Innate and adaptive immunity in experimental glomerulonephritis: a pathfinder tale

Abstract

The role of innate and adaptive immune cells in the experimental model of nephrotoxic serum nephritis (NTS) has been rigorously studied in recent years. The model is dependent on kidney-infiltrating T helper (TH) 17 and TH1 cells, which recruit neutrophils and macrophages, respectively, and cause sustained kidney inflammation. In a later phase of disease, regulatory T cells (Tregs) infiltrate the kidney in an attempt to limit disease activity. In the early stage of NTS, lymph node drainage plays an important role in disease initiation since dendritic cells present the antigen to T cells in the T cell zones of the draining lymph nodes. This results in the differentiation and proliferation of TH17 and TH1 cells. In this setting, immune regulatory cells (Tregs), namely, CCR7-expressing Tregs and mast cells (MCs), which are recruited by Tregs via the production of interleukin-9, exert their immunosuppressive capacity. Together, these two cell populations inhibit T cell differentiation and proliferation, thereby limiting disease activity by as yet unknown mechanisms. In contrast, the spleen plays no role in immune activation in NTS, but constitutes a place of extramedullary haematopoiesis. The complex interactions of immune cells in NTS are still under investigation and might ultimately lead to targeted therapies in glomerulonephritis.

IL-17C/IL-17 Receptor E Signaling in CD4+ T Cells Promotes TH17 Cell-Driven Glomerular Inflammation

“…First, we assessed the serum levels of the IL-17 family members in patients with ANCA-associated crescentic GN and analyzed the systemic and renal expression patterns of these cytokines and their receptors during the time course of an experimental model of crescentic GN (nephrotoxic nephritis [NTN]). 18 Unexpectedly, these analyses demonstrated an upregulation of IL-17C and its specific receptor IL-17RE, suggesting a functional role for the IL-17C/IL-17RE axis in immune-mediated kidney diseases, and represented the rationale for our study.…”

IL-10 Receptor Signaling Empowers Regulatory T Cells to Control Th17 Responses and Protect from GN

“…Interestingly, hyper-Th17 responses developed sequentially and became primarily evident systemically in the spleen and also, the renal lymph node, which is of particular importance for immune activation in the NTN model. 48 At later stages of GN coinciding with development of renal tissue damage, enhanced Th17 immunity was also detected in the inflamed kidneys. Supporting our concept of Th17 cells as pathogenic mediators in GN, 20,35,36,[49][50][51] renal inflammation, histologic damage, and functional impairment were all exacerbated in Foxp3 Cre xIL-10Ra fl/fl mice.…”

Specialized Regulatory T Cells for Optimal Suppression of T Cell Responses in GN

“…1 However, this is questioned by the fact that splenectomy in mice does not have any effect on the phenotype of cGN. 13 Since the lymph node has been proven to be an important site of immune regulation in the cGN model (reviewed Artinger et al 14 ), it would be interesting to study further Th-specific Treg populations in this secondary lymphoid organ.…”