**7. Th17 cells in the kidney**

Early studies performed in gene deficient mice supported a role for Th17 related cytokines in the development of experimental autoimmune glomerulonephritis[109] and sheep anti-mouse glomerular basement membrane disease.[110] A pathogenic role for RORγt, the key IL-17A transcription factor, was also demonstrated in a murine model of crescentic glomeruloneph‐ ritis.[111] A direct role for Th17 cells acting as effectors was subsequently published. The antigen, ovalbumin (OVA), was planted in the kidneys of RAG1-/- mice, after the conjugation of OVA to a non-nephritogenic antibody specific for the glomerular basement membrane. This was followed by the administration of Th-17 polarized ovalbumin specific CD4+ T cells, which resulted in neutrophil mediated proliferative glomerulonephritis.[112] Detailed reviews of the role of Th17 cells in kidney disease have recently been published.[113-114]

Th17 cells are a distinct line of CD4+ T helper cells with unique transcription factors and effector cytokines. These cells are active participants in the development of autoimmunity but are also involved as effector cells in autoimmune conditions including rapidly pro‐ gressive glomerulonephritis.

In addition to CD4+ effector T cells other T cells are likely to contribute to AAV. Several years ago it was demonstrated that CD4+ effector memory cells (Tem) were increased in the blood of GPA patients in remission, compared to those with active disease.[115] While Tem were decreased in the blood, they were increased in the urine of patients with active disease suggesting that these cells may influence renal injury during active disease.[116] Further *in vitro* studies suggested that in GPA patients these cells could mediate endothelial injury and thus play a role in driving glomerular injury.[117] Fewer studies have assessed potential pathogenic roles of CD8+ T cells in AAV, however it would seem likely that these cells are involved. A study assessing gene expression and outcome in AAV and SLE patients suggested that CD8+ T cell signatures and increased CD8+ T cell memory populations were associated with poorer outcomes.[118] It was hoped that results from these studies would facilitate more individualised treatments. It would seem important that we further explore the role of CD8+ T cells in AAV.

Regulatory T cells (Tregs) represent a subset of CD4+ CD25+ T cells which perform a key role in regulating inflammation and tissue injury. These cells are identified through the expression of FoxP3, which is considered a master regulator of Tregs. In several autoimmune diseases, including Goodpasture's disease, Tregs are required for the maintenance of tolerance and loss of Treg function can result in the development of autoimmunity and organ injury.[119] In GPA clinical studies have shown that although circulating FoxP3-expressing Tregs vary in number their suppressive capacity is reduced.[120] In MPA patients (and experimentally) FoxP3 expressing Tregs display diminished capacity to suppress antigen specific MPO responses an effect mediated through tryptophan.[121] Our current understanding of the role of Tregs in AAV is limited and further studies are required to improve our knowledge of their role in disease pathogenesis in order to facilitate treatments aimed at optimizing their therapeutic potential. It is well known that Th17 cells and Tregs require many of the same cytokines for growth and development and it has been postulated that they have an inverse relationship. Whilst this explanation may be simplistic it is attractive to hypothesise that both the initiation of disease and flares seen in AAV could be attributed to an imbalance in the Th17: Treg ratio; with Th17 overactivity promoting disease. This imbalance could be targeted in future treat‐ ment protocols.
