Distinct HLA associations of LGI1 and CASPR2-antibody diseases

Sophie Binks, James Varley, Wanseon Lee, Mateusz Makuch, Katherine Elliott, Jeffrey M Gelfand, Saiju Jacob, M Isabel Leite, Paul Maddison, Mian Chen, Michael D Geschwind, Eleanor Grant, Arjune Sen, Patrick Waters, Mark McCormack, Gianpiero L Cavalleri, Martin Barnardo, Julian C Knight, Sarosh R Irani

Research output: Contribution to journalArticlepeer-review

48 Citations (Scopus)

Abstract

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 × 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 × 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.10.1093/brain/awy109_video1awy109media15796480660001.

Original languageEnglish
Pages (from-to)2263-2271
Number of pages9
JournalBrain
Volume141
Issue number8
DOIs
Publication statusPublished - 1 Aug 2018

Keywords

  • Adult
  • Aged
  • Aged, 80 and over
  • Alleles
  • Autoantibodies/metabolism
  • Epitopes
  • European Continental Ancestry Group/genetics
  • Female
  • Gene Frequency/genetics
  • Genetic Linkage/genetics
  • HLA Antigens/metabolism
  • HLA-DRB1 Chains/genetics
  • Haplotypes
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Male
  • Membrane Proteins/genetics
  • Middle Aged
  • Nerve Tissue Proteins/genetics
  • Potassium Channels, Voltage-Gated/genetics
  • Proteins/genetics

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