High cell surface expression and peptide binding affinity of HLA-DQA1*05:03, a susceptible allele of neuromyelitis optica spectrum disorders (NMOSD).

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

Journal: Scientific reports 2022;12(1):106

PMID: 34997058

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Abstract

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.

Address: Department of Neurology, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.; Department of Neurology, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan. [email protected].; Department of Genome Informatics, Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka, 565-0871, Japan.; Department of Microbiology, Fukushima Medical University, 1 Hikariga-oka, Fukushima, Fukushima, 960-1295, Japan.; Department of Experimental Immunology, WPI Immunology Frontier Research Center, Osaka University, 3-1 Yamadaoka, Suita, Osaka, 565-0871, Japan.; Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.; Graduate School of Data Science, Shiga University, 1-1-1 Banba, Hikone, Shiga, 522-8522, Japan.; Department of Immunochemistry, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka, 565-0871, Japan.; Laboratory of Immunochemistry, WPI Immunology Frontier Research Center, Osaka University, 3-1 Yamadaoka, Suita, Osaka, 565-0871, Japan.; Systems Immunology Laboratory, WPI Immunology Frontier Research Center, Osaka University, 3-1 Yamadaoka, Suita, Osaka, 565-0871, Japan.; Department of Neurology, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan. [email protected].

DOI: 10.1038/s41598-021-04074-1

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MeSH Terms: Amino Acid Sequence, Aquaporin 4, Autoantibodies, Cell Membrane, HEK293 Cells, HLA-DQ alpha-Chains, Humans, Immunodominant Epitopes, Immunoglobulin G, Models, Molecular, Neuromyelitis Optica, Protein Binding, Protein Domains