Th122 - Rank Wise Effect of HLA-DQ5 Explains Risk for the Development of anti-iglon5 Disease

Vicente Peris-Sempere; Sergio Muñiz-Castrillo; Han Yan; Guo Luo; Anna Heidbreder; Michael Bonello; virginie desestret; Christian Hartmann; Sophie Binks; Maria Pia giannoccaro; Rocco Liguori; Sara Mariotto; Yoya Ono; harald Prüß; Bettina Schreiner; Andrew McKeon; Sarosh Irani; Francesc Graus; Joan Santamaria; Josep Dalmau; Lidia Sabater; Carles Gaig; Carsten Finke; Jérôme Honnorat; Emmanuel Mignot

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

Methodology
A multicentric cohort of 62 patients and 433 controls matched by ethnicity using principal component analysis was included. 4-digit resolution HLA imputation on genome-wide association data was used, with selected 8-digit resolution validation typing. Association with individual alleles and haplotypes was tested using stepwise generalised logistic models. Furthermore, we computationally predicted binding of IgLON5-derived peptides to risk-associated HLA-molecules. 

Results
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. HLA-DR effects are likely explained by linkage disequilibrium with DQ, as sequences of associated DR alleles widely diverge, whereas differences between encoded DQ heterodimers are minimal, suggesting a common function. Computational binding predictions support similar, high binding affinity for specific IgLON5 peptide segments in a post-translationally modified (N-deglycosylated) form by all three predisposing HLA-DQs.

Conclusion
Our results indicate a primary role of HLA-DQ versus HLA-DR in anti-IgLON5 disease, with higher reactivity against modified versus physiological peptides, in line with reduced T cell tolerance against these epitopes.