Segregation of Experimental Autoimmune Glomerulonephritis as a Complex Genetic Trait and Exclusion of &lt;i&gt;Col4a3&lt;/i&gt; as a Candidate Gene

Reynolds, John J.; Cook, Paul; Ryan, J J; Norsworthy, Penny J.; Glazier, Anne M.; Duda, Mark A; Evans, David J.; Aitman, Timothy J.; Pusey, C. D.

doi:10.1159/000065297

Cited by 23 publications

(15 citation statements)

References 18 publications

(22 reference statements)

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“…24,27,28 Studies from our group into the genetic contribution to these models have focused on the finding that WKY rats are susceptible to disease induction, whereas Lewis rats are resistant. 29,30 As with our attempts at inducing EAV in the Lewis strain, Lewis rats injected with glomerular basement membrane develop high titers of antibody but no glomerulonephritis. Genome-wide linkage analyses using various breeding strategies have shown a significant area of linkage to glomerulonephritis susceptibility on chromosomes 13 and 16 in NTN, and we have demonstrated that Fc␥-receptor copy number underlies some of this variation in susceptibility to NTN.…”

Section: Discussionmentioning

confidence: 95%

Experimental Autoimmune Vasculitis

Little

Smyth

Salama

et al. 2009

The American Journal of Pathology

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103

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The morbidity burden associated with anti-neutrophil cytoplasmic autoantibody-associated vasculitis is increasing, and many novel biological therapies are now entering the drug development pipeline. There is thus an urgent need to develop a representative animal model to facilitate testing of these agents. We previously examined the effect of antineutrophil cytoplasmic autoantibody on leukocyte-endothelial interactions in WKY rats via immunization with human myeloperoxidase. We now seek to extend this model so that all animals reliably develop crescentic glomerulonephritis and lung hemorrhage. We also wish to investigate whether there is a genetic contribution to vasculitis development in this rat strain. Using escalating doses of human myeloperoxidase, we found that a dose of 1600 g/kg induced pauci-immune crescentic glomerulonephritis and lung hemorrhage in all immunized animals. We also found that the addition of pertussis toxin and killed Mycobacterium tuberculosis to the adjuvant when immunizing with 400 g/kg of myeloperoxidase resulted in crescentic glomerulonephritis and lung hemorrhage in all animals. However, when Lewis, Wistar Furth, or Brown Norway rats were immunized using a similar protocol, no animals developed hematuria or glomerulonephritis, despite having identical levels of anti-human myeloperoxidase antibodies. We conclude that, by adjusting the immunization regimen, all WKY rats immunized with myeloperoxidase develop experimental autoimmune vasculitis, thus facilitating future therapeutic studies. The resistance of Lewis rats to experimental autoimmune vasculitis provides a genetic basis for future studies of anti-myeloperoxidase antibody-associated vasculitis.

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Section: Discussionmentioning

confidence: 95%

Experimental Autoimmune Vasculitis

Little

Smyth

Salama

et al. 2009

The American Journal of Pathology

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103

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“…In fact, resistance to autoimmune disease induction is common in animal models for autoimmune diseases, including other anti-GBM GN models (6,7,(19)(20)(21). A previous study reported that glomerular injury was not observed in LEW rats at 28 day after immunization with recombinant Col4α3 (6).…”

Section: Discussionmentioning

confidence: 99%

Spontaneous recovery from early glomerular inflammation is associated with resistance to anti-GBM glomerulonephritis: tolerance and autoimmune tissue injury

Robertson

Arends

et al. 2008

Journal of Autoimmunity

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Different susceptibility to anti-GBM glomerulonephritis (GN) among animal strains has been reported. Using our rat model for T cell-mediated anti-GBM GN, this study initiated an investigation on the mechanism related with GN-susceptibility. Anti-GBM GN was induced either though immunization with the nephritogenic T cell epitope pCol(28-40) from Col4α3NC1 or through the transfer of specific T cells. WKY rats were highly susceptible to GN while immuno-compatible LEW rats were GN-resistant. GN-resistance in LEW rats was not associated immune response to pCol (28-40). First, both strains mounted a Th1 T cell response to pCol(28-40) with identical specificities; transfer of T cells from LEW to WKY rats induced glomerular injury. Second, co-transfer of antibody from WKY to LEW failed to induce GN. Time-course studies revealed that LEW rats did develop T cell-mediated inflammation in glomeruli at early stages similar to WKY rats, as evidenced by histopathology, proteinuria, CD4 + T cell infiltration in glomeruli, and glomerular expression of inflammatory molecules. However, glomerular inflammation in LEW rats was transient followed by a full recovery. Thus, GN-resistance in LEW rats was due to its ability to contain early T cell-mediated autoimmune glomerular damage. Our model may reveal a potential tolerance mechanism after autoimmune tissue damage has been initiated.

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“…In a study performed on 15 patients, no mutations were found by direct sequencing exons 48–52 of the COL4A3 gene, which encodes α3(IV)NC1 [15]. Similarly, in a rat model of anti-GBM disease, no linkage between disease susceptibility and rat COL4A3 gene was found [16]. These data suggest that alterations of the amino acid sequence translated by the COL4A3 gene are not a major factor in the disease etiology, but may represent pathogenic conformational change [10].…”

Section: Autoantigen and Antigen Presentationmentioning

confidence: 99%

Advances in the Genetics of Anti-Glomerular Basement Membrane Disease

Zhou

Zhao

et al. 2010

Am J Nephrol

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Anti-glomerular basement membrane (GBM) disease is a rare but lethal autoimmune disorder. Over the past few years, the nature of the autoantigen and its epitopes has been defined, as well as the possible pathogenic role played by environmental factors, and by cellular and humoral immunity. However, the majority of data on anti-GBM disease comes from studies conducted on animal models, since human studies are relatively scarce. Genetic studies have highlighted strong positive associations of anti-GBM disease with the HLA-DRB1*1501 allele. In addition, the disease has been associated with genes of the FCGR and KLK families. Important as they are, these findings have to be considered preliminary, if not contentious. Here, we provide an overview of recent discoveries in the genetics of anti-GBM disease that may help elucidate the disease pathogenesis while improving therapeutic approaches. We also discuss the limitations of such discoveries. Finally, we suggest that extensive collaboration between investigators and novel integrative approaches are essential to the progress of our understanding of the anti-GBM disease. We attempted to summarize the current knowledge on the pathogenesis of anti-GBM disease by providing different but complementary perspectives from previous reviews.

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Segregation of Experimental Autoimmune Glomerulonephritis as a Complex Genetic Trait and Exclusion of <i>Col4a3</i> as a Candidate Gene

Cited by 23 publications

References 18 publications

Experimental Autoimmune Vasculitis

Experimental Autoimmune Vasculitis

Spontaneous recovery from early glomerular inflammation is associated with resistance to anti-GBM glomerulonephritis: tolerance and autoimmune tissue injury

Advances in the Genetics of Anti-Glomerular Basement Membrane Disease

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