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 中的双等位基因突变导致组织细胞增多症-淋巴结病加综合征，也称为 H 综合征 (HS)。HS 是一种复杂的疾病，约 25% 的患者出现自身炎症并发症，包括不明原因的发热、持续升高的炎症标志物和不寻常的淋巴结病，浸润 CD68 ⁺、S100 ⁺和 CD1a ^-组织细胞，类似于 Rosai-Dorfman 中发现的免疫表型疾病（RDD）。我们研究了两名 HS 患者的单核细胞、非活化 (M0)、经典活化 (M1) 和交替活化巨噬细胞 (M2) 的转录组谱，其中一名没有自身炎症 (HS1)，另一名有自身炎症并发症 (HS2)。与健康对照 (HC) 相比，RNA 测序揭示了两名 HS 患者的转录组谱异常。与 HS1 相比，HS2 具有几个差异表达的基因，包括与淋巴细胞-组织细胞优势相关的基因（例如NINL）和慢性免疫激活（例如B2M）。HS 患者的转录组和细胞因子谱与具有高水平 TNF 的 SAID 患者相当。SERPINA1在所有研究的患者中发现基因表达上调。此外，与 HC 相比，在两名 HS 患者的血清中发现了更高水平的 IFNγ。HS 患者 DEG 的基因本体（GO）富集分析揭示了术语“I 型 IFN”、“IFNγ 信号通路”和“免疫反应”是单核细胞的前 3 个最重要的术语。散发性和 H 综合征相关 RDD 的淋巴结活检基因表达分析表明存在共同的潜在病理过程。总之，来自两个 HS 患者的单核细胞和巨噬细胞显示出与 SAID 相似的转录组学特征，并且还独特地上调了 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。