Objective Chronic pancreatitis (CP) and autoimmune pancreatitis (AIP) are characterised by different inflammatory processes. If pancreatic inflammation is a prerequisite for autoimmunity is still unclear. AIP is considered mostly a T cell-mediated disease; however, in induction of CP, macrophages play a pivotal role. p21—a member of cyclin-dependent kinase inhibitors—can influence inflammatory processes, in particular can regulate T cell activation and promote macrophage development. We therefore examined the role of p21-mediated inflammation in AIP. Design We intercrossed lymphotoxin (LT) overexpressing mice (Tg(Ela1-LTa,b))—a model to study AIP development—with p21-deficient mice. Furthermore, we characterised p21 expression in human AIP and non-AIP specimens. Results p21 deficiency in LT mice (LTp21−/−) prevented early pancreatic injury and reduced inflammation. In acinar cells, diminished proliferation and abrogated activation of non-canonical nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) pathway was observed. In contrast, 12-month-old LT mice with and without p21 had similar inflammatory signatures and T–B cell infiltration. Interestingly, LT and LTp21−/− mice had comparable tertiary lymphoid organs (TLOs), autoantibodies and elevated IgG levels. However, acinar cell proliferation, acinar-to-ductal metaplasia and acinar non-canonical NF-κB pathway activation remained impaired in LTp21−/− pancreata. Conclusions Our findings indicate that p21 is crucial for pancreatic inflammation in LT-driven pancreatic injury. p21 is involved in early acinar secretion of inflammatory mediators that attract innate immune cells. However, p21 is not essential for humoral immune response, accountable for autoimmunity. Remarkably, p21 renders acinar cells less susceptible to proliferation and transdifferentiation. We therefore suggest that AIP can also develop independent of chronic inflammatory processes.

中文翻译：

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自身免疫性胰腺炎的发生与 CDKN1A/p21 介导的胰腺炎症无关

目的慢性胰腺炎（CP）和自身免疫性胰腺炎（AIP）具有不同的炎症过程。胰腺炎症是否是自身免疫的先决条件尚不清楚。AIP 主要被认为是一种 T 细胞介导的疾病；然而，在 CP 的诱导中，巨噬细胞起着举足轻重的作用。p21——细胞周期蛋白依赖性激酶抑制剂的成员——可以影响炎症过程，特别是可以调节 T 细胞活化和促进巨噬细胞发育。因此，我们检查了 p21 介导的炎症在 AIP 中的作用。设计 我们将淋巴毒素 (LT) 过表达小鼠（Tg(Ela1-LTa,b)）——一种研究 AIP 发展的模型——与 p21 缺陷小鼠杂交。此外，我们表征了人类 AIP 和非 AIP 标本中 p21 的表达。结果 LT 小鼠中的 p21 缺乏 (LTp21-/-) 可防止早期胰腺损伤并减少炎症。在腺泡细胞中，观察到活化 B 细胞 (NF-κB) 通路的非经典核因子 kappa-轻链增强子的增殖减少和消除激活。相比之下，有和没有 p21 的 12 个月大的 LT 小鼠具有相似的炎症特征和 T-B 细胞浸润。有趣的是，LT 和 LTp21-/- 小鼠具有相当的三级淋巴器官 (TLO)、自身抗体和升高的 IgG 水平。然而，腺泡细胞增殖、腺泡到导管化生和腺泡非经典 NF-κB 通路激活在 LTp21-/- 胰腺中仍然受损。结论我们的研究结果表明 p21 对 LT 驱动的胰腺损伤中的胰腺炎症至关重要。p21 参与吸引先天免疫细胞的炎症介质的早期腺泡分泌。然而，p21 不是体液免疫反应所必需的，它负责自身免疫。值得注意的是，p21 使腺泡细胞不易增殖和转分化。因此，我们建议 AIP 也可以独立于慢性炎症过程而发展。