Capecchi Riccardo, Croia Cristina, Puxeddu Ilaria, Pratesi Federico, Cacciato Andrea, Campani Daniela, Boggi Ugo, Morelli Luca, Tavoni Antonio, Migliorini Paola
Immuno-Allergology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
Department of Surgical, Medical and Molecular Pathology and Critical Care Medicine, University of Pisa, Pisa, Italy.
Front Pharmacol. 2021 Oct 26;12:750216. doi: 10.3389/fphar.2021.750216. eCollection 2021.
SDF-1/CXCL12 is a chemokine with pleiotropic functions in hematopoietic stem cell niche homeostasis, germinal center architecture, B cell maturation, neoangiogenesis, and fibrosis. Recently, the CXCL12/CXCR4/CXCR7 axis was associated with cancer metastasis and autoimmune diseases. The IgG4-related disease (IgG4-RD) is a pathological condition characterized by IgG4+ plasma cells infiltrating fibrotic lesions. The aim of this research is to investigate the relevance of SDF-1/CXCL12 in IgG4-RD. Peripheral blood samples were collected before therapy from a single-center cohort of 28 IgG4-RD patients, fulfilling the ACR-EULAR classification criteria. Clinical and serological data were obtained for each patient. In total, 14 healthy donors (NHS), 9 patients with pancreatic ductal adenocarcinoma (PDAC), and 9 with Sjogren syndrome (SSj) were recruited as controls and screened for circulating SDF-1/CXCL12 by ELISA. Moreover, paraffin-embedded pancreatic biopsies obtained from patients with IgG4-RD ( = 7), non-autoimmune pancreatitis ( = 3), PDAC ( = 5), and control tissues ( = 4) were analyzed to study the tissue expression and localization of SDF-1/CXCL12 and one of its receptors, CXCR4, and their potential relation with neutrophil extracellular traps (NETs). IgG4-RD patients had higher serum levels of SDF-1/CXCL12 than normal controls ( = 0.0137). Cytokine levels did not differ between the IgG4-RD autoimmune pancreatitis (AIP) and retroperitoneal fibrosis nor between the single- and multiple-organ involvement. No correlation was seen with the IgG4-RD Responder Index, IgG4 levels, white blood cells, or inflammatory markers in the serum. When compared to SSj, the IgG4-RD AIP subgroup presents higher amounts of serum SDF-1/CXCL12 ( = 0.0275), while no differences are seen in comparison with PDAC. The expression of SDF-1/CXCL12 in the tissue was significantly higher in the IgG4-RD tissue than the normal pancreas, and the tissue with the high SDF-1/CXCL12 expression is characterized by the overall inflammatory cell infiltration, fibrosis, and high level of NETs. Modulating B cell development, neoangiogenesis and fibrosis, and SDF-1/CXCL12 may play a role in IgG4-RD. The higher levels observed in IgG4-RD, as compared to SSj, which closely mimics the disease, can be related to a different pattern of lesions, with prevalent fibrosis seen in IgG4-RD. Taken together, these findings suggest that drugs acting on the CXCL12/CXCR4/CXCR7 axis may affect IgG4-RD.
基质细胞衍生因子-1/趋化因子配体12（SDF-1/CXCL12）是一种在造血干细胞龛稳态、生发中心结构、B细胞成熟、新生血管生成和纤维化过程中具有多种功能的趋化因子。最近，CXCL12/CXCR4/CXCR7轴与癌症转移和自身免疫性疾病相关。IgG4相关疾病（IgG4-RD）是一种以IgG4+浆细胞浸润纤维化病变为特征的病理状态。本研究的目的是探讨SDF-1/CXCL12在IgG4-RD中的相关性。从符合美国风湿病学会（ACR）和欧洲抗风湿病联盟（EULAR）分类标准的28例IgG4-RD患者的单中心队列中收集治疗前的外周血样本。获取每位患者的临床和血清学数据。总共招募了14名健康供体（NHS）、9例胰腺导管腺癌（PDAC）患者和9例干燥综合征（SSj）患者作为对照，并通过酶联免疫吸附测定（ELISA）检测循环中的SDF-1/CXCL12。此外，对从IgG4-RD患者（n = 7）、非自身免疫性胰腺炎患者（n = 3）、PDAC患者（n = 5）和对照组织（n = 4）获取的石蜡包埋胰腺活检组织进行分析，以研究SDF-1/CXCL12及其受体之一CXCR4的组织表达和定位，以及它们与中性粒细胞胞外陷阱（NETs）的潜在关系。IgG4-RD患者血清中的SDF-1/CXCL12水平高于正常对照（P = 0.0137）。IgG4-RD自身免疫性胰腺炎（AIP）和腹膜后纤维化患者之间的细胞因子水平无差异，单器官和多器官受累患者之间也无差异。血清中的SDF-1/CXCL12水平与IgG4-RD反应指数、IgG4水平、白细胞或炎症标志物均无相关性。与SSj相比，IgG4-RD AIP亚组的血清SDF-1/CXCL12含量更高（P = 0.0275），而与PDAC相比无差异。IgG4-RD组织中SDF-1/CXCL12的表达明显高于正常胰腺组织，且SDF-1/CXCL12高表达组织的特征是存在整体炎症细胞浸润、纤维化和高水平的NETs。SDF-1/CXCL12通过调节B细胞发育、新生血管生成和纤维化，可能在IgG4-RD中发挥作用。与SSj相比，IgG4-RD中观察到的较高水平可能与不同的病变模式有关，IgG4-RD中可见明显的纤维化。综上所述，这些发现表明作用于CXCL12/CXCR4/CXCR7轴的药物可能会影响IgG4-RD。
