Portal de Periódicos da CAPES

The Th17 immune response in renal inflammation

2010; Elsevier BV; Volume: 77; Issue: 12 Linguagem: Inglês

10.1038/ki.2010.102

1523-1755

Jan‐Eric Turner, Hans‐Joachim Paust, Oliver M. Steinmetz, Ulf Panzer,

IL-33, ST2, and ILC Pathways

The discovery of interleukin (IL)-17-producing CD4+ T (Th17) cells as a unique T-helper cell lineage has revised our understanding of T-cell-mediated tissue injury. Recent data from studies in humans and mice indicate that autoimmune diseases such as multiple sclerosis and rheumatoid arthritis, classically believed to be Th1-mediated, are predominantly driven by a Th17 immune response. IL-17 (IL-17A), IL-17F, IL-21, IL-22, and possibly also IL-9 produced by Th17 cells promote inflammation by directly causing tissue injury and enhancing secretion of pro-inflammatory cytokines and chemokines by resident cells. This results in augmented infiltration of leukocytes, in particular neutrophils, to the affected tissue where they induce organ inflammation and injury. Recent studies have highlighted the potential importance of the Th17 immune response also in renal inflammatory disease. This includes the identification and characterization of IL-17-producing T cells in nephritic kidneys of mice and humans, as well as evidence for the contribution of IL-17 and the IL-23/Th17 axis to renal tissue injury in glomerulonephritis. In this review, we will briefly summarize general characteristics of Th17 cells and discuss in detail the potential role of the Th17 immune response in human and experimental renal inflammation with a special focus on glomerulonephritis. The discovery of interleukin (IL)-17-producing CD4+ T (Th17) cells as a unique T-helper cell lineage has revised our understanding of T-cell-mediated tissue injury. Recent data from studies in humans and mice indicate that autoimmune diseases such as multiple sclerosis and rheumatoid arthritis, classically believed to be Th1-mediated, are predominantly driven by a Th17 immune response. IL-17 (IL-17A), IL-17F, IL-21, IL-22, and possibly also IL-9 produced by Th17 cells promote inflammation by directly causing tissue injury and enhancing secretion of pro-inflammatory cytokines and chemokines by resident cells. This results in augmented infiltration of leukocytes, in particular neutrophils, to the affected tissue where they induce organ inflammation and injury. Recent studies have highlighted the potential importance of the Th17 immune response also in renal inflammatory disease. This includes the identification and characterization of IL-17-producing T cells in nephritic kidneys of mice and humans, as well as evidence for the contribution of IL-17 and the IL-23/Th17 axis to renal tissue injury in glomerulonephritis. In this review, we will briefly summarize general characteristics of Th17 cells and discuss in detail the potential role of the Th17 immune response in human and experimental renal inflammation with a special focus on glomerulonephritis. CD4+ T-helper cells have a central role in the regulation of the adaptive immune response. Although activation of CD4+ T-helper cells is critical for the control and elimination of a wide array of invading pathogens, autoimmune disease can arise if CD4+ T cells become erroneously activated in response to self-antigens. One of the key mechanisms used by the immune system to prevent autoimmunity is thus to precisely regulate the activation and differentiation of CD4+ T-helper cells.1.Zhu J. Paul W.E. CD4 T cells: fates, functions, and faults.Blood. 2008; 112: 1557-1569Crossref PubMed Scopus (1165) Google Scholar Based on their cytokine secretion profile and expression of specific transcription factors, CD4+ T cells are today classified into four major subsets: Th1, Th2, Th17, and regulatory T cells (Tregs), although further T-helper cell lineages might exist.2.Palmer M.T. Weaver C.T. Autoimmunity: increasing suspects in the CD4+ T cell lineup.Nat Immunol. 2010; 11: 36-40Crossref PubMed Scopus (76) Google Scholar First evidence for the heterogeneity of CD4+ T cells derived in 1986 from the seminal work by Robert Coffman and Tim Mosmann who proposed that CD4+ T cells can be subdivided into two independent subsets, called T-helper 1 cells (Th1) and T-helper 2 cells (Th2).3.Mosmann T.R. Cherwinski H. Bond M.W. et al.Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins.J Immunol. 1986; 136: 2348-2357PubMed Google Scholar Th1 cells mainly produce interferon-γ (IFN-γ), which is essential for macrophage activation, and are predominantly involved in the clearance of intracellular pathogens. In contrast, Th2 cells are characterized by the production of interleukin (IL)-4, IL-5, and IL-13 and are critical for IgE production, eosinophil recruitment, and participate in the elimination of extracellular pathogens and parasites. IL-12 mainly produced by antigen-presenting cells is critical for Th1 differentiation whereas IL-4 has the major role in Th2 differentiation. Data from humans and experimental models provided strong evidence that Th1 cells are also involved in cell-mediated autoimmune disease (for example, multiple sclerosis, Crohn's disease, rheumatoid arthritis, and crescentic glomerulonephritis) whereas Th2 cells have been associated with allergic diseases. The concept that the Th1 immune response is of central importance in development of autoimmunity was challenged by the observation that animals lacking the ability to mount a functional Th1 response due to IFN-γ or IL-12 deficiency still develop significant and occasionally even exacerbated experimental arthritis and autoimmune encephalomyelitis. These effects were subsequently explained by the discovery of a highly pathogenic IL-17-producing CD4+ effector T-cell subset, termed Th17. Th17 cells differ from Th1 and Th2 cells not only by their cytokine expression profile, but also by the cytokines that drive their differentiation. Under the influence of IL-6, transforming growth factor-β (TGF-β), IL-1, and IL-21 the key transcription factors RORγt, RORα, and STAT3 are induced and mediate Th17 cell differentiation in mice and humans.2.Palmer M.T. Weaver C.T. Autoimmunity: increasing suspects in the CD4+ T cell lineup.Nat Immunol. 2010; 11: 36-40Crossref PubMed Scopus (76) Google Scholar Remarkably, recent studies indicate that there might be also TGF-β-independent pathways for differentiation of Th17 cells.4.Das J. Ren G. Zhang L. et al.Transforming growth factor beta is dispensable for the molecular orchestration of Th17 cell differentiation.J Exp Med. 2009; 206: 2407-2416Crossref PubMed Scopus (180) Google Scholar At later stages, IL-23 is essential for stabilization and expansion of the Th17 cell population. An overview of the differentiation factors and effector functions of CD4+ T-cell subsets is shown in Figure 1. The contribution of Th17 cells to autoimmune disease was first shown in mice deficient for the IL-23 subunit p19 (IL-23p19).5.Cua D.J. Sherlock J. Chen Y. et al.Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain.Nature. 2003; 421: 744-748Crossref PubMed Scopus (2361) Google Scholar IL-23p19−/− animals mount normal Th1 responses but have substantially reduced numbers of Th17 cells. Most importantly, these mice were resistant to the development of experimental autoimmune encephalomyelitis5.Cua D.J. Sherlock J. Chen Y. et al.Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain.Nature. 2003; 421: 744-748Crossref PubMed Scopus (2361) Google Scholar and collagen-induced arthritis,6.Murphy C.A. Langrish C.L. Chen Y. et al.Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation.J Exp Med. 2003; 198: 1951-1957Crossref PubMed Scopus (1382) Google Scholar models resembling human multiple sclerosis and rheumatoid arthritis. Likewise, IL-17-deficient mice also developed less severe autoimmune disease, providing further evidence for the functional importance of the Th17 immune response.7.Komiyama Y. Nakae S. Matsuki T. et al.IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis.J Immunol. 