Log In

Forgot Password?
Create New Account

Loading... please wait

Abstract Details

Rank wise effect of HLA-DQ5 explains risk for the development of anti-IgLON5 disease
Autoimmune Neurology
C15 - Unusual Presentations of Neurologic Autoimmunity (4:20 PM-4:25 PM)
P2 - Poster Session 2 (9:00 AM-3:00 PM)
027

Anti-IgLON5 disease is a rare, but likely underdiagnosed type of autoantibody encephalitis with a heterogeneous clinical phenotype, including sleep, movement and brainstem dysfunction. Its pathophysiology remains elusive, although dominant association with HLA-DRB1*10:01-DQB1*05:01 strongly supports an autoimmune basis.

To better characterize the genetic association between human leukocyte antigen (HLA) and anti-IgLON5 disease and to explore auto-antigen binding to associated HLA molecules and their functional involvement in pathophysiology.

A multicentric cohort of 62 patients and 433 controls matched by principal component analysis was included. Genome-wide association analysis was performed with 4-digit resolution HLA imputation and selected 8-digit resolution validation typing. A generalized logistic model was used to determine the association with individual alleles and haplotype counts to establish haplotype associations. Furthermore, we computationally predicted binding of IgLON5-derived peptides to risk-associated HLA-molecules.

Our results indicate a rank wise effect of HLA-DQA1*01:05~DQB1*05:01 (heterozygotes: OR 46.6), HLA-DQA1*01:01~DQB1*05:01 (homozygotes: OR 26.9; heterozygotes: OR 2.5) and HLA-DQA1*01:04-~DQB1*05:03 (homozygotes: OR 30.9; heterozygotes: OR 5.6), in order of descending relative risk predisposition. Differences between encoded heterodimers are minimal (a few amino acids outside the main HLA sequence binding region), suggesting a common function.  Computational binding predictions support similar, high binding affinity for IgLON5275-283 in a post-translationally modified (N-deglycosylated) form by all three of these HLA-DQ molecules and other common binders. In contrast, association analysis suggests that effects of HLA-DR are likely explained by linkage disequilibrium.

This study is the, so far, largest genetic study on anti-IgLON5 disease. Our results strongly suggest HLA-DQ over HLA-DR association, with higher reactivity against post-translationally modified versus physiological peptides, in line with reduced T cell priming against these epitopes. Further studies should address the functional implications of these HLA associations.

Authors/Disclosures
Selina Yogeshwar, MSc (Stanford University)
PRESENTER
Miss Yogeshwar has received research support from Einstein Center for Neurosciences.
Vicente Peris Sempere No disclosure on file
Sergio Muniz-Castrillo, MD, PhD (Stanford university) Dr. Muniz-Castrillo has nothing to disclose.
No disclosure on file
Carsten Finke, MD (Charité Berlin) Carsten Finke, MD has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Bristol Myer Squibb. The institution of Carsten Finke, MD has received research support from Euroimmun.
Jerome Honnorat, MD, PhD (Hospices Civils de Lyon) The institution of Jerome Honnorat, MD, PhD has received personal compensation in the range of $0-$499 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for journal of neurology.
Emmanuel Mignot, MD, PhD (Stanford University) Dr. Mignot has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Takeda. Dr. Mignot has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Jazz Pharmaceutical. Dr. Mignot has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eisai Pharmaceuticals, Inc. . Dr. Mignot has received personal compensation in the range of $0-$499 for serving as a Consultant for EcoR1. Dr. Mignot has received personal compensation in the range of $0-$499 for serving as a Consultant for ApneaCo. Dr. Mignot has received personal compensation in the range of $0-$499 for serving as a Consultant for Eisai Pharmaceuticals. Dr. Mignot has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Centessa .
No disclosure on file