Department of Pediatrics, Jichi Medical University, School of Medicine, Shimotsuke, Japan.
Department of Pediatrics, Jichi Medical University, School of Medicine, Shimotsuke, Japan.
Cytokine. 2017 Sep;97:73-79. doi: 10.1016/j.cyto.2017.05.026. Epub 2017 Jun 2.
Langerhans cell histiocytosis (LCH) is characterized by immature dendritic cell proliferation, infiltration of LCH lesions by various inflammatory cells, and a lesional cytokine storm. It is classified into three groups on the basis of disease extent, namely, multisystem with risk-organ involvement (MS+), multisystem without risk-organ involvement (MS-), and single-system (SS) disease. We comprehensively analyzed whether serum levels of cytokines/chemokines reflect the disease extent.
Serum samples from 52 children with LCH (eight, 25, and 19 with MS+, MS-, and SS, respectively) and 34 control children were analyzed quantitatively for 48 humoral factors. DNA samples extracted from biopsied LCH lesions from 12 patients were tested for BRAF V600E status.
The LCH patients had significantly higher serum levels of IL-1Ra, IL-3, IL-6, IL-8, IL-9, IL-10, IL12, IL-13, IL-15, IL-17, IL-18, TNF-α, G-CSF, M-CSF, MIF, HGF, VEGF, CCL2, CCL3, CCL7, CXCL1, and CXCL9 than the controls by univariate analysis. Of these IL-9, IL-15 and MIF were significant by multivariate analysis; but not differed between MS and SS diseases. MS disease associated with significantly higher IL-2R, IL-3, IL-8, IL-18, M-CSF, HGF, CCL2, CXCL1, and CXCL9 levels than SS disease by univariate analysis. Of these, CCL2 and M-CSF were significant by multivariate analysis. IL-18 levels were significantly higher in MS+ disease than MS- disease. The LCH patients with BRAF V600E mutation had higher serum levels of CCL7.
Numerous inflammatory cytokines and chemokines play a role in LCH. Of those, more specific ones reflect the disease extent (MS vs. SS and MS+ vs. MS-) or the BRAF V600E mutation status. It is thought that the most responsible cytokines and chemokines involved in the poor outcome may become future candidate therapeutic targets in LCH.
朗格汉斯细胞组织细胞增生症（LCH）的特征是不成熟树突状细胞增殖、LCH 病变浸润各种炎症细胞以及病变细胞因子风暴。根据疾病范围，将其分为三组，即伴有风险器官受累的多系统（MS+）、无风险器官受累的多系统（MS-）和单系统（SS）疾病。我们全面分析了血清细胞因子/趋化因子水平是否反映疾病范围。
分析 52 例 LCH 患儿（8 例、25 例和 19 例分别为 MS+、MS-和 SS）和 34 例对照儿童的血清样本，定量分析 48 种体液因子。从 12 例 LCH 病变活检样本中提取 DNA 样本，检测 BRAF V600E 状态。
LCH 患者的血清白细胞介素-1受体拮抗剂（IL-1Ra）、白细胞介素-3（IL-3）、白细胞介素-6（IL-6）、白细胞介素-8（IL-8）、白细胞介素-9（IL-9）、白细胞介素-10（IL-10）、白细胞介素-12（IL-12）、白细胞介素-13（IL-13）、白细胞介素-15（IL-15）、白细胞介素-17（IL-17）、白细胞介素-18（IL-18）、肿瘤坏死因子-α（TNF-α）、粒细胞集落刺激因子（G-CSF）、巨噬细胞集落刺激因子（M-CSF）、巨噬细胞移动抑制因子（MIF）、肝细胞生长因子（HGF）、血管内皮生长因子（VEGF）、趋化因子配体 2（CCL2）、CCL3、CCL7、趋化因子（C-X-C）配体 1（CXCL1）和 CXCL9 水平明显高于对照组，经单因素分析。其中，IL-9、IL-15 和 MIF 经多因素分析有统计学意义，但在 MS 和 SS 疾病之间无差异。MS 疾病与 IL-2R、IL-3、IL-8、IL-18、M-CSF、HGF、CCL2、CXCL1 和 CXCL9 水平明显高于 SS 疾病有关，其中 CCL2 和 M-CSF 经多因素分析有统计学意义。MS+疾病的 IL-18 水平明显高于 MS-疾病。BRAF V600E 突变的 LCH 患者血清 CCL7 水平较高。
许多炎症细胞因子和趋化因子在 LCH 中起作用。其中，更特异的细胞因子反映疾病范围（MS 与 SS 和 MS+与 MS-）或 BRAF V600E 突变状态。因此，参与不良预后的最具代表性的细胞因子和趋化因子可能成为 LCH 的未来候选治疗靶点。
