Developmental stages of tertiary lymphoid tissue reflect local injury and inflammation in mouse and human kidneys

Abstract

Tertiary lymphoid tissues (TLTs) are inducible ectopic lymphoid tissues in chronic inflammatory states and function as sites of priming local immune responses. We previously demonstrated that aged but not young mice exhibited multiple TLTs after acute kidney injury and that TLTs were also detected in human aged and diseased kidneys. However, the forms of progression and the implication for kidney injury remain unclear. To clarify this we analyzed surgically resected kidneys from aged patients with or without chronic kidney disease as well as kidneys resected for pyelonephritis, and classified TLTs into three distinct developmental stages based on the presence of follicular dendritic cells and germinal centers. In injury-induced murine TLT models, the stages advanced with the extent of kidney injury, and decreased with dexamethasone accompanied with improvement of renal function, fibrosis and inflammation. Kidneys from aged patients with chronic kidney disease consistently exhibited more frequent and advanced stages of TLTs than those without chronic kidney disease. Kidneys of patients with pyelonephritis exhibited more frequent TLTs with more advanced stages than aged kidneys. Additionally, TLTs in both cohorts shared similar locations and components, suggesting that TLT formation may not be a disease-specific phenomenon but rather a common pathological process. Thus, our findings provide the insights into biological features of TLT in the kidney and implicate TLT stage as a potential marker reflecting local injury and inflammation.