Division of Gastroenterology and Hepatology, The Third Department of Internal Medicine, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, 573-1010, Japan.
Department of Gastroenterology and Hepatology, Kochi Medical School, Kochi University, 185-1 Kohasu Okocho, Nankoku, Kochi, 783-8505, Japan.
J Gastroenterol. 2020 Aug;55(8):789-799. doi: 10.1007/s00535-020-01689-5. Epub 2020 May 6.
IgG4-related disease (IgG4-RD) is a systemic inflammatory disease, which includes type 1 autoimmune pancreatitis (AIP). Interleukin-35 (IL-35) exhibits immunosuppressive effects in several autoimmune diseases. However, the expression of IL-35 had not been reported so far in type 1 AIP. We evaluated the association between IL-35 and several cytokines, which mediate the function of Tregs in type 1 AIP.
Plasma was collected from patients with type 1 AIP, alcoholic chronic pancreatitis (ACP), and healthy controls (HC) and assayed for cytokine expression. Total mRNA separated from peripheral blood was isolated from naïve Tregs (nTregs) and effector Tregs (eTregs). EBI3 and IL-12p35 gene expressions were tested in these cells by quantitative PCR. In addition, expression of IL-35 subunits in the pancreatic tissues of patients with type 1 AIP and ACP was analyzed by immunohistochemistry.
IL-35 was significantly elevated in type 1 AIP (n = 32) plasma compared with ACP (n = 16) and HC (n = 22), but IL-27 was not. We also detected many cells expressing both EBI3 and IL-12p35 in type 1 AIP tissues. Moreover, in peripheral blood lymphocyte, the percentage of nTregs and eTregs of CD4 T cells in patients with type 1 AIP (n = 14) compared with HC (n = 15) was significantly decreased and increased, respectively. There were no significant differences of gene expression in patients with type 1 AIP and HC.
This study identified elevated expression of plasma IL-35 and tissue IL-35 subunits in patients with type 1 AIP. This might lead to inflammation suppression via activated eTregs. IL-35 might be associated with this anti-inflammatory role, especially against the Th2 response through several cytokines and the differentiation of Tregs in type 1 AIP.
IgG4 相关疾病（IgG4-RD）是一种系统性炎症性疾病，包括 1 型自身免疫性胰腺炎（AIP）。白细胞介素 35（IL-35）在几种自身免疫性疾病中表现出免疫抑制作用。然而，目前尚未报道 1 型 AIP 中 IL-35 的表达。我们评估了 IL-35 与几种细胞因子之间的关联，这些细胞因子介导 1 型 AIP 中 Tregs 的功能。
从 1 型 AIP、酒精性慢性胰腺炎（ACP）患者和健康对照者（HC）中采集血浆，并检测细胞因子表达。从外周血中分离出幼稚 T regs（nTregs）和效应 Tregs（eTregs）的总 mRNA。通过定量 PCR 测试这些细胞中的 EBI3 和 IL-12p35 基因表达。此外，通过免疫组织化学分析 1 型 AIP 和 ACP 患者胰腺组织中 IL-35 亚基的表达。
与 ACP（n=16）和 HC（n=22）相比，1 型 AIP（n=32）血浆中 IL-35 显著升高，而 IL-27 则没有。我们还在 1 型 AIP 组织中检测到许多同时表达 EBI3 和 IL-12p35 的细胞。此外，与 HC（n=15）相比，1 型 AIP 患者（n=14）外周血淋巴细胞中 CD4 T 细胞的 nTregs 和 eTregs 的比例分别显著降低和升高。1 型 AIP 患者和 HC 之间的基因表达没有显著差异。
本研究鉴定出 1 型 AIP 患者血浆中 IL-35 和组织中 IL-35 亚基的表达升高。这可能通过激活 eTregs 导致炎症抑制。IL-35 可能与这种抗炎作用有关，特别是在 1 型 AIP 中通过几种细胞因子和 Tregs 的分化来对抗 Th2 反应。
