Glomerulonephritis Induced in Sheep by Injections of Heterologous Glomerular Basement Membrane and Freund's Complete Adjuvant

Steblay, Raymond William

doi:10.1084/jem.116.2.253

Cited by 201 publications

(66 citation statements)

References 23 publications

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“…This protocol depends on the presence of shared antigenic determinants in human and mouse kidney. There was reason to believe that renal antigens would be shared across species (33,34). Studies of established animal models of Goodpasture's syndrome, an autoimmune glomerulonephritis caused by antiglomerular basement membrane (anti-GBM) antibodies, have demonstrated the conservation of mammalian GBM structures (33,34).…”

Section: Autoantibodies That Bind Glomeruli 2407mentioning

confidence: 99%

“…There was reason to believe that renal antigens would be shared across species (33,34). Studies of established animal models of Goodpasture's syndrome, an autoimmune glomerulonephritis caused by antiglomerular basement membrane (anti-GBM) antibodies, have demonstrated the conservation of mammalian GBM structures (33,34). Moreover, sequence analysis of the Goodpasture's antigen of 9 mammalian species, including human and mouse, shows more than 90% identity spanning ϳ200 amino acids (35).…”

Section: Autoantibodies That Bind Glomeruli 2407mentioning

confidence: 99%

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Autoantibodies that bind glomeruli: Cross‐reactivity with bacterial antigen

Chowdhry¹,

Kowal²,

Hardin³

et al. 2005

Arthritis & Rheumatism

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Objective. Systemic lupus erythematosus (SLE) is characterized by the production of multiple autoantibodies. Anti-DNA antibodies are associated with glomerulonephritis in SLE. It has been shown that anti-DNA antibodies cross-react with bacterial polysaccharide and, thus, might be elicited by microbial exposure. Non-DNA-binding antibodies also contribute significantly to the pathogenesis of lupus nephritis. The goal of this study was to characterize non-DNA-binding, kidneybinding antibodies.Methods. We generated a combinatorial library derived from spleen cells of a patient with SLE who had just previously received pneumococcal vaccine. The phage library was used in an in vivo biopanning technique to identify non-DNA-binding, kidney-binding antibodies. Antibodies were then analyzed for binding to bacterial polysaccharide and to renal antigens.Results. Eight antibodies were characterized that bound glomeruli, but not DNA. All antibodies isolated by this protocol were IgG class, suggesting that there is affinity maturation for glomerular binding. Four of the antibodies cross-reacted with pneumococcal polysaccharide. Six of the antibodies bound to renal antigens that have previously been reported to be cross-reactive with DNA; the other 2 bound to histone.Conclusion. This study suggests that both DNAbinding and non-DNA-binding antibodies in SLE may be elicited by the same bacterial antigens.

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Section: Autoantibodies That Bind Glomeruli 2407mentioning

confidence: 99%

Section: Autoantibodies That Bind Glomeruli 2407mentioning

confidence: 99%

Autoantibodies that bind glomeruli: Cross‐reactivity with bacterial antigen

Chowdhry¹,

Kowal²,

Hardin³

et al. 2005

Arthritis & Rheumatism

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“…Anti-GBM GN has been studied in a number of animal models using immunizations with heterologous or homologous GBM preparations or a3IV-NC1 to breach tolerance against the autoantigen, often referred to as experimental autoimmune GN (EAG) (10)(11)(12)(13). We have previously characterized the T cell response to heterologous human a3IV-NC1 in DBA/1 mice and found a biphasic disease course.…”

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confidence: 99%

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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“…A ntiglomerular basement membrane (GBM) 3 disease, or Goodpasture's syndrome, was one of the earliest recognized human autoimmune diseases (1,2). Clinical symptoms of the disease include glomerulonephritis (GN) and/or pulmonary hemorrhage (1).…”

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confidence: 99%

T Cell Epitope Mimicry in Antiglomerular Basement Membrane Disease

Arends

Borillo

et al. 2006

The Journal of Immunology

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Antiglomerular basement membrane (GBM) disease or Goodpasture’s syndrome is among the earliest recognized human autoimmune diseases. Although collagen 4α3 NC1 (Col4α3NC1) has been identified as the responsible autoantigen, it remains unknown how autoimmunity to this autoantigen is provoked. We have demonstrated in our rat model that a single nephritogenic T cell epitope pCol28–40 of Col4α3NC1 induces glomerulonephritis. We hypothesized that microbial peptides that mimic this T cell epitope could induce the disease. Based on the critical residue motif (xxtTxNPsxx) of pCol28–40, seven peptides derived from human infection-related microbes were chosen through GenBank search and synthesized. All peptides showed cross-reactivity with pCol28–40-specific T cells at various levels. Only four peptides induced transient proteinuria and minor glomerular injury. However, the other three peptides induced severe proteinuria and modest to severe glomerulonephritis in 16–25% of the immunized rats. Unexpectedly, the most nephritogenic peptide, pCB, derived from Clostridium botulinum, also induced modest (25%) to severe (25%) pulmonary hemorrhage, another important feature of anti-GBM disease; this was not correlated with the severity of glomerulonephritis. This finding suggests that subtle variations in T cell epitope specificity may lead to different clinical manifestations of anti-GBM disease. In summary, our study raises the possibility that a single T cell epitope mimicry by microbial Ag may be sufficient to induce the anti-GBM disease.

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Glomerulonephritis Induced in Sheep by Injections of Heterologous Glomerular Basement Membrane and Freund's Complete Adjuvant

Cited by 201 publications

References 23 publications

Autoantibodies that bind glomeruli: Cross‐reactivity with bacterial antigen

Autoantibodies that bind glomeruli: Cross‐reactivity with bacterial antigen

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

T Cell Epitope Mimicry in Antiglomerular Basement Membrane Disease

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