Toll-Like Receptor 2 Agonists Exacerbate Accelerated Nephrotoxic Nephritis

Brown, Heather J.; Sacks, Steven H.; Robson, Michael G.

doi:10.1681/asn.2005111167

Cited by 53 publications

(52 citation statements)

References 42 publications

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“…We have recently demonstrated that TLR2 ligands given at the time of priming to the planted antigen can exacerbate disease in this model by modulating the nephritogenic immune response. 16 In addition to our own studies, Fu et al 17 also gave endotoxin and other TLR ligands to mice at the same time as nephrotoxic antibody. However, in this work there was no measurement of the immune response to the nephritogenic antigen sheep IgG, and so the relative roles of effects on the adaptive immune response or on innate mechanisms were not clear.…”

mentioning

confidence: 58%

“…16 In brief, crescents and thrombosis were scored on samples fixed in Bouin's solution and stained with PAS. For thrombosis, 50 glomeruli were each scored out of 4.…”

Section: Assessment Of Diseasementioning

confidence: 99%

“…mice have less than 50 g/ml of albuminuria using this assay, as previously reported (n ϭ 12). 16 Serum creatinine was measured by mass spectrometry as described. 16 …”

Section: Assessment Of Diseasementioning

confidence: 99%

“…Sandwich enzyme-linked immunosorbent assays (ELISAs) to measure the immune response to sheep IgG were performed as before 16 with modification for IgG2c. Detecting antibodies for IgG1, IgG2b, and IgG3 were from Southern Biotechnology (Birmingham, Alabama).…”

Section: Assessment Of the Nephritogenic Immune Responsementioning

confidence: 99%

“…We began by exploring the effect of TLR4 stimulation at priming on the adaptive immune response and disease severity in nephrotoxic nephritis to discover if our previously described results for TLR2 16 were generally applicable to other TLRs. Disease was induced by using protocol A (as shown in Figure 1 and described in Materials and Methods) in wild-type and TLR4-deficient mice.…”

Section: Toll-like Receptor 4 Stimulation At the Time Of Immunizationmentioning

confidence: 99%

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Toll-Like Receptor 4 Stimulation Triggers Crescentic Glomerulonephritis by Multiple Mechanisms Including a Direct Effect on Renal Cells

Giorgini

Brown

Sacks

et al. 2010

The American Journal of Pathology

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A role for toll-like receptor 4 (TLR4) has been suggested in previous studies of glomerulonephritis, but the complex integration of these effects has not been explored. To separate effects on the innate and adaptive immune responses, we use the autologous nephrotoxic nephritis model with two disease induction protocols. First, we give a TLR4 ligand at the time of immunization and show the effects are mediated via TLR4 by comparing wild-type and TLR4-deficient mice. In wild-type mice histological measures of disease and serum creatinine are all at least twice as high as TLR4-deficient mice, due to an enhanced immune response to the nephritogenic sheep IgG. Second, we stimulate TLR4 later in the course of disease development and construct four groups of bone marrow chimeric or sham chimeric mice to study the role of TLR4 on bone marrow or renal cells. The most striking finding is that renal cell TLR4 stimulation increases glomerular crescent formation, with a mean of 21% and 25% in the two groups of mice with renal cell TLR4 compared with 0.1% and 0.6% in the two groups without, with differences mirrored by changes in serum creatinine. These findings, in a single disease model, illustrate that TLR4 stimulation triggers crescentic glomerulonephritis by effects on both the adaptive and innate immune response, with a crucial direct effect on renal cells.

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mentioning

confidence: 58%

“…16 In brief, crescents and thrombosis were scored on samples fixed in Bouin's solution and stained with PAS. For thrombosis, 50 glomeruli were each scored out of 4.…”

Section: Assessment Of Diseasementioning

confidence: 99%

“…mice have less than 50 g/ml of albuminuria using this assay, as previously reported (n ϭ 12). 16 Serum creatinine was measured by mass spectrometry as described. 16 …”

Section: Assessment Of Diseasementioning

confidence: 99%

Section: Assessment Of the Nephritogenic Immune Responsementioning

confidence: 99%

Section: Toll-like Receptor 4 Stimulation At the Time Of Immunizationmentioning

confidence: 99%

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Toll-Like Receptor 4 Stimulation Triggers Crescentic Glomerulonephritis by Multiple Mechanisms Including a Direct Effect on Renal Cells

