HLA-DQB1*05 subtypes and not DRB1*10:01 mediates risk in anti-IgLON5 disease

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Abstract
Anti-IgLON5 disease is a rare and likely underdiagnosed subtype of autoimmune encephalitis. The disease displays a heterogeneous phenotype that includes sleep, movement, and bulbar-associated dysfunction. Presence of IgLON5-antibodies in CSF/serum, together with a strong association with HLA-DRB1*10:01∼DQB1*05:01, support an autoimmune basis. In this study, a multicentric HLA study of 87 anti-IgLON5 patients revealed a stronger association with HLA-DQ than HLA-DR. Specifically, we identified a predisposing rank-wise association with HLA-DQA1*01:05∼DQB1*05:01, HLA-DQA1*01:01∼DQB1*05:01 and HLA-DQA1*01:04∼DQB1*05:03 in 85% of patients. HLA sequences and binding cores for these three DQ heterodimers were similar, unlike those of linked DRB1 alleles, supporting a causal link to HLA-DQ. This association was further reflected in an increasingly later age of onset across each genotype group, with a delay of up to 11 years, while HLA-DQ-dosage dependent effects were also suggested by reduced risk in the presence of non-predisposing DQ1 alleles. The functional relevance of the observed HLA-DQ molecules was studied with competition binding assays. These proof-of-concept experiments revealed preferential binding of IgLON5 in a post-translationally modified, but not native, state to all three risk-associated HLA-DQ receptors. Further, a deamidated peptide from the Ig2-domain of IgLON5 activated T cells in two patients, compared to one control carrying HLA-DQA1*01:05∼DQB1*05:01. Taken together, these data support a HLA-DQ-mediated T cell response to IgLON5 as a potentially key step in the initiation of autoimmunity in this disease.
Funding Information
  • The Stanford Autoimmune & Allergy Supergroup
  • National Institutes of Health (NIH-5U01NS120885-02)
  • Einstein Center for Neurosciences Berlin
  • German-Academic Exchange Service
  • French National Research Agency (ANR-18-RHUS-0012)
  • European Reference Networks
  • Research and Innovative Technology Administration
  • LABEX CORTEX (ANR-11-LABX-0042)
  • Deutsche Forschungsgemeinschaft (FI 2309/1-1, FI 2309/2-1)
  • Bundesministerium für Forschung, Technologie und Raumfahrt (01GM1908D)
  • Medical Research Council (MR/V007173/1)
  • Wellcome Trust (104079/Z/14/Z)
  • British Medical Association
  • Epilepsy Research Institute UK
  • US-UK Fulbright Commission
  • National Institute for Health Research
  • NIHR
  • Oxford Biomedical Research Centre
  • European Regional Development Fund
  • Betty and David Koetser Foundation
  • Neuromuscular Research Association Basel (22K07492, JP21K07457)
  • Helmholtz Association (HIL-A03 BaoBab)
  • German Federal Ministry of Education and Research (01GM1908D)
  • Caixa Research Health 2022 (HR22-00221)
  • Instituto de Salud Carlos III
  • European Union’s Horizon 2020

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