High nephritogenicity of monoclonal antibodies belonging to IgG2a and IgG2b subclasses in rat anti-GBM nephritis

Kohda, Takayuki; Okada, Shinichi; Hayashi, Akira; Kanzaki, Sho; Ninomiya, Yoshifumi; Taki, Masafumi; Sado, Yoshikazu

doi:10.1111/j.1523-1755.2004.00719.x

Cited by 48 publications

(45 citation statements)

References 32 publications

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“…Nephritogenic anti-GBM monoclonal antibody (clone b35) was purchased from Chondrex (Redmond, Wash, USA). 40 Microemulsion formulations (self-microemulsifying drug delivery system) of mTOR inhibitor, everolimus, and vehicle, were kindly donated by Novartis Pharma AG (Basel, Switzerland). 2-Amino-2 norbornate-carboxylic acid (BCH), a specific functional inhibitor of LAT1 and LAT2, was purchased from Sigma.…”

Section: Materials and Methods Antibodies And Reagentsmentioning

confidence: 99%

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Role of amino acid transporter LAT2 in the activation of mTORC1 pathway and the pathogenesis of crescentic glomerulonephritis

Kurayama

Ito

Nishibori

et al. 2011

Laboratory Investigation

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Molecular mechanisms and signaling pathways leading to cellular proliferation and lesion formation in the crescentic glomerulonephritis (CGN) remain elusive. In the present study we have explored a potential role of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway and amino acid transporter (LAT) in the pathogenesis of CGN. Immunohistochemistry and western blot analysis of glomeruli isolated from a rat model of CGN revealed that activation of mTORC1 preceded crescent formation in glomerular parietal epithelial cells (PECs) and podocytes. Daily treatment of rats with the mTOR inhibitor everolimus just after induction of CGN was not beneficial and instead led to increased cellular necrosis of PECs. However, daily treatment starting 7 days after the onset of CGN was beneficial and maintained intact glomeruli. Out of three forms of L-type neutral amino acid transporters (LAT1-LAT3) studied here, only LAT2 was found to be upregulated in the PECs and podocytes in advance of the crescent formation as well as in the crescent lesion itself. Cell culture study revealed that plasma membrane expression of LAT2 markedly stimulated mTORC1 signaling pathway, which was significantly abrogated by coexistence of LAT inhibitor. Finally, LAT inhibitor significantly abrogated development of crescent formation of CGN on day 7. Our data suggest that LAT2 may have a pivotal role in the pathogenesis of CGN by activating the mTORC1 pathway in the glomerular epithelial cells. Crescentic glomerulonephritis (CGN) is the most severe form of glomerulonephritis, and if untreated, progresses to endstage renal failure within days or weeks of diagnosis. Despite different etiologies and clinical manifestations among patients with CGN, there is a common glomerular pathology characterized by the disruption of glomerular basement membrane (GBM), followed by the flow of plasma proteins and inflammatory cells into the Bowman's space. 1 Several studies suggest that proliferating glomerular epithelial cells and accumulation of infiltrated macrophages are the main components of the cellular crescents. 2-6 Recent reports have further revealed that the cellular crescent lesions in CGN consist of podocytes in addition to glomerular parietal epithelial cells (PECs) and macrophages. [7][8][9] It is increasingly evident that proinflammatory cytokines and growth hormones released by proliferating cells in the glomerulus are involved in the pathogenesis of crescent formation. [10][11][12][13] These factors stimulate the p38 mitogen-activated protein kinase (MAPK) pathway, resulting in the production of inflammatory mediators. [14][15][16] The involvement of the MAPK pathway in the pathogenesis of CGN was first reported by Bokemeyer et al, 17 who demonstrated a rapid and sustained activation of extracellular signal-regulated kinase in the glomeruli isolated from rat model of anti-GBM nephritis. A further study demonstrated that both podocytes and the crescent lesion are the main source of p38MAPK activation, although additional signaling path...

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Section: Materials and Methods Antibodies And Reagentsmentioning

confidence: 99%

“…To do so, anti-GBM antibody or saline solution was intraperitoneally injected to 42 rats (Supplementary Table 1). 40 Animals were caged individually in metabolic cages for urine sample collection. Individual 24-h urine samples collected from each rat were used for urine analysis.…”

Section: Animal Experimentsmentioning

confidence: 99%

Role of amino acid transporter LAT2 in the activation of mTORC1 pathway and the pathogenesis of crescentic glomerulonephritis

Kurayama

Ito

Nishibori

et al. 2011

Laboratory Investigation

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“…Rat mAb RH42 (anti-␣4NC1 [17]), b14 (anti-␣5NC1 [18]), and B66 (anti-␣6NC1 [4]) were used for immunofluorescence staining, and affinity-purified rabbit polyclonal antibodies were used for detection of ␣1/2(IV) collagen. Rat mAb M54 and M69 (19) were used for specific detection of murine ␣5 and ␣6 NC1 domains in Western blots; other chain-specific mAb were as described (17).…”

Section: Methodsmentioning

confidence: 99%

Loss of α3/α4(IV) Collagen from the Glomerular Basement Membrane Induces a Strain-Dependent Isoform Switch to α5α6(IV) Collagen Associated with Longer Renal Survival in Col4a3 −/− Alport Mice

