Distinct HLA associations of LGI1 and CASPR2-antibody diseases.

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

doi:10.1093/brain/awy109

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.

Highlights

Given these significant and distinct allelic and haplotypic human leucocyte antigen (HLA) associations, for each serologically-defined group, we evaluated their value in explaining sub-phenotypes, long-term outcomes or adverse drug reactions (Supplementary Table 1), and found no significant HLA allele or haplotype associations
Given the frequently overlapping clinical features in patients with LGI1 and contactin-associated protein 2 (CASPR2) antibodies, and their co-expression in VGKC complexes, these findings indicate that dichotomous predisposing HLA variants govern the generation of LGI1 versus CASPR2 antibodies
While HLA-DRB1*07:01 and linked class II alleles, including the haplotype HLA-DRB1*07:01-DQA1*02:01DQB1*02:02, showed very strong associations with LGI1-antibody patients, this was not observed among CASPR2-antibody patients in whom we found clear associations with HLA-DRB1*11:01 only

Summary

Introduction

The discovery of autoantibodies against leucine-rich, glioma-inactivated 1 (LGI1), contactin-associated protein 2 (CASPR2) (Irani et al, 2010; Lai et al, 2010) and, more recently, intracellular epitopes of voltage-gated potassium channels (VGKCs) (Lang et al, 2017), have redefined the immunology of the VGKC-complex (Thieben et al, 2004; Vincent et al, 2004). Patients with LGI1 or CASPR2 antibodies often have clinically-indistinguishable late-onset forms of limbic encephalitis and neuromyotonia with associated dysautonomia, sleep disturbances, pain and seizures (Irani et al, 2010; Lai et al, 2010; Klein et al, 2013; Gadoth et al, 2017) While these features occur at different rates in LGI1versus CASPR2-antibody cohorts, only faciobrachial dystonic seizures (FBDS) robustly predict LGI1 reactivity (Irani et al, 2011; Gadoth et al, 2017; Thompson et al, 2018). Human leucocyte antigen (HLA) variants, intimately related to antigen presentation, may play critical roles in distinguishing the aetiology of these syndromes

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Conclusion