
Funder
Japan Society for the Promotion of Science
Japan Agency for Medical Research and Development
Publisher
Springer Science and Business Media LLC