If, however, these Th cell responses are not regulated, immune disease ensues. In the glomerulus, this leads to inflammatory impairment, or glomerulonephritis (GN). In GN, disease outcomes have largely been explained around

the Th1–Th2 paradigm. Th1 immunopathology is characterized by an influx of delayed type hypersensitivity (DTH) effectors (macrophages, T cells and fibrin) and IgG subclass switching to IgG1 and IgG3 subclasses (in humans), while Th2 immunopathology is associated with the absence of DTH effectors and a predominance of the IgG4 antibody subclass. The explosive nature of crescentic GN is often associated with the Th1 cell subset exemplified in anti-glomerular basement selleckchem membrane (GBM) GN and pauci-immune crescentic GN while glomerular diseases such as membranous GN are associated with the Th2 cell subset. Some diseases such as IgA nephropathy and lupus nephritis are not exclusively Th1 or Th2 mediated but exhibit heterogeneic characteristics.2 A further distinct subset of Th cells, the Th17 subset, was identified in 2005, called Th17 cells because they produce IL-17A and IL-17F, members of the IL-17 cytokine family.3 Th17 cells

have been implicated in experimental models of organ-specific autoimmune inflammation, and their roles in GN will be the find more focus of this review. The discovery of Th17 cells in mice came from studies that documented the effects of IL-12 and IL-23 in experimental murine models of multiple sclerosis, rheumatoid arthritis and inflammatory bowel disease.4–6 In all three models of autoimmune disease, IL-23 played an important role whereby IL-23-deficient, but not IL-12-deficient mice, were completely protected from disease. IL-12 and IL-23 are heterodimeric cytokines of the same family and share

the same p40 subunit with different second subunits, p35 and p19, respectively.7 Prior to the identification of the p19 subunit and hence 4��8C IL-23, it was believed that IL-12 was the key cytokine in inflammatory diseases as neutralizing antibodies to p40 ameliorated disease in experimental autoimmune encephalomyelitis (EAE) (a mouse model of multiple sclerosis).8,9 IL-12 had been known to direct Th1–IFN-γ responses,10 and it was presumed that inflammatory diseases were caused by an unregulated Th1 response. It was however unexpectedly observed that mice deficient in IFN-γ11 or the receptor for IFN-γ were not protected from EAE.12 Shortly after these paradoxical observations, the IL-23p19 subunit was discovered7 and as mentioned, IL-23 is now regarded as the key cytokine in the pathogenesis of EAE, collagen induced arthritis (CIA) and mouse inflammatory bowel disease. Experimental evidence in EAE showed that IL-23 was responsible for driving the development and expansion of the distinct Th17 subset that produces IL-17A, IL-17F, tumour necrosis factor (TNF)-α and IL-6.