From the Department of Neurology (Y.S.Y.S.N., K.R., K.A., H.K., F.F., A.G.), Tel-Aviv Medical Center; Neuroimmunology Unit (K.R., K.A., H.K.), Tel-Aviv Medical Center; Sackler Faculty of Medicine (K.A., O.A.), Tel-Aviv University; Sagol School of Neuroscience (K.A.), Tel-Aviv University; Epilepsy and EEG Unit (F.F.), Tel Aviv Medical Center; Encephalitis Center (O.A., Y.P., Y.A., A.G.), Tel-Aviv Medical Center; Department of Radiology (O.A.), Tel-Aviv Medical Center; Infectious Diseases Department (Y.P.), Tel-Aviv Medical Center; Department of Mathematics (Y.L., S.I.), Bar Ilan University, Ramat Gan; Tissue Typing Laboratory (R.L., N.S.), Sheba Medical Center, Ramat Gan; Immunology Laboratory (Y.A.), Tel Aviv Medical Center, Israel; and Department of Neurological Surgery (I.R.), University of Pittsburgh School of Medicine, PA.
Neurol Neuroimmunol Neuroinflamm. 2023 Mar 27;10(3). doi: 10.1212/NXI.0000000000200103. Print 2023 May.
To 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.
Seventeen 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.
Our 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 DRB107:01 (OR: 3.18, CI: 20.9 < 1.e-5) and DRB104:02 (OR: 3.8, CI: 20.1 < 1.e-5), as well as of the DQ allele DQB102:02 (OR: 2.8, CI: 14.2 < 0.0001) as previously reported. A novel overrepresentation observed among our patients was of the DQB103:02 allele (OR: 2.3, CI: 6.9 < 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, DQB03:02 is not fully associated with DRB104:02, 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.
Our cohort presents distinct immune characteristics with substantially higher overrepresentation of DRB104:02 and slightly lower overrepresentation of DQB107:01 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.
从以色列的一个大型单一中心，探讨抗亮氨酸丰富的胶质瘤失活 1 脑炎（LGI1E）患者的临床特征和 HLA 相关性。抗 LGI1E 是成人中最常见的抗体相关脑炎综合征。来自不同人群的最新研究显示与特定的 HLA 基因有显著相关性。我们检查了以色列患者队列的临床特征和 HLA 相关性。
纳入 2011 年至 2018 年期间在特拉维夫医疗中心诊断为抗 LGI1E 的 17 例连续患者。使用 Sheba 医疗中心的组织配型实验室进行下一代测序进行 HLA 分型，并与 Ezer Mizion 骨髓供者登记处的超过 100 万样本的数据进行比较。
我们的队列显示男性为主，发病中位年龄为 70 岁，与之前的报道一致。最常见的首发症状是癫痫发作。值得注意的是，阵发性头晕发作明显比以前报道的更常见（35%），而面臂肌张力障碍性癫痫发作仅占 23%。HLA 分析显示 DRB107:01（OR：3.18，CI：20.9 < 1.e-5）和 DRB104:02（OR：3.8，CI：20.1 < 1.e-5）过度表达，以及 DQB102:02（OR：2.8，CI：14.2 < 0.0001）等位基因的 DQB102:02 过度表达。我们的患者中观察到一个新的 DQB103:02 等位基因过度表达（OR：2.3，CI：6.9 < 0.008）。此外，我们在抗 LGI1E 患者中发现了 DR-DQ 关联，表现出完全或近乎完全的连锁不平衡（LD）。通过对史无前例的大型对照队列进行 LD 分析，我们能够表明，尽管在普通人群中，DQB03:02 与 DRB104:02 不完全相关，但在患者群体中，这两个等位基因总是相互关联的，表明 DRB104:02 与疾病易感性的相关性是主要的。对过度表达的 DQ 等位基因进行的计算预测表明，它们是 LGI1 衍生肽的强结合物，与过度表达的 DR 等位基因类似。这些预测表明，配对 DR-DQ 等位基因的肽结合位点之间可能存在相关性。
与之前的报告相比，我们的队列表现出明显不同的免疫特征，DRB104:02 的过度表达明显更高，而 DQB107:01 的过度表达略低，这表明不同人群之间存在差异。我们队列中发现的 DQ-DR 相互作用可能进一步阐明免疫遗传学在抗 LGI1E 发病机制中的复杂作用，暗示某些 DQ 等位基因和 DR-DQ 相互作用可能具有相关性。
