Department of Medicine and Biosystemic Sciences, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
Department of Cancer Stem Cell Research, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
Front Immunol. 2022 Oct 20;13:1016914. doi: 10.3389/fimmu.2022.1016914. eCollection 2022.
Systemic sclerosis (SSc) is a multiple-organ disease characterized by vascular damage, autoimmunity, and tissue fibrosis. Organ injuries such as interstitial lung diseases (ILD), resulting from inflammatory and fibrosis processes, lead to poor prognosis. Although autoantibodies are detected in the serum of patients with SSc, the mechanisms by which immune cells are involved in tissue inflammation and fibrosis is not fully understood. Recent studies have revealed carcinoembryonic antigen related cell adhesion molecule (CEACAM)-positive monocytes are involved in murine bleomycin-induced lung fibrosis. We investigated CEACAM-positive monocytes in patients with SSc to clarify the role of monocytes in the pathogenesis of SSc.
The proportion of of CEACAM-positive classical monocytes in healthy controls (HCs) and patients with rheumatoid arthritis (RA) and SSc was evaluated using flow cytometry. The correlation between the proportion of CEACAM-positive monocytes and clinical parameters was analyzed in patients with SSc. Gene expression microarrays were performed in CEACAM-positive and negative monocytes in patients with SSc. Infiltration of CEACAM-positive monocytes into scleroderma skin was evaluated by immunohistochemical staining.
The proportion of CEACAM-positive classical monocytes was increased in patients with early SSc within 2 years after diagnosis, which positively correlated with ESR, serum IgG, and serum KL-6 and negatively correlated with %forced vital capacity. The percentage of CEACAM-positive monocytes decreased after immunosuppressive therapy. CEACAM6-positive cells among classical monocytes were significantly increased in patients with SSc compared with HCs and patients with rheumatoid arthritis. SSc serum induced CEACAM6 expression on monocytes from HCs. Functionally, CEACAM-positive monocytes produced higher levels of TNF-α and IL-1β compared to CEACAM-negative cells and showed activation of the NF-κB pathway. Furthermore, CEACAM6-positive monocytes infiltrated the dermis of SSc.
CEACAM-positive monocytes showed inflammatory phenotypes and may be involved in the tissue inflammation and fibrosis in early SSc. CEACAM-positive monocytes may be one of biomarkers to detect patients with progressive ILD, requiring therapeutic intervention.
系统性硬化症（SSc）是一种多器官疾病，其特征为血管损伤、自身免疫和组织纤维化。由于炎症和纤维化过程，器官损伤如间质性肺疾病（ILD）导致预后不良。虽然在 SSc 患者的血清中检测到自身抗体，但免疫细胞如何参与组织炎症和纤维化的机制尚不完全清楚。最近的研究表明癌胚抗原相关细胞黏附分子（CEACAM）阳性单核细胞参与了小鼠博来霉素诱导的肺纤维化。我们研究了 SSc 患者中的 CEACAM 阳性单核细胞，以阐明单核细胞在 SSc 发病机制中的作用。
使用流式细胞术评估健康对照（HC）、类风湿关节炎（RA）和 SSc 患者中 CEACAM 阳性经典单核细胞的比例。分析 SSc 患者中 CEACAM 阳性单核细胞比例与临床参数的相关性。对 SSc 患者中 CEACAM 阳性和阴性单核细胞进行基因表达微阵列分析。通过免疫组织化学染色评估 CEACAM 阳性单核细胞浸润硬皮病皮肤。
在诊断后 2 年内的早期 SSc 患者中，CEACAM 阳性经典单核细胞的比例增加，与 ESR、血清 IgG 和血清 KL-6 呈正相关，与 %用力肺活量呈负相关。免疫抑制治疗后，CEACAM 阳性单核细胞的比例降低。与 HC 和 RA 患者相比，SSc 患者的 CEACAM6 阳性细胞在经典单核细胞中显著增加。SSc 血清诱导 HC 单核细胞中 CEACAM6 的表达。功能上，CEACAM 阳性单核细胞比 CEACAM 阴性细胞产生更高水平的 TNF-α和 IL-1β，并显示 NF-κB 途径的激活。此外，CEACAM6 阳性单核细胞浸润 SSc 的真皮。
CEACAM 阳性单核细胞表现出炎症表型，可能参与早期 SSc 的组织炎症和纤维化。CEACAM 阳性单核细胞可能是检测需要治疗干预的进行性ILD 患者的生物标志物之一。
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