Innate and adaptive immunity in experimental glomerulonephritis: a pathfinder tale

The nephrotoxic serum nephritis (NTS) model is a mouse model which is commonly used to study a type of immune complex-mediated, rapidly progressive glomerulonephritis (GN). It is induced by the injection of antibodies raised either in rabbits or sheep that are directed against the glomerular basement membrane (GBM). In the model used in our laboratory, a subcutaneous immunization against rabbit immunoglobulin G (IgG) prior to injection of the antiserum is needed to induce rapid-progressive GN within 7 to 14 days [1, 2, 3]. Other research groups using sheep anti-GBM antibody have reported that the immunization step is not required to induce a form of rapid-progressive GN [4, 5]. The so-called autologous phase of disease is characterized by nephrotic range albuminuria, a proliferative form of GN with crescent formation as well as infiltration of immune cells into the kidney [3]. The pathogenesis has been shown to be dependent on innate and adaptive immune cells as well as on the complement system. Kurts and coworkers recently published an excellent summary of the time course of kidney-infiltrating immune cells in NTS [6]. Gamma delta (γδ) T cells are the first cells to find their way into the kidney, attracting neutrophil granulocytes via the cytokine interleukin (IL)-17 [7]. Neutrophils, recruited via C-X-C motif chemokine ligand 1 (CXCL-1) [8], immediately infiltrate the kidney, mainly the glomeruli where they cause damage to glomerular cells. The absence of γδ T cells has been proven to protect mice from NTS [2]. Next, T helper (TH) 17 cells expressing CC chemokine receptor (CCR) 6 infiltrate the renal interstitium and glomeruli and in turn recruit neutrophils which infiltrate mainly the interstitium [9]. The recruitment of these neutrophils has been proven to be dependent on CXCL-5 rather than CXCL-1. CXCL-5 is induced in renal tubular epithelial cells by TH17 cells [8]. The prolonged infiltration of these adaptive immune cells seems to be dependent on dendritic cells (DCs) expressing CX3CR1 and CCR2 [10]. The latter also recruit TH1 cells, which lead to the infiltration of macrophages by the secretion of interferon-γ [11]. Depletion of either TH17 or TH1 cells significantly ameliorates the NTS phenotype in mice [5, 12]. DCs also recruit and activate effector T cells in the kidney by activation of the inflammasome and subsequent production of IL-1β and IL-18 [13]. In addition, activation of the inflammasome in macrophages by the P2X7 receptor increases disease activity [14].

Interestingly, not only pro-inflammatory cells infiltrate the kidney in NTS, but also regulatory immune cells which limit the on-going pro-inflammatory processes. In the early phase of disease, immature DCs recruit CCR6, expressing invariant natural killer T (iNKT) cells via the secretion of CXCL16 [15]. iNKT cells also have regulatory properties and suppress early infiltrating TH17 cells via the cytokines IL-4 and IL-10 [15]. TH17-specific STAT3-positive Tregs have recently been shown to infiltrate the kidney in the early phase of NTS and limit TH17 cell activation [16]. In the later phase of disease, regulatory T cells (Tregs) also infiltrate the kidney and limit TH1 activation by IL-10 secretion [6, 17, 18]. In early studies conducted in our laboratory, we did not detect early infiltration of Tregs into the kidneys [3, 19], but only infiltration in the prolonged phase of disease (Eller et al., unpublished observation). This difference might be explained by the different anti-GBM antibodies used as well as the need for immunization in our model.

Of note, the complement system activated by the IgG deposited in the glomeruli is also involved in the pathogenesis of NTS, especially in the model of accelerated NTS which needs pre-immunization against IgG. In the majority of studies, inhibition of the complement pathways resulted in an improvement of accelerated NTS [20, 21, 22]. In contrast, C1q deficiency—an early step of activation of the classical complement pathway—results in accelerated NTS disease activity probably due to a defect in the clearance of immune complexes and/or apoptotic cells from glomeruli [23].

Thus, both pro- and anti-inflammatory cell populations, including innate and adaptive immune cells, infiltrate the kidney during the course of NTS. Nevertheless, essential early immune regulation in NTS takes place in the secondary lymphoid organs, especially in draining lymph nodes. This is described in the following sections of this review.