Close Association between Altered Urine-Urothelium Barrier and Tertiary Lymphoid Structure Formation in the Renal Pelvis during Nephritis.

BACKGROUND: 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. METHODS: 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. RESULTS: 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-γ 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-γ, 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. CONCLUSIONS: 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.

Altered morpho-functional features of bones in autoimmune disease-prone BXSB/MpJ- Yaa mice.

IMPACT STATEMENT: Bone disease, such as osteoporosis and rheumatoid arthritis, increases because of the progression of an aging society. Autoimmune disease are important and predisposing factors for the pathogenesis of the bone disease; however, the pathological mechanism is unclear. We have demonstrated that systemic autoimmune disease in BXSB/MpJ- Yaa is closely associated with the morpho-functional abnormalities of bones including bone marrow and has complicated pathology. The abnormalities are characterized by altered regulations of serum calcium, anemia tendency, and hematopoiesis with increased WBCs and decreased PLs, short length and low mass of long bones, imbalance in the populations of osteoclasts and osteoblasts, and increased expression of candidate genes for causing and/or exacerbating their phenotypes. Therefore, BXSB/MpJ- Yaa serves as a model to elucidate bone phenotypes in systemic autoimmune disease that would be affected by the factors in the bone as well as the other immune and/or mineral metabolism organs both in human and experimental medicine.

Overexpression of toll-like receptor 9 correlates with podocyte injury in a murine model of autoimmune membranoproliferative glomerulonephritis.

Toll-like receptors (Tlrs) are sensors of danger signals which promote the activation of immune cells and intrinsic renal cells. Podocytes, the intrinsic cells of glomerulus, are continuously exposed to various plasma solutes and danger signals due to their unique location in the glomerulus. Herein, we show that Tlr9 is overexpressed in podocytes and the mechanisms which cause its injury and development of membranoproliferative glomerulonephritis (MPGN) in model BXSB/MpJ-Yaa (Yaa) mice. Yaa mice developed typical lesions of MPGN and showed strong expression of Tlr9 mRNA throughout the glomerulus particularly toward the periphery of the glomerulus. However, BXSB/MpJ (BXSB) mice showed no lesion for MPGN but a very weak expression of Tlr9 mRNA. Relative mRNA expression of Tlr9 and its downstream cytokines, including interleukin 1 beta (Il1b), Il6, interferon gamma (Ifng) and tumour necrosis factor alpha (Tnfa) was markedly increased in glomeruli isolated from Yaa mice. Tlr9 protein expression was almost absent in BXSB mice but intense expression was found in Yaa mice. Podocyte protein expression was normal in BXSB mice but decreased in Yaa mice and colocalized with Tlr9 protein. Furthermore, electron microscopy examination revealed podocyte injury and electron-dense materials in thickened glomerular basement membrane of Yaa mice. Glomerular Tlr9 mRNA expression was significantly correlated with anti-dsDNA antibody, proteinuria, renal function indices (sBUN and sCr), glomerular histopathology indices, downstream factors of Tlr family (Ilb and Tnfa), podocyte injury parameters (p < .05 and p < .01). In conclusion, overexpression of TLR9 correlates with podocyte injury and development of MPGN.