2006; 177: 566-573Crossref PubMed Scopus (1309) Google Scholar Th17 cells promote inflammation by the secretion of IL-17 (also called IL-17A), IL-17F, IL-21, IL-22, and tumor necrosis factor α (TNF-α) leading to upregulated expression of numerous pro-inflammatory cytokines and chemokines such as IL-6, CXCL1, CXCL8, and CCL2 by local tissue and infiltrating inflammatory cells. These inflammatory mediators further enhance the recruitment of different leukocyte subsets, predominantly neutrophils, ultimately leading to target organ injury. IL-17 was isolated and characterized 10 years before identification of the Th17 lineage from a rodent CD4+ T-cell cDNA library.8.Fossiez F. Djossou O. Chomarat P. et al.T cell interleukin-17 induces stromal cells to produce proinflammatory and hematopoietic cytokines.J Exp Med. 1996; 183: 2593-2603Crossref PubMed Scopus (1249) Google Scholar It represents the founder member of a cytokine family that includes IL-17, IL-17B, IL-17C, IL-17D, IL-17E, IL-17F (also called IL-25) and the five receptors IL-17RA, IL-17RB, IL-17RC, IL-17RD, and IL-17RE.9.Gaffen S.L. Structure and signalling in the IL-17 receptor family.Nat Rev Immunol. 2009; 9: 556-567Crossref PubMed Scopus (1058) Google Scholar The best characterized and biologically most potent member of the family is IL-17A, which binds to the IL-17RA and IL-17RC. The primary function of the Th17 immune response is in the defense against infections by extracellular bacterial and fungal pathogens.10.Puel A. Doffinger R. Natividad A. et al.Autoantibodies against IL-17A, IL-17F, and IL-22 in patients with chronic mucocutaneous candidiasis and autoimmune polyendocrine syndrome type I.J Exp Med. 2010; 207: 291-297Crossref PubMed Scopus (535) Google Scholar,11.Kisand K. Boe Wolff A.S. Podkrajsek K.T. et al.Chronic mucocutaneous candidiasis in APECED or thymoma patients correlates with autoimmunity to Th17-associated cytokines.J Exp Med. 2010; 207: 299-308Crossref PubMed Scopus (472) Google Scholar The presence of IL-17-producing T cells in biopsies of patients with Crohn's disease, multiple sclerosis, and rheumatoid arthritis suggests that the Th17 immune response also contributes to tissue injury in human inflammatory and autoimmune disease.12.Miossec P. Korn T. Kuchroo V.K. Interleukin-17 and type 17 helper T cells.N Engl J Med. 2009; 361: 888-898Crossref PubMed Scopus (1154) Google Scholar However, numbers of IL-17-producing T cells at the site of inflammation are usually low and they are often found together with a more prominent infiltrate of Th1 cells. This suggests that the combined action of pathogenic Th1 and Th17 cell subsets might be responsible for establishment of full-blown autoimmunity in humans. First evidence for contribution of IL-17 to inflammatory reactions in the kidney comes from an in vitro study on tubular epithelial cells that was published in 1998 more than 7 years before the discovery of Th17 cells in 2005.13.Van Kooten C. Boonstra J.G. Paape M.E. et al.Interleukin-17 activates human renal epithelial cells in vitro and is expressed during renal allograft rejection.J Am Soc Nephrol. 1998; 9: 1526-1534Crossref PubMed Google Scholar This study shows that IL-17 contributes to the induction of an inflammatory milieu in the kidney by stimulating the production of IL-6, CXCL8, and CCL2 in primary cultures of human proximal tubular epithelial cells (Figure 2). Anticipating future concepts, the authors identify activated T cells as the major source of IL-17 in the kidney.13.Van Kooten C. Boonstra J.G. Paape M.E. et al.Interleukin-17 activates human renal epithelial cells in vitro and is expressed during renal allograft rejection.J Am Soc Nephrol. 1998; 9: 1526-1534Crossref PubMed Google Scholar Almost 10 years after this initial publication, Th17-polarized CD4+ T cells were first identified and characterized in the kidney during renal inflammation.14.Dong X. Bachman L.A. Miller M.N. et al.Dendritic cells facilitate accumulation of IL-17 T cells in the kidney following acute renal obstruction.Kidney Int. 2008; 74: 1294-1309Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar Using flow cytometric analyses combined with intracellular cytokine staining, Dong and Griffin showed presence of an IL-17-producing CD4+ T-cell subset in murine kidneys after ureteral obstruction. These cells displayed an activated memory phenotype and could be readily stimulated to produce high levels of the effector cytokine IL-17, indicating that these lymphocytes had undergone prior differentiation.14.Dong X. Bachman L.A. Miller M.N. et al.Dendritic cells facilitate accumulation of IL-17 T cells in the kidney following acute renal obstruction.Kidney Int. 2008; 74: 1294-1309Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar Although the authors thoroughly characterized this newly identified intrarenal T-cell subset, they did not investigate the functional significance of these cells. The initial evidence for functional importance of Th17 cells in renal inflammation was provided in 2009 in a murine model of crescentic glomerulonephritis.15.Paust H.J. Turner J.E. Steinmetz O.M. et al.The IL-23/Th17 axis contributes to renal injury in experimental glomerulonephritis.J Am Soc Nephrol. 