The HLA-DRB1*15

Ooi, Joshua D.; Chang, Joan; O’Sullivan, Kim M.; Pedchenko, Vadim; Hudson, Billy G.; Vandenbark, Arthur A.; Fugger, Lars; Holdsworth, Stephen R.; Kitching, A. Richard

doi:10.1681/asn.2012070705

Cited by 67 publications

(79 citation statements)

References 51 publications

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“…None of the peptides induced clinical signs of EAG and neither focal necrotizing nor crescentic GN was seen by histology. Our findings are in line with the results reported in the HLA-DRB1*15:01 transgenic mouse model, but the findings in mice contrast to the results obtained in WKY rats, where a single immunization with an immunodominant peptide is sufficient to induce crescentic GN (21,(26)(27)(28). Immune responses launch dose-dependently.…”

Section: Discussionsupporting

confidence: 92%

“…Although the renal CD3 cell count and its strong correlation with the percentage of glomerular crescents hint at a causal relationship, transfer experiments are necessary to prove this point. 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%

“…Our results as well as T cell transfer assays in mouse and rat EAG suggest that T cells may be the principal mediators of crescent formation and subsequent/associated tubulointerstitial damage (15,20,21). However, we failed to detect crescentic GN in P71-immunized mice despite the induction of P71-specific CD4 + T cells.…”

Section: Discussionmentioning

confidence: 55%

“…These epitopes differed from those recently described in a human HLA-DRB1*15:01-restricted transgenic mouse model of anti-GBM disease and from T cell epitopes identified in HLA-DR15 + patients with Goodpasture's disease (7,21). Interestingly, P05 includes the dominant epitope found in the WKY rat EAG model (26)(27)(28).…”

Section: Discussionmentioning

confidence: 61%

“…Compared to the immunizations with complete m-a3IV-NC1, we used a 50-fold peptide dose (∼1 nmol versus ∼50 nmol). It was comparable to the dose used in the transgenic mouse study, and related to the body weight it was higher than the ones used in the WKY rat studies (21,(26)(27)(28). It is interesting that the extreme susceptibility of WKY rats for EAG is dependent on non-MHC genes and in particular the Fcgr3 has been shown to be relevant in the context of crescentic GN (29,30).…”

Section: Discussionmentioning

confidence: 75%

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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: 92%

Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 55%

Section: Discussionmentioning

confidence: 61%

Section: Discussionmentioning

confidence: 75%

See 3 more Smart Citations

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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T Cell Mediated Autoimmune Glomerular Disease in Mice

et al. 2014

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Many forms of glomerulonephritis are mediated by autoimmunity. While autoantibodies are often pathogenic, cell-mediated immunity plays an important role in a number of forms of rapidly progressive glomerulonephritis. This unit describes the induction of cell-mediated autoimmune glomerular disease in mice. One disease model, experimental anti-glomerular basement membrane (GBM) disease, features autoreactivity to a well-defined component of type IV collagen found in the GBM, α3(IV)NC1. The other models the cell-mediated effector response in forms of renal vasculitis, where autoantibodies to myeloperoxidase result in systemic neutrophil activation, resulting in their localization to the glomerulus and the subsequent deposition of myeloperoxidase within glomerular capillaries. There, myeloperoxidase acts as a "planted" autoantigen and is recognized by effector autoreactive myeloperoxidase-specific T cells. These models are useful both in defining mechanisms germane to the development of autoimmunity to α3(IV)NC1 and myeloperoxidase, and in dissecting the role of cell-mediated responses in effecting glomerular injury.

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Regulatory T cells in renal disease

et al. 2018

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The kidney is vulnerable to injury, both acute and chronic from a variety of immune and metabolic insults, all of which at least to some degree involve inflammation. Regulatory T cells modulate systemic autoimmune and allogenic responses in glomerulonephritis and transplantation. Intrarenal regulatory T cells (Tregs), including those recruited to the kidney, have suppressive effects on both adaptive and innate immune cells, and probably also intrinsic kidney cells. Evidence from autoimmune glomerulonephritis implicates antigen‐specific Tregs in HLA‐mediated dominant protection, while in several human renal diseases Tregs are abnormal in number or phenotype. Experimentally, Tregs can protect the kidney from injury in a variety of renal diseases. Mechanisms of Treg recruitment to the kidney include via the chemokine receptors CCR6 and CXCR3 and potentially, at least in innate injury TLR9. The effects of Tregs may be context dependent, with evidence for roles for immunoregulatory roles both for endogenous Tbet‐expressing Tregs and STAT‐3‐expressing Tregs in experimental glomerulonephritis. Most experimental work and some of the ongoing human trials in renal transplantation have focussed on unfractionated thymically derived Tregs (tTregs). However, induced Tregs (iTregs), type 1 regulatory T (Tr1) cells and in particular antigen‐specific Tregs also have therapeutic potential not only in renal transplantation, but also in other kidney diseases.

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The HLA-DRB1*15

Cited by 67 publications

References 51 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 Mediated Autoimmune Glomerular Disease in Mice

Regulatory T cells in renal disease

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