Kang

Wang

Miner

et al. 2006

Journal of the American Society of Nephrology

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Mutations in COL4A3/4/5 genes that affect the normal assembly of the ␣3/4/5(IV) collagen network in the glomerular basement membrane (GBM) cause Alport syndrome. Patients progress to renal failure at variable rates that are determined by the underlying mutation and putative modifier genes. Col4a3 ؊/؊ mice, a model for autosomal recessive Alport syndrome, progress to renal failure significantly slower on the C57BL/6 than on the 129X1/Sv background. Reported here is a novel strain-specific alternative collagen IV isoform switch that is associated with the differential renal survival in Col4a3 ؊/؊ Alport mice. The downregulation or the absence of ␣3/4(IV) collagen chains in the GBM of Lmx1b ؊/؊ and Col4a3 ؊/؊ mice was found to induce ectopic deposition of ␣5/6(IV) collagen. The GBM deposition of ␣5/6(IV) collagen was abundant in C57BL/6 Col4a3 ؊/؊ mice but almost undetectable in 129X1/Sv Col4a3 ؊/؊ mice. This strain difference was due to overall low expression of ␣6(IV) chain and ␣5/6(IV) protomers in the tissues of 129X1/SvJ mice, a natural Col4a6 knockdown. In (129 ؋ B6)F1 Col4a3 ؊/؊ mice, the amount of ␣5/6(IV) collagen in the GBM was inherited in a mother-to-son manner, suggesting that it is controlled by one or more X-linked loci, possibly Col4a6 itself. Importantly, high levels of ectopic ␣5/6(IV) collagen in the GBM were associated with approximately 46% longer renal survival. These findings suggest that ␣5/6(IV) collagen, the biologic role of which has been hitherto unknown, may partially substitute for ␣3/4/5(IV) collagen. Therapeutically induced GBM deposition of ␣5/6(IV) collagen may provide a novel strategy for delaying renal failure in patients with autosomal recessive Alport syndrome.

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“…The pathogenic role of circulating antibodies against the Goodpasture autoantigen has been demonstrated in passive transfer studies (10)(11)(12)(13). However, there is now compelling evidence for the importance of T cell-mediated autoimmunity in the initiation of disease.…”

Section: Introductionmentioning

confidence: 99%

Antibodies against Linear Epitopes on the Goodpasture Autoantigen and Kidney Injury

Jia

Cui²,

Yang³

et al. 2012

Clinical Journal of the American Society of Nephrology

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SummaryBackground and objectives Linear epitopes on the Goodpasture autoantigen involved in human anti-glomerular basement membrane (GBM) disease are not fully defined. This study investigated the linear epitopes recognized by circulating antibodies in anti-GBM patients, aiming to identify the potential nephrogenic linear epitopes and their clinical significance.Design, setting, participants, & measurements Sixty-eight patients with anti-GBM disease were enrolled. Twentyfour overlapping linear peptides were synthesized across the whole sequence of the human Goodpasture autoantigen. ELISA detected circulating antibodies against linear epitopes. Their associations with clinical features were further analyzed.Results Antibodies against linear peptides were detected in sera from 55 patients (80.9%). Three major epitopes with high frequencies were identified: P14 (41%), P16 (36.8%), and P18 (57%). P14, a formerly defined T cell epitope, was a mutual B cell epitope. Antibodies against P14 were frequently detected in patients with positive antineutrophil cytoplasmic antibodies (39.3% versus 12.5%; P=0.01). Patients with anti-P16 antibodies presented with higher serum creatinine on diagnosis (665.56227.2 versus 443.76296.8 mmol/L; P=0.001) and worse renal outcome during follow-up (hazard ratio, 2.10; 95% confidence interval, 1.10-3.90; P=0.02). The level of anti-P18 antibodies positively correlated with the percentage of crescents in glomeruli (r=0.54; P=0.008). Recognition of P22 was an independent predictor for patient death (hazard ratio, 3.02; 95% confidence interval, 1.20-7.57; P=0.02).Conclusions Antibodies against linear epitopes on the Goodpasture autoantigen could be detected in human anti-GBM disease and were associated with kidney injury. P14 was a mutual T and B cell epitope, implying its nephrogenic role in disease initiation.

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High nephritogenicity of monoclonal antibodies belonging to IgG2a and IgG2b subclasses in rat anti-GBM nephritis

Abstract: The severity of nephritis was dependent on both subclass and dose of autoantibodies. It becomes clear that pulmonary hemorrhage in anti-GBM nephritis is induced by autoantibodies.

Cited by 48 publications

References 32 publications

Role of amino acid transporter LAT2 in the activation of mTORC1 pathway and the pathogenesis of crescentic glomerulonephritis

Role of amino acid transporter LAT2 in the activation of mTORC1 pathway and the pathogenesis of crescentic glomerulonephritis

Loss of α3/α4(IV) Collagen from the Glomerular Basement Membrane Induces a Strain-Dependent Isoform Switch to α5α6(IV) Collagen Associated with Longer Renal Survival in Col4a3 −/− Alport Mice

Antibodies against Linear Epitopes on the Goodpasture Autoantigen and Kidney Injury

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