Giorgini

Brown

Sacks

et al. 2010

The American Journal of Pathology

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Experimentally‐induced anti‐myeloperoxidase vasculitis does not require properdin, MASP‐2 or bone marrow‐derived C5

Freeley

Popat

Parmar

et al. 2016

The Journal of Pathology

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Anti‐neutrophil cytoplasmic antibody vasculitis is a systemic autoimmune disease with glomerulonephritis and pulmonary haemorrhage as major clinical manifestations. The name reflects the presence of autoantibodies to myeloperoxidase and proteinase‐3, which bind to both neutrophils and monocytes. Evidence of the pathogenicity of these autoantibodies is provided by the observation that injection of anti‐myeloperoxidase antibodies into mice causes a pauci‐immune focal segmental necrotizing glomerulonephritis which is histologically similar to the changes seen on renal biopsy in patients. Previous studies in this model have implicated the alternative pathway of complement activation and the anaphylatoxin C5a. Despite this progress, the factors that initiate complement activation have not been defined. In addition, the relative importance of bone marrow‐derived and circulating C5 is not known. This is of interest given the recently identified roles for complement within leukocytes. We induced anti‐myeloperoxidase vasculitis in mice and confirmed a role for complement activation by demonstrating protection in C3‐deficient mice. We showed that neither MASP‐2‐ nor properdin‐deficient mice were protected, suggesting that alternative pathway activation does not require properdin or the lectin pathway. We induced disease in bone marrow chimaeric mice and found that circulating and not bone marrow‐derived C5 was required for disease. We have therefore excluded properdin and the lectin pathway as initiators of complement activation and this means that future work should be directed at other potential factors within diseased tissue. In addition, in view of our finding that circulating and not bone marrow‐derived C5 mediates disease, therapies that decrease hepatic C5 secretion may be considered as an alternative to those that target C5 and C5a. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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‘Experimentally‐induced anti‐myeloperoxidase vasculitis does not require properdin, MASP‐2 or bone marrow‐derived C5’

2022

The Journal of Pathology

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Anti-neutrophil cytoplasmic antibody vasculitis is a systemic autoimmune disease with glomerulonephritis and pulmonary haemorrhage as major clinical manifestations. The name reflects the presence of autoantibodies to myeloperoxidase and proteinase-3, which bind to both neutrophils and monocytes. Evidence of the pathogenicity of these autoantibodies is provided by the observation that injection of anti-myeloperoxidase antibodies into mice causes a pauci-immune focal segmental necrotizing glomerulonephritis which is histologically similar to the changes seen on renal biopsy in patients. Previous studies in this model have implicated the alternative pathway of complement activation and the anaphylatoxin C5a. Despite this progress, the factors that initiate complement activation have not been defined. In addition, the relative importance of bone marrow-derived and circulating C5 is not known. This is of interest given the recently identified roles for complement within leukocytes. We induced anti-myeloperoxidase vasculitis in mice and confirmed a role for complement activation by demonstrating protection in C3-deficient mice. We showed that neither MASP-2-nor properdin-deficient mice were protected, suggesting that alternative pathway activation does not require properdin or the lectin pathway. We induced disease in bone marrow chimaeric mice and found that circulating and not bone marrow-derived C5 was required for disease. We have therefore excluded properdin and the lectin pathway as initiators of complement activation and this means that future work should be directed at other potential factors within diseased tissue. In addition, in view of our finding that circulating and not bone marrow-derived C5 mediates disease, therapies that decrease hepatic C5 secretion may be considered as an alternative to those that target C5 and C5a.

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Toll-Like Receptor 2 Agonists Exacerbate Accelerated Nephrotoxic Nephritis

Cited by 53 publications

References 42 publications

Toll-Like Receptor 4 Stimulation Triggers Crescentic Glomerulonephritis by Multiple Mechanisms Including a Direct Effect on Renal Cells

Toll-Like Receptor 4 Stimulation Triggers Crescentic Glomerulonephritis by Multiple Mechanisms Including a Direct Effect on Renal Cells

Experimentally‐induced anti‐myeloperoxidase vasculitis does not require properdin, MASP‐2 or bone marrow‐derived C5

‘Experimentally‐induced anti‐myeloperoxidase vasculitis does not require properdin, MASP‐2 or bone marrow‐derived C5’

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