Kothur Kavitha, Gill Deepak, Wong Melanie, Mohammad Shekeeb S, Bandodkar Sushil, Arbunckle Susan, Wienholt Louise, Dale Russell C
Neuroimmunology Group, Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, University of Sydney, Sydney, NSW, Australia.
The T.Y. Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, Sydney, NSW, Australia.
Dev Med Child Neurol. 2017 Aug;59(8):806-814. doi: 10.1111/dmcn.13431. Epub 2017 Apr 25.
To examine the cytokine/chemokine profile of cerebrospinal fluid (CSF) during acute herpes simplex virus-induced N-methyl-d-aspartate receptor (NMDAR) autoimmunity and in chronic/relapsing post-herpes simplex virus encephalitis (HSE) neurological syndromes.
We measured longitudinal serial CSF cyto-/chemokines (n=34) and a glial marker (calcium-binding astroglial protein, S100B) in one patient during acute HSE and subsequent anti-NMDAR encephalitis, and compared the results with those from two patients with anti-NMDAR encephalitis without preceding HSE. We also compared cyto-/chemokines in cross-sectional CSF samples from three children with previous HSE who had ongoing chronic or relapsing neurological symptoms (2yr 9 mo-16y after HSE) with those in a group of children having non-inflammatory neurological conditions (n=20).
Acute HSE showed elevation of a broad range of all T-helper-subset-related cyto-/chemokines and S100B whereas the post-HSE anti-NMDAR encephalitis phase showed persistent elevation of two of five T-helper-1 (chemokine [C-X-C motif] ligand 9 [CXCL9], CXCL10), three of five predominantly B-cell (CXCL13, CCL19, a proliferation-inducing ligand [APRIL])-mediated cyto-/chemokines, and interferon-α. The post-HSE anti-NMDAR encephalitis inflammatory response was more pronounced than anti-NMDAR encephalitis. All three chronic post-HSE cases showed persistent elevation of CXCL9, CXCL10, and interferon-α, and there was histopathological evidence of chronic lymphocytic inflammation in one biopsied case 7 years after HSE. Two of three chronic cases showed a modest response to immune therapy.
HSE-induced anti-NMDAR encephalitis is a complex and pronounced inflammatory syndrome. There is persistent CSF upregulation of cyto-/chemokines in chronic or relapsing post-HSE neurological symptoms, which may be modifiable with immune therapy. The elevated cyto-/chemokines may be targets of monoclonal therapies.
研究急性单纯疱疹病毒诱导的N-甲基-D-天冬氨酸受体（NMDAR）自身免疫期间以及慢性/复发性单纯疱疹病毒性脑炎（HSE）神经综合征患者脑脊液（CSF）中的细胞因子/趋化因子谱。
我们在1例急性HSE及随后的抗NMDAR脑炎患者中纵向连续检测了CSF细胞因子/趋化因子（n = 34）和一种神经胶质标志物（钙结合星形胶质蛋白，S100B），并将结果与2例无先前HSE病史的抗NMDAR脑炎患者的结果进行比较。我们还比较了3例既往有HSE且有持续慢性或复发性神经症状（HSE后2年9个月至16岁）儿童的横断面CSF样本中的细胞因子/趋化因子与一组患有非炎性神经疾病儿童（n = 20）的细胞因子/趋化因子。
急性HSE显示多种与所有辅助性T细胞亚群相关的细胞因子/趋化因子和S100B升高，而HSE后抗NMDAR脑炎阶段显示5种辅助性T细胞1型（趋化因子[C-X-C基序]配体9 [CXCL9]、CXCL10）中的2种、5种主要由B细胞介导（CXCL13、CCL19、增殖诱导配体[APRIL]）的细胞因子/趋化因子中的3种以及干扰素-α持续升高。HSE后抗NMDAR脑炎的炎症反应比抗NMDAR脑炎更明显。所有3例HSE后慢性病例均显示CXCL9、CXCL10和干扰素-α持续升高，并且在1例HSE后7年活检病例中有慢性淋巴细胞炎症的组织病理学证据。3例慢性病例中有2例对免疫治疗有适度反应。
HSE诱导的抗NMDAR脑炎是一种复杂且明显的炎症综合征。在慢性或复发性HSE后神经症状中，CSF细胞因子/趋化因子持续上调，这可能可通过免疫治疗进行调节。升高的细胞因子/趋化因子可能是单克隆治疗的靶点。
