IL-23, not IL-12, Directs Autoimmunity to the Goodpasture Antigen

Ooi, Joshua D.; Phoon, Richard K.S.; Holdsworth, Stephen R.; Kitching, A. Richard

doi:10.1681/asn.2008080891

Cited by 112 publications

(106 citation statements)

References 46 publications

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“…Indeed, T cell transfers in WKY rats or in HLA-DRB1*15:01 transgenic mice have also suggested a direct participation of T cells in the emergence of crescentic GN (20,21). Our results also support studies in the EAG and the nephrotoxic nephritis model, which suggest a role of both Th1 and Th17 cells in the development of crescentic GN (15,(20)(21)(22)(23)(24)(25).…”

Section: Discussionsupporting

confidence: 86%

Glomerulopathy Induced by Immunization with a Peptide Derived from the Goodpasture Antigen α3IV-NC1

Hopfer

Hünemörder

Treder

et al. 2015

The Journal of Immunology

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Mouse experimental autoimmune glomerulonephritis, a model of human antiglomerular basement membrane disease, depends on both Ab and T cell responses to the Goodpasture Ag noncollagenous domain 1 of the α3-chain of type IV collagen (α3IV-NC1). The aim of our study was to further characterize the T cell–mediated immune response. Repeated immunization with mouse α3IV-NC1 caused fatal glomerulonephritis in DBA/1 mice. Although two immunizations were sufficient to generate high α3IV-NC1–specific IgG titers, Ab and complement deposition along the glomerular basement membranes, and a nephrotic syndrome, two additional immunizations were needed to induce a necrotizing/crescentic glomerulonephritis. Ten days after the first immunization, α3IV-NC1–specific CD4+ cells producing TNF-α, IFN-γ, or IL-17A were detected in the spleen. With the emergence of necrotizing/crescentic glomerulonephritis, ∼0.15% of renal CD4+ cells were specific for α3IV-NC1. Using peptides spanning the whole α3IV-NC1 domain, three immunodominant T cell epitopes were identified. Immunization with these peptides did not lead to clinical signs of experimental autoimmune glomerulonephritis or necrotizing/crescentic glomerulonephritis. However, mice immunized with one of the peptides (STVKAGDLEKIISRC) developed circulating Abs against mouse α3IV-NC1 first detected at 8 wk, and 50% of the mice showed mild proteinuria at 18–24 wk due to membranous glomerulopathy. Taken together, our results suggest that autoreactive T cells are able to induce the formation of pathologic autoantibodies. The quality and quantity of α3IV-NC1–specific Ab and T cell responses are critical for the phenotype of the glomerulonephritis.

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Section: Discussionsupporting

confidence: 86%

Glomerulopathy Induced by Immunization with a Peptide Derived from the Goodpasture Antigen α3IV-NC1

Hopfer

Hünemörder

Treder

et al. 2015

The Journal of Immunology

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“…IL17-producing Th17 cells accounted for much of the T cell-induced inflammation (Miossec et al, 2009;Kitching and Holdsworth, 2011). The presence of Th17 cells has been demonstrated in inflamed kidneys, and the IL23/Th17 axis is considered central to the mediation of kidney injury in anti-GBM models (Ooi et al, 2009). Paust et al provided mechanistic evidence for a cytokine-chemokine-driven feedback loop that orchestrated the differential Th1 and Th17 cell infiltrations into inflamed kidneys (Paust et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…IL-23-deficient mice immunized with 3(IV)NC1 may develop anti-GBM disease. While the autoantibody titers are lower in these mice, cellular reactivity is reduced and renal injury is less severe than that in non-IL-23-deficient mice (Ooi et al, 2009). In human anti-GBM disease, T cell involvement can be implied from strong human leukocyte antigen (HLA) associations (Phelps and Rees, 1999).…”

Section: Introductionmentioning

confidence: 99%

T cell infiltration is associated with kidney injury in patients with anti-glomerular basement membrane disease

Jia²,

Li³

et al. 2016

Sci. China Life Sci.

