Characterizing the VZV-induced inflammatory response in temporal arteries from patients with giant cell arteritis

水痘带状疱疹病毒(VZV)是老年人最常见的病毒学病因。原发感染 引起水痘，之后病毒潜伏在沿着整个神经轴的神经节中。到2050年，&gt；8300万 美国人将年满65岁，95%的人患有潜伏的VZV。随着免疫系统的老化，VZV将 在85岁之前，50%的美国人重新激活以产生带状疱疹，这可能会因 带状疱疹后遗神经痛。在重新激活期间，VZV还会导致巨细胞性动脉炎(GCA)，这是最严重的 老年人常见的系统性脉管炎，以严重头痛和头皮压痛为特征，以及 有下巴跛行、风湿性多发性肌痛、发烧、盗汗、体重减轻、疲劳和抬高的病史。 血清炎性标志物。GCA是一种导致视力丧失的医疗紧急情况；因此，患者得到了治疗 使用皮质类固醇，尽管接受了治疗，50%的患者仍会复发或进展为中风和视力丧失。到2050年， 在美国，由于GCA造成的视力损害估计成本将超过760亿美元。GCA的TA活组织检查 患者通常表现为跨壁炎症、中层损害和多核巨细胞/上皮样细胞。 (GCA阳性的TA)，但可能是病理阴性(GCA阴性)。最近，我们发现70%的GCA- 阳性的TA和58%的GCA阴性的TA含有VZV抗原以及VZV DNA和疱疹病毒颗粒 在一个亚群中，只有18%的正常TA含有VZV抗原。GCA阳性和GCA阳性的病理表现 -阴性TAS是一种持续性炎症，我们怀疑是由VZV引发的血管壁损伤 感染。综上所述，我们假设VZV引起患者TA的持续性血管炎症 通过产生促炎环境和招募VZV特异性T细胞而导致巨细胞性动脉炎 细胞。我们将通过分析促炎环境和识别生物标记物来检验这一假设 在FFPE GCA阳性、GCA阴性和正常TAS中支持VZV感染的途径 在不含VZV抗原的情况下，使用TEMPO-SEQ和途径分析程序(目标1)并确定VZV- 特定的CD4T细胞在GCA新鲜TA活检组织中局部浓缩(目标2)。阐明VZV在VZV中的作用 GCA将提供有关有希望的靶向途径的信息，以缓解GCA和生物标志物 疾病易感性可能扩展到其他VZV血管病变，最终指导临床决策- 制造和治疗，以及提高生活质量和降低医疗费用。成功完成 这些目标中的一个得到了神经学、眼科专家的多学科合作的支持 免疫学生物信息学/统计学，存档的FFPE TA和新鲜活检组织的可用性以及 科罗拉多大学神经病学系神经病毒学家的绝佳环境。澄清 VZV在GCA中的作用将提供有关有希望的靶向途径的信息，以缓解GCA和 关于疾病易感性的生物标志物，可能延伸到其他VZV血管病变，最终指导 临床决策和治疗，以及提高生活质量和降低医疗费用。

Varicella zoster virus (VZV) is the most common virological cause of disease in the elderly. Primary infection causes varicella, after which virus becomes latent in ganglia along the entire neuraxis. By 2050, >83 million Americans will be >65 years old with 95% harboring latent VZV. As the immune system ages, VZV will reactivate in >50% of Americans by 85 years of age to produce zoster, which can be complicated by postherpetic neuralgia. During reactivation, VZV can also cause giant cell arteritis (GCA), which is the most common systemic vasculitis in the elderly characterized by severe headache and scalp tenderness, as well as a history of jaw claudication, polymyalgia rheumatica, fever, night sweats, weight loss, fatigue, and elevated serum inflammatory markers. GCA is a medical emergency that leads to vision loss; thus, patients are treated with corticosteroids, with 50% relapsing or progressing to stroke and vision loss despite therapy. By 2050, in the US, the estimated cost from visual impairment due GCA will exceed $76 billion. TA biopsy from GCA patients typically reveals transmural inflammation, medial damage and multinucleated giant/epithelioid cells (GCA-positive TAs) but may be pathologically negative (GCA-negative). Recently, we showed that 70% GCA- positive TAs and 58% GCA-negative TAs contain VZV antigen, as well as VZV DNA and herpesvirus particles in a subset, whereas only 18% normal TAs contained VZV antigen. The pathologic finding in GCA-positive and -negative TAs is persistent inflammation leading to vascular wall damage that we suspect is triggered by VZV infection. Taken together, we hypothesize that VZV elicits persistent vascular inflammation in TAs of patients with giant cell arteritis through production of a proinflammatory environment and recruitment of VZV-specific T cells. We will test this hypothesis by analyzing the proinflammatory environment and identifying biomarkers and pathways supportive of VZV infection in FFPE GCA-positive, GCA-negative and normal TAs with and without VZV antigen using TempO-Seq and pathway analysis programs (Aim 1) and determining if VZV- specific CD4 T cells are locally enriched in fresh TA biopsies of GCA (Aim 2). Elucidating the role of VZV in GCA will provide information on promising pathways to target in order to mitigate GCA and on biomarkers for disease susceptibility that may be extended to other VZV vasculopathies, ultimately guiding clinical decision- making and therapies, as well as improving quality of life and reducing health care costs. Successful completion of these Aims is supported by multidisciplinary collaborations by experts in neurology, ophthalmology immunology bioinformatics/statistics, the availability of archived FFPE TAs and fresh biopsy tissue and excellent environment of neurovirologists at the University of Colorado Department of Neurology. Elucidating the role of VZV in GCA will provide information on promising pathways to target in order to mitigate GCA and on biomarkers for disease susceptibility that may be extended to other VZV vasculopathies, ultimately guiding clinical decision-making and therapies, as well as improving quality of life and reducing health care costs.