2009; 20: 969-979Crossref PubMed Scopus (193) Google Scholar Analysis of nephrotoxic nephritis in IL-23p19 and IL-17 knockout mice showed attenuated renal pathology and preserved renal function in both strains, despite an intact Th1 response. Consistent with the early studies on human tubular epithelial cells, the effector cytokine IL-17 (alone or in synergy with TNF-α) induced expression of monocyte and Th1 cell-attracting chemokines in murine mesangial cells,15.Paust H.J. Turner J.E. Steinmetz O.M. et al.The IL-23/Th17 axis contributes to renal injury in experimental glomerulonephritis.J Am Soc Nephrol. 2009; 20: 969-979Crossref PubMed Scopus (193) Google Scholar providing a possible mechanism for Th17-induced renal injury (Figure 2). Further support for involvement of the IL-23/Th17 axis in renal autoimmunity comes from a simultaneous study in experimental autoimmune glomerulonephritis, a mouse model for Goodpasture's syndrome.16.Ooi J.D. Phoon R.K. Holdsworth S.R. et al.IL-23, not IL-12, directs autoimmunity to the Goodpasture antigen.J Am Soc Nephrol. 2009; 20: 980-989Crossref PubMed Scopus (104) Google Scholar Using different mouse strains with deficiency in IL-23, IL-12, and combined deficiency of both cytokines, the group of Kitching and Holdsworth dissected the separate roles of IL-23 (Th17-associated) and IL-12 (Th1-associated) in the systemic immune response to the Goodpasture antigen. Knockout of IL-23, but not IL-12, led to reduced proliferation and activation of T and B cells in secondary lymphoid organs and reduced cytokine and antibody production by immune cells, resulting in protection from immune-mediated kidney injury.16.Ooi J.D. Phoon R.K. Holdsworth S.R. et al.IL-23, not IL-12, directs autoimmunity to the Goodpasture antigen.J Am Soc Nephrol. 2009; 20: 980-989Crossref PubMed Scopus (104) Google Scholar In a subsequent study, the same group of investigators showed that both Th1 and Th17 cells can mediate renal injury.17.Summers S.A. Steinmetz O.M. Li M. et al.Th1 and Th17 cells induce proliferative glomerulonephritis.J Am Soc Nephrol. 2009; 20: 2518-2524Crossref PubMed Scopus (144) Google Scholar Differences in immunopathology induced by the two T-cell subsets were assessed by the transfer of antigen-specific Th1 or Th17 cells (polarized in vitro) into mice with the T-cell antigen planted on the glomerular basement membrane. Interestingly, the time kinetic and predominance of certain cellular and soluble effectors were different in Th1 cell- and Th17 cell-injected animals. Although Th17 cells induced expression of CXCL1, neutrophil recruitment, and early renal injury, Th1 cell-recipients showed more CCL2 and CCL5, along with increased macrophage activity and renal injury at later time points.17.Summers S.A. Steinmetz O.M. Li M. et al.Th1 and Th17 cells induce proliferative glomerulonephritis.J Am Soc Nephrol. 2009; 20: 2518-2524Crossref PubMed Scopus (144) Google Scholar Finally, the same group showed a crucial role for IL-17 in mediation of renal tissue damage in a murine model of vasculitis induced by the autoantigen myeloperoxidase. Importantly, IL-17 knockout mice were protected from kidney injury due to impairment of both, the innate and the adaptive arms of the immune response (Gan et al.,18.Gan P.Y. Steinmetz O.M. Tan D.S. et al.Th17 cells promote autoimmune anti-myeloperoxidase glomerulonephritis.J Am Soc Nephrol. 2010; (Mar 18. (E-pub))Google Scholar 2010). A potential cross-regulation between Th1 and Th17 cells was shown by a study that examined the development of nephrotoxic nephritis in T-bet-deficient mice, lacking a functional Th1 response.19.Phoon R.K. Kitching A.R. Odobasic D. et al.T-bet deficiency attenuates renal injury in experimental crescentic glomerulonephritis.J Am Soc Nephrol. 