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

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.

SUBMITTER: Beppu S

PROVIDER: S-EPMC8742014 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundNeuromyelitis Optica Spectrum Disorder (NMOSD) is an inflammatory disease of the central nervous system with preferential involvement of the optic nerve and spinal cord. However, data on NMOSD incidences in China, a country encompassing 20% of the world's population and covering vast areas of Eastern Asia, are unknown.MethodsWe conducted the first nationwide survey of NMOSD, based on the database of the National Hospital Quality Monitoring System (HQMS) of China, which covers all 1665 tertiary hospitals. The "Medical Record Homepage" of all patients were consistently collected via a standard protocol across each tertiary hospital. The primary outcome was the incidence of NMOSD, diagnosed according to the 2015 International Panel for Neuromyelitis Optica Diagnosis criteria and identified by ICD-10 code (G36•0). Burden of hospitalization, comorbidities, and death were also evaluated.FindingsWe identified 33,489 hospital admissions for 17,416 NMOSD diagnosed patients from 2016 to 2018. 11,973 patients were newly diagnosed NMOSD. The age and sex adjusted incidence per 100,000 person years was 0•278 (95% confidence interval [CI], 0•273-0•283), with 0•075 (0•069-0•08) in child and 0•347 (0•34-0•353) in adult. The peak age of onset NMOSD is 45-65 years with an incidence 0•445/100,000 (95% CI, 0•433-0•457). The female to male ratio was 4•71 (p<0•001, 95% CI, 4•50-4•94). Geographical distribution of NMOSD is not related to the latitude gradient. Sjögren's syndrome (1,124/17,416, 6•5%) and systemic lupus erythematosus (387/17,416, 2•2%) are the most frequently autoimmune comorbidities. 106 adults and 4 children of the 17,416 NMOSD cohort died.InterpretationThe incidence of NMOSD in China per 100,000 person years was 0•278, with 0•075 in child and 0•347 in adult. The geographical distribution of NMOSD is not related to the latitude gradient.FundingNational Science Foundation of China (91949208, 91642205, and 81830038); Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing.

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

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