Kidneys with chronic inflammation develop tertiary lymphoid structures (TLSs). Infectious pyelonephritis is characterized by renal pelvis (RP) inflammation. However, the pathologic features of TLSs, including their formation and association with non-infectious nephritis, are unclear.

RPs from humans and mice that were healthy or had non-infectious chronic nephritis were analyzed for TLS development, and the mechanism of TLS formation investigated using urothelium or lymphoid structure cultures.

Regardless of infection, TLSs in the RP, termed urinary tract–associated lymphoid structures (UTALSs), formed in humans and mice with chronic nephritis. Moreover, urine played a unique role in UTALS formation. Specifically, we identified urinary IFN- as a candidate factor affecting urothelial barrier integrity because it alters occludin expression. In a nephritis mouse model, urine leaked from the lumen of the RP into the parenchyma. In addition, urine immunologically stimulated UTALS-forming cells via cytokine (IFN-, TNF-α) and chemokine (CXCL9, CXCL13) production. CXCL9 and CXCL13 were expressed in UTALS stromal cells and urine stimulation specifically induced CXCL13 in cultured fibroblasts. Characteristically, type XVII collagen (BP180), a candidate autoantigen of bullous pemphigoid, was ectopically localized in the urothelium covering UTALSs and associated with UTALS development by stimulating CXCL9 or IL-22 induction via the TNF-α/FOS/JUN pathway. Notably, UTALS development indices were positively correlated with chronic nephritis development.

TLS formation in the RP is possible and altered urine–urothelium barrier–based UTALS formation may represent a novel mechanism underlying the pathogenesis of chronic nephritis, regardless of urinary tract infection.

患有慢性炎症的肾脏会形成三级淋巴结构 (TLS)。传染性肾盂肾炎的特征是肾盂 (RP) 炎症。然而，TLS 的病理特征，包括它们的形成和与非感染性肾炎的关联，尚不清楚。

分析来自健康或患有非传染性慢性肾炎的人和小鼠的 RP 的 TLS 发展，并使用尿路上皮或淋巴结构培养物研究 TLS 形成的机制。

无论感染如何，RP 中的 TLS，称为尿路相关淋巴结构 (UTALS)，在患有慢性肾炎的人类和小鼠中形成。此外，尿液在 UTALS 形成中发挥了独特的作用。具体来说，我们确定了尿液 IFN-作为影响尿路上皮屏障完整性的候选因素，因为它改变了 occludin 的表达。在肾炎小鼠模型中，尿液从 RP 的管腔泄漏到实质中。此外，尿液通过细胞因子（IFN-, TNF- α ) 和趋化因子 (CXCL9, CXCL13) 的产生。CXCL9 和 CXCL13 在 UTALS 基质细胞中表达，尿液刺激在培养的成纤维细胞中特异性诱导 CXCL13。典型地，大疱性类天疱疮的候选自身抗原 XVII 型胶原蛋白 (BP180) 异位定位于覆盖 UTALS 的尿路上皮，并通过TNF - α /FOS/JUN 途径刺激 CXCL9 或 IL-22 诱导与 UTALS 发展相关。值得注意的是，UTALS 发展指数与慢性肾炎发展呈正相关。

RP 中的 TLS 形成是可能的，并且改变的基于尿-尿路上皮屏障的 UTALS 形成可能代表慢性肾炎发病机制的新机制，与尿路感染无关。