2008; 19: 477-485Crossref PubMed Scopus (57) Google Scholar Despite an increased renal and splenic expression of IL-17, presumably due to increased numbers of Th17 cells, T-bet-deficient mice showed attenuated nephritis, indicating that Th1 cells might be required for full pathogenicity of Th17 cells in this model. In another murine model of renal autoimmune disease, the MRL-Faslpr model of lupus nephritis, a considerable percentage of IL-17-producing T cells seem to belong to a unique population of CD4 CD8 double-negative T cells that are selectively expanded in these lupus-prone mice.20.Zhang Z. Kyttaris V.C. Tsokos G.C. The role of IL-23/IL-17 axis in lupus nephritis.J Immunol. 2009; 183: 3160-3169Crossref PubMed Scopus (246) Google Scholar Immunohistochemical co-staining of the pan T-cell marker CD3 and IL-17 revealed that the tubulointerstitial infiltrates of these mice with lupus nephritis contained CD3+IL-17+ cells, suggesting a role in renal injury. Furthermore, renal autoimmune disease could be transferred to lymphocyte-deficient hosts by injection of IL-23-treated cells from B6-Faslpr lymph nodes that contain high percentages of double-negative IL-17+ T cells.20.Zhang Z. Kyttaris V.C. Tsokos G.C. The role of IL-23/IL-17 axis in lupus nephritis.J Immunol. 2009; 183: 3160-3169Crossref PubMed Scopus (246) Google Scholar The potential contribution of Th17 cells to pathogenesis of lupus nephritis was supported by examination of another lupus-prone mouse strain (New Zealand Black × New Zealand White F1 mice).21.Jacob N. Yang H. Pricop L. et al.Accelerated pathological and clinical nephritis in systemic lupus erythematosus-prone New Zealand Mixed 2328 mice doubly deficient in TNF receptor 1 and TNF receptor 2 via a Th17-associated pathway.J Immunol. 2009; 182: 2532-2541Crossref PubMed Scopus (86) Google Scholar The absence of both TNF receptors (TNFR1 and TNFR2) in these lupus-prone mice resulted in accelerated renal disease in combination with increased numbers of memory Th17 cells in the spleen, indicating a role for TNF signaling in regulation of the systemic Th17 response. Additional evidence for Th17 pathogenicity came from another study in the MRL-Faslpr model that showed ‘classical’ CD4+IL-17+ T cells also contribute to the IL-17-producing T-cell subset in the kidney of lupus-prone mice.22.Steinmetz O.M. Turner J.E. Paust H.J. et al.CXCR3 mediates renal Th1 and Th17 immune response in murine lupus nephritis.J Immunol. 2009; 183: 4693-4704Crossref PubMed Scopus (127) Google Scholar In this study, the chemokine receptor CXCR3 was identified as an important trafficking receptor not only for Th1 cells, but also for Th17 cells, making it an attractive target for treatment of T-cell-mediated autoimmune disease.22.Steinmetz O.M. Turner J.E. Paust H.J. et al.CXCR3 mediates renal Th1 and Th17 immune response in murine lupus nephritis.J Immunol. 2009; 183: 4693-4704Crossref PubMed Scopus (127) Google Scholar As further characterization of intrarenal Th17 cells in nephrotoxic nephritis revealed that the chemokine receptor CCR6 also contributes to kidney-directed migration of Th17 cells (Turner et al.,23.Turner J.E. Paust H.J. Steinmetz O.M. et al.CCR6 recruits regulatory T cells and Th17 cells to the kidney in glomerulonephritis.J Am Soc Nephrol. 2010; (Mar 18. (E-pub))Google Scholar 2010), this trafficking receptor represents another potential target for inhibition of the Th17 response in renal autoimmunity. Another therapeutic approach for modulation of systemic and renal Th17 response was suggested by a recent study that showed downregulation of Th17-related gene products in renal lymph nodes and kidneys of nephritic mice treated with the HMG-CoA reductase inhibitor atorvastatin.24.Eller P. Eller K. Wolf A.M. et al.Atorvastatin attenuates murine anti-glomerular basement membrane glomerulonephritis.Kidney Int. 2010; 77: 428-435Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar Very recently, an additional role of IL-17 as a mediator of innate immunity in kidney disease has been shown.25.Li L. Huang L. Vergis A.L. et al.IL-17 produced by neutrophils regulates IFN-gamma-mediated neutrophil migration in mouse kidney ischemia-reperfusion injury.J Clin Invest. 2010; 120: 331-342Crossref PubMed Scopus (399) Google Scholar Detailed studies in the kidney ischemia and reperfusion model have identified murine neutrophils as an early source of IL-17 in renal inflammation. This and other studies26.Kapsenberg M.L. Gammadelta T cell receptors without a job.Immunity. 