Journal Article

High cell surface expression and peptide binding affinity of HLA-DQA105:03, a susceptible allele of neuromyelitis optica spectrum disorders (NMOSD)

Okuno, Tatsusada, Mochizuki, Hideki, Beppu, Shohei, Sugiyama, Yasuko, Arase, Hisashi, Shiraishi, Naoyuki, Tada, Satoru, Wilamowski, Jan, Koda, Toru, Sugimoto, Tomoyuki, Standley, Daron M., Kinoshita, Makoto, Suenaga, Tadahiro, Kihara, Keigo, Yasumizu, Yoshiaki, Ishikura, Teruyuki, Ogawa, Kotaro, Murata, Hisashi

2022

Overview

Neuromyelitis optica spectrum disorder (NMOSD) is a relapsing autoimmune disease characterized by the presence of pathogenic autoantibodies, anti-aquaporin 4 (AQP4) antibodies. Recently, HLA-DQA1*05:03 was shown to be significantly associated with NMOSD in a Japanese patient cohort. However, the specific mechanism by which HLA-DQA1*05:03 is associated with the development of NMOSD has yet to be elucidated. In the current study, we revealed that HLA-DQA1*05:03 exhibited significantly higher cell surface expression levels compared to other various DQA1 alleles, and that its expression strongly depended on the amino acid sequence of the α1 domain, with a preference for leucine at position 75. Moreover, in silico analysis indicated that the HLA-DQ encoded by HLA-DQA1*05:03 preferentially presents immunodominant AQP4 peptides, and that the peptide major histocompatibility complexes (pMHCs) are more energetically stable in the presence of HLA-DQA1*05:03 than other HLA-DQA1 alleles. In silico 3D structural models were also applied to investigate the validity of the energetic stability of pMHCs. Taken together, our findings indicate that HLA-DQA1*05:03 possesses a distinct property to play a pathogenic role in the development of NMOSD.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 631/250/371 / 631/250/38 / Alleles / Amino Acid Sequence / Amino acids / Aquaporin 4 / Aquaporin 4 - immunology / Aquaporin 4 - metabolism / Autoantibodies / Autoantibodies - blood / Autoimmune diseases / Cell Membrane - immunology / Cell Membrane - metabolism / Cell surface / DQA1 protein / HEK293 Cells / Histocompatibility antigen HLA / HLA-DQ alpha-Chains - genetics / HLA-DQ alpha-Chains - immunology / HLA-DQ alpha-Chains - metabolism / Humanities and Social Sciences / Humans / Immunodominant Epitopes / Immunoglobulin G - blood / Models, Molecular / multidisciplinary / Neuromyelitis / Neuromyelitis Optica - diagnosis / Neuromyelitis Optica - genetics / Neuromyelitis Optica - immunology / Neuromyelitis Optica - metabolism / Peptides / Protein Binding / Protein Domains / Science / Science (multidisciplinary) / Structural models