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“…In mouse MCs, IL-17 enhances the production of MCP-1/ CCL2, MIP-1␣/CCL3, LARC/CCL20, and MIP-2/CXCL2 through the MAPK pathways (p38 MAPK and ERK1/2) to recruit T cells and monocytes. [21][22][23] Mice infused with Th17 cells also develop albuminuria, which is associated with higher levels of renal GRO-␣/ CXCL1 and neutrophils in glomeruli. 24 …”

Section: Chemokines and Chemokine Receptorsmentioning

confidence: 99%

Chemokines in Renal Injury

Chung

Lan

2011

Journal of the American Society of Nephrology

238

181

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Renal inflammation underlies many chronic kidney diseases and the infiltration of leukocytes mediates much of the nephritogenic inflammatory response. As several recent reviews have dealt with the basic biology, mouse models, and blockade studies of chemokines in renal diseases, [1][2][3][4][5][6][7][8][9][10][11] we focus here on recent developments in pathophysiology of that chemokine effect. CHEMOKINES AND CHEMOKINE RECEPTORSChemokines are a group of chemotactic cytokines (approximately 8 to 17 kD) with the ability to bind G-proteincoupled receptors and act as potent attractants for leukocytes in acute and chronic inflammation. There are four subfamilies of chemokines, including CCL, CXCL, CX3CL, and CL (Figure 1). 7,6 At present, 19 receptors are known ( Figure 1). 6,7 The large CC chemokine family has the first two cysteine residues adjacent to each other, whereas the CXC family has a single amino acid residue in between the first two cysteines. Fractalkine (CX3CL1) is the only member of the CX3C chemokine family where three amino acid residues separate the first two cysteines. Finally, two related chemokines absent the two cysteine residues that bind the XCR1 receptor belong to the XC family. As shown in Figure 1, many chemokines bind multiple receptors and most receptors bind multiple chemokines. However, CC chemokine receptors exclusively bind CC chemokines and CXC receptors bind only CXC chemokines.Chemokines and their corresponding receptors are expressed in different cell types (Figure 2). 7,12 Generally speaking, monocytes are mostly attracted by CCL chemokines acting through CCR1, CCR2, andCCR5receptors,whereasneutrophilsare the target of CXCL chemokines through REGULATION OF CHEMOKINE EXPRESSIONOn the basis of their regulation and production, chemokines can be classified broadly as homeostatic/lymphoid or inflammatory chemokines. The former is responsible for leukocyte homing and ABSTRACTThe main function of chemokines is to guide inflammatory cells in their migration to sites of inflammation. During the last 2 decades, an expanding number of chemokines and their receptors have driven broad inquiry into how inflammatory cells are recruited in a variety of diseases. Although this review focuses on chemokines and their receptors in renal injury, proinflammatory IL-17, TGF␤, and TWEAK signaling pathways also play a critical role in their expression. Recent studies in transgenic mice as well as blockade of chemokine signaling by neutralizing ligands or receptor antagonists now allow direct interrogation of chemokine action. The emerging role of regulatory T cells and Th17 cells during renal injury also forges tight relationships between chemokines and T cell infiltration in the development of kidney disease. As chemokine receptor blockade inches toward clinical use, the field remains an attractive area with potential for unexpected opportunity in the future.

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IL-23, not IL-12, Directs Autoimmunity to the Goodpasture Antigen

Cited by 112 publications

References 46 publications

Glomerulopathy Induced by Immunization with a Peptide Derived from the Goodpasture Antigen α3IV-NC1

Glomerulopathy Induced by Immunization with a Peptide Derived from the Goodpasture Antigen α3IV-NC1

T cell infiltration is associated with kidney injury in patients with anti-glomerular basement membrane disease

Chemokines in Renal Injury

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