2009; 31: 181-183Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar suggest that a wider spectrum of cell types contribute to IL-17 production in vivo than previously thought. Early studies in renal transplant recipients indicated that IL-17 might have a role for the inflammatory response during allograft rejection. IL-17 mRNA and protein could be detected in rejecting renal allografts, whereas pretransplant biopsies and normal kidneys were negative.13.Van Kooten C. Boonstra J.G. Paape M.E. et al.Interleukin-17 activates human renal epithelial cells in vitro and is expressed during renal allograft rejection.J Am Soc Nephrol. 1998; 9: 1526-1534Crossref PubMed Google Scholar,27.Loong C.C. Hsieh H.G. Lui W.Y. et al.Evidence for the early involvement of interleukin 17 in human and experimental renal allograft rejection.J Pathol. 2002; 197: 322-332Crossref PubMed Scopus (154) Google Scholar Furthermore, IL-17 mRNA expression in mononuclear cells of the urine sediment distinguished patients with borderline rejection from patients without signs of acute rejection in the renal biopsy,27.Loong C.C. Hsieh H.G. Lui W.Y. et al.Evidence for the early involvement of interleukin 17 in human and experimental renal allograft rejection.J Pathol. 2002; 197: 322-332Crossref PubMed Scopus (154) Google Scholar identifying it as a possible marker for subclinical allograft rejection. Currently, there is only limited evidence for an involvement of IL-17 in the pathogenesis of renal autoimmunity in humans. A number of studies, however, suggest a potential role of the Th17 axis. Freshly isolated peripheral blood T cells of patients with systemic lupus erythematodes (SLE) contain a higher percentage of IL-17+ T cells compared to healthy controls.28.Crispin J.C. Oukka M. Bayliss G. et al.Expanded double negative T cells in patients with systemic lupus erythematosus produce IL-17 and infiltrate the kidneys.J Immunol. 2008; 181: 8761-8766Crossref PubMed Scopus (580) Google Scholar As in the MRL-Faslpr model of human SLE, a population of CD4 CD8 double-negative T cells contributes to the IL-17+ population in these patients. Furthermore, sporadic IL-17+ CD3+ cells are found in the tubulointerstitial infiltrates in kidney biopsies from patients with lupus nephritis.28.Crispin J.C. Oukka M. Bayliss G. et al.Expanded double negative T cells in patients with systemic lupus erythematosus produce IL-17 and infiltrate the kidneys.J Immunol. 2008; 181: 8761-8766Crossref PubMed Scopus (580) Google Scholar As predicted from the relative rareness of Th17 cells in human peripheral blood and the inflamed kidney, measurement of total IL-17 in serum and urine of SLE patients have produced inconsistent results.29.Zhao X.F. Pan H.F. Yuan H. et al.Increased serum interleukin 17 in patients with systemic lupus erythematosus.Mol Biol Rep. 2010; 37: 81-85Crossref PubMed Scopus (113) Google Scholar,30.Kwan B.C. Tam L.S. Lai K.B. et al.The gene expression of type 17 T-helper cell-related cytokines in the urinary sediment of patients with systemic lupus erythematosus.Rheumatology (Oxford). 2009; 48: 1491-1497Crossref PubMed Scopus (70) Google Scholar Although lupus patients show a moderate increase in serum IL-17 protein compared to healthy individuals, there was no correlation of the serum cytokine levels with disease activity scores, renal involvement, or any other specific organ involvement.29.Zhao X.F. Pan H.F. Yuan H. et al.Increased serum interleukin 17 in patients with systemic lupus erythematosus.Mol Biol Rep. 2010; 37: 81-85Crossref PubMed Scopus (113) Google Scholar In a separate study, another group of investigators showed upregulation of IL-17 mRNA expression in the urine sediment of patients with SLE.30.Kwan B.C. Tam L.S. Lai K.B. et al.The gene expression of type 17 T-helper cell-related cytokines in the urinary sediment of patients with systemic lupus erythematosus.Rheumatology (Oxford). 2009; 48: 1491-1497Crossref PubMed Scopus (70) Google Scholar Remarkably, this upregulation was also present in patients without renal involvement and, moreover, the presence of active lupus nephritis was correlated with a significant decrease of urinary IL-17 mRNA.30.Kwan B.C. Tam L.S. Lai K.B. et al.The gene expression of type 17 T-helper cell-related cytokines in the urinary sediment of patients with systemic lupus erythematosus.Rheumatology (Oxford). 