Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, Rheumatology section - "P. Giaccone", University of Palermo, Palermo, Sicilia, Italy
Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, Rheumatology section - "P. Giaccone", University of Palermo, Palermo, Sicilia, Italy.
RMD Open. 2023 May;9(2). doi: 10.1136/rmdopen-2022-002738.
Aim of this study was to investigate the expression of interleukin (IL)-40, a new cytokine associated with B cells homoeostasis and immune response, in primary Sjögren syndrome (pSS) and in pSS-associated lymphomas.
29 patients with pSS and 24 controls were enrolled. Minor salivary gland (MSG) biopsies from patients, controls and parotid gland biopsies from pSS-associated lymphoma were obtained. Quantitative gene expression analysis by TaqMan real-time PCR and immunohistochemistry for IL-40 were performed on MSG. MSG cellular sources of IL-40 were determined by flow-cytometry and immunofluorescence. Serum concentration of IL-40 was assessed by ELISA and cellular sources of IL-40 were determined by flow-cytometry. An in vitro assay with recombinant IL-40 (rIL-40) was performed to detect the effect on cytokine production from peripheral blood mononuclear cells (PBMCs).
IL-40 was significantly increased in the lymphocytic infiltrated MSG of patients with pSS and correlated with focus score and with IL-4 and transforming growth factor-β expression. In addition, IL-40 was increased in the serum of pSS and its levels correlated with the EULAR Sjögren's Syndrome Disease Activity Index score. B cells from patients were shown to be the major source of IL-40 at both tissue and peripheral level. PBMCs from patients, exposed to rIL-40 in vitro, released proinflammatory cytokines, specifically interferon-γ from B cells and T-CD8 and tumour necrosis factor-α and IL-17 from both T-CD4 and T-CD8. IL-40 expression in parotid glands of pSS-associated lymphomas was also increased. Moreover, IL-40-driven NETosis was evidenced in neutrophils obtained from pSS.
Our results suggest that IL-40 may play a role in pSS pathogenesis and pSS-associated lymphomas.
本研究旨在探讨白细胞介素（IL）-40 的表达，一种与 B 细胞稳态和免疫反应相关的新细胞因子，在原发性干燥综合征（pSS）和 pSS 相关淋巴瘤中的作用。
纳入 29 例 pSS 患者和 24 例对照者。采集患者和对照者的唾液腺活检标本及 pSS 相关淋巴瘤患者的腮腺活检标本。采用 TaqMan 实时 PCR 和免疫组化方法检测 IL-40 在唾液腺中的表达。采用流式细胞术和免疫荧光法确定 IL-40 的唾液腺细胞来源。采用 ELISA 法检测 IL-40 的血清浓度，采用流式细胞术确定 IL-40 的细胞来源。通过重组白细胞介素（rIL）-40 的体外试验检测其对外周血单个核细胞（PBMCs）细胞因子产生的影响。
pSS 患者淋巴细胞浸润的唾液腺中 IL-40 显著增加，并与焦点评分以及 IL-4 和转化生长因子-β的表达相关。此外，pSS 患者的血清中 IL-40 增加，其水平与 EULAR 干燥综合征疾病活动指数评分相关。患者的 B 细胞在组织和外周水平均为 IL-40 的主要来源。体外暴露于 rIL-40 的患者 PBMCs 释放促炎细胞因子，具体而言，B 细胞释放干扰素-γ，T-CD8 细胞和 T-CD4 细胞释放肿瘤坏死因子-α和 IL-17。pSS 相关淋巴瘤腮腺中 IL-40 的表达也增加。此外，在 pSS 患者的中性粒细胞中也证实了由 IL-40 驱动的 NETosis。
我们的研究结果表明，IL-40 可能在 pSS 发病机制和 pSS 相关淋巴瘤中发挥作用。
