Distinct HLA associations of LGI1 and CASPR2-antibody diseases.

Binks, Sophie and Varley, James and Lee, Wanseon and Makuch, Mateusz and Elliott, Katherine and Gelfand, Jeffrey M and Jacob, Saiju and Leite, M Isabel and Maddison, Paul and Chen, Mian and Geschwind, Michael D and Grant, Eleanor and Sen, Arjune and Waters, Patrick and McCormack, Mark and Cavalleri, Gianpiero L and Barnardo, Martin and Knight, Julian C and Irani, Sarosh R (2018) Distinct HLA associations of LGI1 and CASPR2-antibody diseases. Brain : a journal of neurology, 141 (8). pp. 2263-2271. ISSN 1460-2156. This article is available to all UHB staff and students via ASK Discovery tool http://tinyurl.com/z795c8c by using their UHB Athens login IDs

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Official URL: https://academic.oup.com/brain/article/141/8/2263/...

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.

Item Type: Article
Additional Information: This article is available to all UHB staff and students via ASK Discovery tool http://tinyurl.com/z795c8c by using their UHB Athens login IDs
Subjects: WL Nervous system. Neurology
Divisions: Emergency Services > Neurology
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Depositing User: Mrs Semanti Chakraborty
Date Deposited: 19 Jul 2019 12:02
Last Modified: 19 Jul 2019 12:02
URI: http://www.repository.uhblibrary.co.uk/id/eprint/2246

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