2009; 48: 1491-1497Crossref PubMed Scopus (70) Google Scholar Most recently, elevated serum levels of IL-17 and IL-23 were also reported in patients with systemic antineutrophil cytoplasmic antibody-associated vasculitis.31.Nogueira E. Hamour S. Sawant D. et al.Serum IL-17 and IL-23 levels and autoantigen-specific Th17 cells are elevated in patients with ANCA-associated vasculitis.Nephrol Dial Transplant. 2010; (Jan 25. (E-pub))Google Scholar However, this increase of circulating Th17-associated cytokines was again not significantly correlated with active disease. Taken together, it is conceivable that putative pathogenic alterations of the Th17 response in human autoimmunity can only rely on more elaborate detection methods, than measurement of systemic IL-17 levels. A sophisticated approach to analyze IL-17 expression within the kidney on a single-cell level was provided in a recent study by Wang et al.32.Wang Y. Ito S. Chino Y. et al.Laser microdissection-based analysis of cytokine balance in the kidneys of patients with lupus nephritis.Clin Exp Immunol. 2010; 159: 1-10Crossref PubMed Scopus (101) Google Scholar Kidney-infiltrating cells were captured from renal biopsies of patients with lupus nephritis by a laser microdissection technique and subjected to nested reverse transcriptase–PCR analysis for IL-17 and T-cell receptor (TCR) mRNA expression. The percentage of IL-17+ TCR+ cells within the kidney positively correlated with hematuria and disease activity scores in lupus nephritis.32.Wang Y. Ito S. Chino Y. et al.Laser microdissection-based analysis of cytokine balance in the kidneys of patients with lupus nephritis.Clin Exp Immunol. 2010; 159: 1-10Crossref PubMed Scopus (101) Google Scholar However, the complexity of this method, the mRNA-restricted approach, and some inconsistencies within the experimental groups32.Wang Y. Ito S. Chino Y. et al.Laser microdissection-based analysis of cytokine balance in the kidneys of patients with lupus nephritis.Clin Exp Immunol. 2010; 159: 1-10Crossref PubMed Scopus (101) Google Scholar emphasize the necessity for further confirmation of these promising results. In summary, further studies are clearly needed to establish a potential link between Th17 cells and the pathogenesis of SLE. With regard to the Th17 response in other renal inflammatory diseases, such as antineutrophil cytoplasmic antibody-associated glomerulonephritis, Goodpasture's syndrome, IgA nephropathy, or acute interstitial nephritis, there are no data available, underlining the urgent need for further research efforts in this field. On the basis of the available human and experimental studies, it is plausible that the development of renal autoimmune disease cannot be clearly attributed to a single T-helper cell subset. The character and stage of inflammatory kidney disease are likely to be decisive for composition of the renal T-cell infiltrate. Initial data implicate Th17 cells (and other IL-17-producing leukocytes) as important early mediators of inflammatory responses. Further studies are, however, necessary to elucidate spatiotemporal aspects of the Th17 response in the kidney. The cross-regulation between Th17, Th1, and Treg cells, as well as the possibility of their interlineage conversion within the target organ,33.Bluestone J.A. Mackay C.R. O’Shea J.J. et al.The functional plasticity of T cell subsets.Nat Rev Immunol. 2009; 9: 811-816Crossref PubMed Scopus (200) Google Scholar represent two other important issues in understanding of T-helper cell responses during renal inflammation. Addressing these questions will help to identify new therapeutic targets and to determine the optimal timing for interference with the IL-23/Th-17 axis in renal disease. As Th17 cells secrete a variety of potentially pathogenic mediators, it seems a reasonable therapeutic strategy to intervene upstream from the effector cytokine level. The use of antibodies directed against p40, the shared subunit of IL-23 and IL-12, allows simultaneous inhibition of both Th17 and Th1 cells.34.Steinman L. Mixed results with modulation of TH-17 cells in human autoimmune diseases.Nat Immunol. 