Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, LS9 7TF, UK.
Leeds Institute of Medical Research, University of Leeds, Leeds, LS9 7TF, UK.
J Clin Immunol. 2021 Feb;41(2):441-457. doi: 10.1007/s10875-020-00932-1. Epub 2020 Dec 7.
Biallelic mutations in SLC29A3 cause histiocytosis-lymphadenopathy plus syndrome, also known as H syndrome (HS). HS is a complex disorder, with ~ 25% of patients developing autoinflammatory complications consisting of unexplained fevers, persistently elevated inflammatory markers, and unusual lymphadenopathies, with infiltrating CD68, S100, and CD1a histiocytes, resembling the immunophenotype found in Rosai-Dorfman disease (RDD). We investigated the transcriptomic profiles of monocytes, non-activated (M0), classically activated (M1), and alternatively activated macrophages (M2) in two patients with HS, one without autoinflammatory (HS1) and one with autoinflammatory complications (HS2). RNA sequencing revealed a dysregulated transcriptomic profile in both HS patients compared to healthy controls (HC). HS2, when compared to HS1, had several differentially expressed genes, including genes associated with lymphocytic-histiocytic predominance (e.g. NINL) and chronic immune activation (e.g. B2M). The transcriptomic and cytokine profiles of HS patients were comparable to patients with SAID with high levels of TNF. SERPINA1 gene expression was found to be upregulated in all patients studied. Moreover, higher levels of IFNγ were found in the serum of both HS patients when compared to HC. Gene ontology (GO) enrichment analysis of the DEGs in HS patients revealed the terms "type I IFN," "IFNγ signaling pathway," and "immune responses" as the top 3 most significant terms for monocytes. Gene expression analysis of lymph node biopsies from sporadic and H syndrome-associated RDD suggests common underlying pathological process. In conclusion, monocytes and macrophages from both HS patients showed transcriptomic profiles similar to SAIDs and also uniquely upregulated IFNγ signature. These findings may help find better therapeutic options for this rare disorder.
SLC29A3 的双等位基因突变导致组织细胞增生症-淋巴结病综合征，也称为 H 综合征 (HS)。HS 是一种复杂的疾病，约有 25%的患者出现自身炎症并发症，包括原因不明的发热、持续升高的炎症标志物和异常的淋巴结病，伴有浸润性 CD68、S100 和 CD1a 组织细胞，类似于 Rosai-Dorfman 病 (RDD) 中发现的免疫表型。我们研究了两名 HS 患者（一名无自身炎症 HS1 和一名有自身炎症并发症 HS2）的单核细胞、非激活（M0）、经典激活（M1）和替代激活巨噬细胞（M2）的转录组谱。RNA 测序显示，与健康对照（HC）相比，两名 HS 患者的转录组谱均失调。与 HS1 相比，HS2 有几个差异表达基因，包括与淋巴细胞-组织细胞优势相关的基因（如 NINL）和慢性免疫激活相关的基因（如 B2M）。HS 患者的转录组和细胞因子谱与 TNF 水平较高的 SAID 患者相似。发现所有研究患者的 SERPINA1 基因表达上调。此外，与 HC 相比，两名 HS 患者的血清中 IFNγ 水平更高。HS 患者差异表达基因的基因本体 (GO) 富集分析显示，“I 型 IFN”、“IFNγ 信号通路”和“免疫反应”是单核细胞中前 3 个最重要的术语。来自散发性和 H 综合征相关 RDD 的淋巴结活检的基因表达分析表明存在共同的潜在病理过程。总之，两名 HS 患者的单核细胞和巨噬细胞表现出与 SAID 相似的转录组谱，也独特地上调 IFNγ 特征。这些发现可能有助于为这种罕见疾病找到更好的治疗选择。
