Journal
BRAIN
Volume 141, Issue -, Pages 2263-2271Publisher
OXFORD UNIV PRESS
DOI: 10.1093/brain/awy109
Keywords
human leucocyte antigen; leucine-rich glioma-inactivated 1; contactin-associated protein 2; voltage-gated potassium channel; major histocompatibility complex
Categories
Funding
- Wellcome [104079/Z/14/Z]
- BMA Research Grants- Vera Down grant
- Margaret Temple grant
- Epilepsy Research UK [P1201]
- Fulbright UK-US commission (MS-Society research award)
- National Institute for Health Research (NIHR) Oxford Biomedical Research Centre
- Arthritis Research UK [20773]
- Wellcome Investigator Award [204969/Z/16/Z]
- Association of British Neurologists and Guarantors of Brain
- NIH/NIA [R01 AG AG031189]
- Quest Diagnostics, Inc.
- Tau Consortium
- Michael J. Homer Family Fund
- Wellcome Trust [204969/Z/16/Z, 104079/Z/14/Z] Funding Source: Wellcome Trust
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The recent biochemical distinction between antibodies against leucine-rich, glioma-inactivated-1 (LGI1), contactin-associated protein-2 (CASPR2) and intracellular epitopes of voltage-gated potassium-channels (VGKCs) demands aetiological explanations. Given established associations between human leucocyte antigen (HLA) alleles and adverse drug reactions, and our clinical observation of frequent adverse drugs reactions in patients with LGI1 antibodies, we compared HLA alleles between healthy controls (n = 5553) and 111 Caucasian patients with VGKC-complex autoantibodies. In patients with LGI1 antibodies (n = 68), HLA-DRB1* 07: 01 was strongly represented [odds ratio = 27.6 (95% confidence interval 12.9-72.2), P = 4.1 x 10(-26)]. In contrast, patients with CASPR2 antibodies (n = 31) showed over-representation of HLA-DRB1* 11:01 [odds ratio = 9.4 (95% confidence interval 4.6-19.3), P = 5.7 x 10(-6)]. Other allelic associations for patients with LGI1 antibodies reflected linkage, and significant haplotypic associations included HLA-DRB1* 07: 01-DQA1* 02:01-DQB1* 02:02, by comparison to DRB1* 11: 01-DQA1* 05: 01-DQB1* 03: 01 in CASPR2-antibody patients. Conditional analysis in LGI1-antibody patients resolved further independent class I and II associations. By comparison, patients with both LGI1 and CASPR2 antibodies (n = 3) carried yet another complement of HLA variants, and patients with intracellular VGKC antibodies (n = 9) lacked significant HLA associations. Within LGI1- or CASPR2-antibody patients, HLA associations did not correlate with clinical features. In silico predictions identified unique CASPR2- and LGI1-derived peptides potentially presented by the respective over-represented HLA molecules. These highly significant HLA associations dichotomize the underlying immunology in patients with LGI1 or CASPR2 antibodies, and inform T cell specificities and cellular interactions at disease initiation.
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