2010; 11: 41-44Crossref PubMed Scopus (96) Google Scholar Currently, the two monoclonal antibodies ustekinumab and ABT-874 have been tested in psoriasis, Crohn's disease, and multiple sclerosis. In phase 2 clinical trials, both biologicals were effective in treatment of moderate to severe psoriasis.34.Steinman L. Mixed results with modulation of TH-17 cells in human autoimmune diseases.Nat Immunol. 2010; 11: 41-44Crossref PubMed Scopus (96) Google Scholar In another recent study on psoriasis patients, ustekinumab was even more effective compared to the long approved therapy with TNF-α-targeting substances.35.Griffiths C.E. Strober B.E. van de Kerkhof P. et al.Comparison of ustekinumab and etanercept for moderate-to-severe psoriasis.N Engl J Med. 2010; 362: 118-128Crossref PubMed Scopus (716) Google Scholar Ongoing clinical trials of ustekinumab in Crohn's disease have also been successful so far.34.Steinman L. Mixed results with modulation of TH-17 cells in human autoimmune diseases.Nat Immunol. 2010; 11: 41-44Crossref PubMed Scopus (96) Google Scholar In contrast, the p40 antibody did not reduce the incidence of demyelinating lesions in phase 2 clinical trials on patients with relapsing-remitting multiple sclerosis. Because evidence is accumulating that Th17 cells may not be the only cellular source of IL-17 in early inflammatory responses, which would presumably translate to a reduced effectiveness of IL-23-targeted therapy, the blockade of the effector cytokine IL-17 itself represents another therapeutic approach. Preliminary data from human trials using anti-IL-17 antibodies have shown promising results in treatment of rheumatoid arthritis.34.Steinman L. Mixed results with modulation of TH-17 cells in human autoimmune diseases.Nat Immunol. 2010; 11: 41-44Crossref PubMed Scopus (96) Google Scholar Other experimental approaches to therapeutically influence the Th17 response in autoimmunity include the blockade of prostaglandins36.Yao C. Sakata D. Esaki Y. et al.Prostaglandin E2-EP4 signaling promotes immune inflammation through Th1 cell differentiation and Th17 cell expansion.Nat Med. 2009; 15: 633-640Crossref PubMed Scopus (431) Google Scholar and osteopontin,37.Shinohara M.L. Kim J.H. Garcia V.A. et al.Engagement of the type I interferon receptor on dendritic cells inhibits T helper 17 cell development: role of intracellular osteopontin.Immunity. 2008; 29: 68-78Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar as well as interference with target organ-directed trafficking of Th17 cells by blockade of specific chemokine receptors.34.Steinman L. Mixed results with modulation of TH-17 cells in human autoimmune diseases.Nat Immunol. 2010; 11: 41-44Crossref PubMed Scopus (96) Google Scholar Interestingly, the blockade of the renin–angiotensin–aldosterone system has also been shown to downregulate the Th17 response and ameliorate autoimmune encephalomyelitis in mice.38.Platten M. Youssef S. Hur E.M. et al.Blocking angiotensin-converting enzyme induces potent regulatory T cells and modulates TH1- and TH17-mediated autoimmunity.Proc Natl Acad Sci USA. 2009; 106: 14948-14953Crossref PubMed Scopus (255) Google Scholar,39.Stegbauer J. Lee D.H. Seubert S. et al.Role of the renin-angiotensin system in autoimmune inflammation of the central nervous system.Proc Natl Acad Sci USA. 2009; 106: 14942-14947Crossref PubMed Scopus (163) Google Scholar The discovery of Th17 cells has substantially changed our view of T-cell-mediated autoimmunity. To date, there is convincing experimental evidence to support the notion that IL-17-producing T cells contribute to kidney injury in renal inflammatory diseases, such as glomerulonephritis and transplant rejection. With respect to human disease, the findings from animal models await further confirmation in larger patient cohorts and additional entities of renal disease. Data from first clinical trials in patients with ‘non-renal’ autoimmune disease indicate that targeting of the IL-23/Th17 axis may evolve as a promising therapeutic strategy in renal inflammation. All the authors declared no competing interests. This work was supported by grants from the Deutsche Forschungsgemeinschaft (KFO 228 TP1 to UP and JET). We thank Hans-Willi Mittrücker for critical reading of the article.