Neuroimmunology Program, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, 08036 Barcelona, Spain.
Pediatric Neuroimmunology Unit, Neurology Department, Sant Joan de Déu Children's Hospital, University of Barcelona, 08950 Esplugues de Llobregat, Barcelona, Spain.
Brain. 2023 Oct 3;146(10):4306-4319. doi: 10.1093/brain/awad238.
Patients with herpes simplex virus (HSV) encephalitis (HSE) often develop neuronal autoantibody-associated encephalitis (AE) post-infection. Risk factors of AE are unknown. We tested the hypotheses that predisposition for AE post-HSE may be involved, including genetic variants at specific loci, human leucocyte (HLA) haplotypes, or the blood innate immune response against HSV, including type I interferon (IFN) immunity. Patients of all ages with HSE diagnosed between 1 January 2014 and 31 December 2021 were included in one of two cohorts depending on whether the recruitment was at HSE onset (Spanish Cohort A) or by the time of new neurological manifestations (international Cohort B). Patients were assessed for the type of neurological syndromes; HLA haplotypes; blood type I-IFN signature [RNA quantification of 6 or 28 IFN-response genes (IRG)] and toll-like receptor (TLR3)-type I IFN-related gene mutations. Overall, 190 patients (52% male) were recruited, 93 in Cohort A and 97 in Cohort B. Thirty-nine (42%) patients from Cohort A developed neuronal autoantibodies, and 21 (54%) of them developed AE. Three syndromes (choreoathetosis, anti-NMDAR-like encephalitis and behavioural-psychiatric) showed a high (≥95% cases) association with neuronal autoantibodies. Patients who developed AE post-HSE were less likely to carry the allele HLA-A02 (4/21, 19%) than those who did not develop AE (42/65, 65%, P = 0.0003) or the Spanish general population (2005/4335, 46%, P = 0.0145). Blood IFN signatures using 6 or 28 IRG were positive in 19/21 (91%) and 18/21 (86%) patients at HSE onset, and rapidly decreased during follow-up. At Day 21 after HSE onset, patients who later developed AE had higher median IFN signature compared with those who did not develop AE [median Zs-6-IRG 1.4 (0.6; 2.0) versus 0.2 (-0.4; 0.8), P = 0.03]. However, a very high median Zs-6-IRG (>4) or persistently increased IFN signature associated with uncontrolled viral infection. Whole exome sequencing showed that the percentage of TLR3-IFN-related mutations in patients who developed AE was not different from those who did not develop AE [3/37 (8%) versus 2/57 (4%), P = 0.379]. Multivariate logistic regression showed that a moderate increase of the blood IFN signature at Day 21 (median Zs-6-IRG >1.5 but <4) was the most important predictor of AE post-HSE [odds ratio 34.8, interquartile ratio (1.7-691.9)]. Altogether, these findings show that most AE post-HSE manifest with three distinct syndromes, and HLA-A02, but not TLR3-IFN-related mutations, confer protection from developing AE. In addition to neuronal autoantibodies, the blood IFN signature in the context of HSE may be potentially useful for the diagnosis and monitoring of HSE complications.
患者感染单纯疱疹病毒（HSV）后常发生神经元自身抗体相关脑炎（AE）。AE 的风险因素尚不清楚。我们检验了以下假设：HSV 后脑炎后发生 AE 的易感性可能与特定基因座的遗传变异、人类白细胞（HLA）单倍型或针对 HSV 的血液固有免疫反应（包括 I 型干扰素（IFN）免疫）有关。纳入了所有年龄的 190 名 HSE 患者（52%为男性），他们被分为两组，一组是在 HSE 发病时（西班牙队列 A）招募的，另一组是在出现新的神经系统表现时（国际队列 B）招募的。评估患者的神经综合征类型、HLA 单倍型、I 型 IFN 特征（6 或 28 个 IFN 反应基因（IRG）的 RNA 定量）和 Toll 样受体（TLR3）-I 型 IFN 相关基因突变。总的来说，93 名患者来自队列 A，97 名患者来自队列 B。队列 A 中有 39 名（42%）患者发生了神经元自身抗体，其中 21 名（54%）患者发生了 AE。三种综合征（舞蹈手足徐动症、抗 NMDAR 样脑炎和行为-精神）与神经元自身抗体有很高的（≥95%病例）相关性。发生 HSE 后脑炎的患者携带 HLA-A02 等位基因的可能性低于未发生 AE 的患者（4/21，19%比 65%，P = 0.0003）或西班牙一般人群（2005/4335，46%，P = 0.0145）。在 HSE 发病时，19/21（91%）和 18/21（86%）患者的 6 或 28 IRG 的 IFN 特征呈阳性，在随访期间迅速下降。在 HSE 发病后第 21 天，与未发生 AE 的患者相比，后来发生 AE 的患者 IFN 特征中位数更高[中位数 Zs-6-IRG 1.4（0.6；2.0）比 0.2（-0.4；0.8），P = 0.03]。然而，非常高的中位 Zs-6-IRG（>4）或持续升高的 IFN 特征与病毒感染失控有关。全外显子组测序显示，发生 AE 的患者 TLR3-IFN 相关突变的比例与未发生 AE 的患者没有差异[3/37（8%）比 2/57（4%），P = 0.379]。多变量逻辑回归显示，第 21 天血液 IFN 特征的中度增加（中位数 Zs-6-IRG >1.5 但 <4）是发生 HSE 后脑炎的最重要预测因素[比值比 34.8，四分位距（1.7-691.9）]。总的来说，这些发现表明，大多数 HSE 后脑炎表现为三种不同的综合征，HLA-A02 而不是 TLR3-IFN 相关突变，可预防发生 AE。除了神经元自身抗体外，HSV 时的血液 IFN 特征可能对 HSE 并发症的诊断和监测有用。
