DataSheet_6_Rubella Virus Infected Macrophages and Neutrophils Define Patterns of Granulomatous Inflammation in Inborn and Acquired Errors of Immunity.pdf

Rubella virus (RuV) has recently been found in association with granulomatous inflammation of the skin and several internal organs in patients with inborn errors of immunity (IEI). The cellular tropism and molecular mechanisms of RuV persistence and pathogenesis in select immunocompromised hosts are not clear. We provide clinical, immunological, virological, and histological data on a cohort of 28 patients with a broad spectrum of IEI and RuV-associated granulomas in skin and nine extracutaneous tissues to further delineate this relationship. Combined immunodeficiency was the most frequent diagnosis (67.8%) among patients. Patients with previously undocumented conditions, i.e., humoral immunodeficiencies, a secondary immunodeficiency, and a defect of innate immunity were identified as being susceptible to RuV-associated granulomas. Hematopoietic cell transplantation was the most successful treatment in this case series resulting in granuloma resolution; steroids, and TNF-α and IL-1R inhibitors were moderately effective. In addition to M2 macrophages, neutrophils were identified by immunohistochemical analysis as a novel cell type infected with RuV. Four patterns of RuV-associated granulomatous inflammation were classified based on the structural organization of granulomas and identity and location of cell types harboring RuV antigen. Identification of conditions that increase susceptibility to RuV-associated granulomas combined with structural characterization of the granulomas may lead to a better understanding of the pathogenesis of RuV-associated granulomas and discover new targets for therapeutic interventions.

近期研究发现，风疹病毒（Rubella virus, RuV）与原发性免疫缺陷病（inborn errors of immunity, IEI）患者的皮肤及多脏器肉芽肿性炎症存在关联。目前尚不清楚风疹病毒在特定免疫受损宿主中的细胞嗜性、持续感染及致病的分子机制。本研究纳入28例罹患多种原发性免疫缺陷病且伴皮肤及9种皮肤外组织风疹病毒相关性肉芽肿的患者队列，提供其临床、免疫学、病毒学及组织学数据，以进一步阐明二者间的关联。患者中最常见的诊断为联合免疫缺陷，占比达67.8%。本研究还发现了此前未被报道的、易感风疹病毒相关性肉芽肿的疾病类型，包括体液免疫缺陷、继发性免疫缺陷及先天免疫缺陷。造血细胞移植是本病例系列中疗效最佳的治疗手段，可实现肉芽肿消退；糖皮质激素、肿瘤坏死因子-α（TNF-α）及白细胞介素-1受体（IL-1R）抑制剂的治疗效果中等。除M2巨噬细胞外，免疫组化分析证实中性粒细胞是一种新的风疹病毒感染细胞类型。研究人员根据肉芽肿的结构组织特征、携带风疹病毒抗原的细胞类型及其定位，将风疹病毒相关性肉芽肿性炎症分为四种类型。明确易患风疹病毒相关性肉芽肿的疾病类型并对肉芽肿进行结构表征，有助于进一步阐明风疹病毒相关性肉芽肿的致病机制，为治疗干预提供新靶点。