New Insights on DR and DQ Human Leukocyte Antigens in Anti-LGI1 Encephalitis

Abstract

Background and ObjectivesTo explore the clinical characteristics and HLA associations of patients with anti–leucine-rich glioma-inactivated 1 encephalitis (LGI1E) from a large single center in Israel. Anti-LGI1E is the most commonly diagnosed antibody-associated encephalitic syndrome in adults. Recent studies of various populations reveal significant associations with specific HLA genes. We examined the clinical characteristics and HLA associations of a cohort of Israeli patients.MethodsSeventeen consecutive patients with anti-LGI1E diagnosed at Tel Aviv Medical Center between the years 2011 and 2018 were included. HLA typing was performed using next-generation sequencing at the tissue typing laboratory of Sheba Medical Center and compared with data from the Ezer Mizion Bone Marrow Donor Registry, containing over 1,000,000 samples.ResultsOur cohort displayed a male predominance and median age at onset in the 7th decade, as previously reported. The most common presenting symptom was seizures. Notably, paroxysmal dizziness spells were significantly more common than previously reported (35%), whereas faciobrachial dystonic seizures were found only in 23%. HLA analysis revealed overrepresentation of DRB1*07:01 (OR: 3.18, CI: 20.9p< 1.e-5) and DRB1*04:02 (OR: 3.8, CI: 20.1p< 1.e-5), as well as of the DQ allele DQB1*02:02 (OR: 2.8, CI: 14.2p< 0.0001) as previously reported. A novel overrepresentation observed among our patients was of the DQB1*03:02 allele (OR: 2.3, CI: 6.9p< 0.008). In addition, we found DR-DQ associations, among patients with anti-LGI1E, that showed complete or near-complete linkage disequilibrium (LD). By applying LD analysis to an unprecedentedly large control cohort, we were able to show that although in the general population, DQB*03:02 is not fully associated with DRB1*04:02, in the patient population, both alleles are always coupled, suggesting the DRB1*04:02 association to be primary to disease predisposition. In silico predictions performed for the overrepresented DQ alleles reveal them to be strong binders of LGI1-derived peptides, similarly to overrepresented DR alleles. These predictions suggest a possible correlation between peptide binding sites of paired DR-DQ alleles.DiscussionOur cohort presents distinct immune characteristics with substantially higher overrepresentation of DRB1*04:02 and slightly lower overrepresentation of DQB1*07:01 compared with previous reports implying differences between different populations. DQ-DR interactions found in our cohort may shed additional light on the complex role of immunogenetics in the pathogenesis of anti-LGI1E, implying a possible relevance of certain DQ alleles and DR-DQ interactions.

Genetic predisposition to autoimmune encephalitis and paraneoplastic neurological syndromes

“…This study also confirmed the particular demographic characteristics of the non- DRB1∗07 : 01 carriers and, in addition, established a secondary association, both in DRB1∗07 : 01 heterozygous and noncarriers, with another allele, DRB1∗04 : 02 [63 ▪▪ ]. This allele is especially frequent in Jewish populations and, accordingly, was recently reported in another study from Israel [64 ▪ ]. Likewise, young female Chinese patients that are non- DRB1∗07 : 01 seem to carry more frequently DRB1∗03 : 01 [65].…”

Mechanisms of autoimmune encephalitis

“…LGI1 (e.g., HLA-DRB1Ã07:01, HLA-DQA1Ã02:01) [80][81][82][83]84 && ], and Caspr2 (e.g., HLA-DRB1Ã11:01) [85,86] encephalitis. By contrast, HLA-related predisposition is weaker in NMDAR encephalitis [83,87].…”