Distinct HLA associations of LGI1 and CASPR2-antibody diseases

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.

Figure 1

HLA allele and haplotype associations in patients with LGI1 and CASPR2 antibodies. Bar chart depicting allele (A) and haplotype (B) associations and their frequency in patients with antibodies to LGI1 (n = 68, red denotes significant associations) and CASPR2 (n = 31, blue denotes significant associations), together with the frequency of these alleles or haplotypes in 5553 healthy controls (black bars). HC = healthy controls.

Figure 2

Peptides derived from full-length LGI1 and CASPR2 predicted to bind MHC-dimers encoded by over-represented HLA haplotypes. Rankings and position of peptides derived from full-length sequences of LGI1 (A and B) and CASPR2 (C and D). The haplotypes correspond to Fig. 1B and when in bold they relate to those observed in patients with antibodies to the corresponding protein. Red circles denote the LGI1-antibody cohort and blue the CASPR2-antibody cohort. Grey circles and italicized haplotypes relate to peptides from the other antigenic protein (i.e. CASPR2 in A and B; and LGI1 in C and D). Rank describes the predicted peptide affinities (IC₅₀, nM) by comparison to 200 000 random peptides of the same length. Dotted lines represent the 3% cut-off for peptide rank. Within B and D, circles represent the highly-ranked peptides across the full-length sequences of LGI1 or CASPR2: black circles represent peptides with some predicted promiscuity across LGI1- and CASPR2-antibody HLA variants, whereas pink circles highlight peptides that are not predicted to cross-react.