The Role of Cationic Proteins in the Pathogenesis of Immune Complex Glomerulonephritis

Vogt, Arnold; Schmiedeke, Thomas; Stockl, F.; Sugisaki, Yuichi; Mertz, A.; Batsford, Stephen

doi:10.1093/ndt/5.suppl_1.6

Cited by 35 publications

(15 citation statements)

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“…Several studies have demonstrated the presence of antihistone along with anti-DNA antibodies in eluates from nephritic kidneys. Such data are consistent with the deposition of histones in GBM (15,(43)(44)(45). Minota et al reported selective accumulation of antihistones including anti-H1 antibodies together with anti-DNA antibodies in nephritic glomeruli of lupus-prone lpr mice (37).…”

Section: Discussionsupporting

confidence: 80%

Critical comparative analyses of anti–α‐actinin and glomerulus‐bound antibodies in human and murine lupus nephritis

Kalaaji¹,

Sturfelt²,

Mjelle³

et al. 2006

Arthritis & Rheumatism

102

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Objective. Although anti-double-stranded DNA (anti-dsDNA) antibodies are important in lupus nephritis, the question regarding which glomerular structures (␣-actinin, nucleosomes, or others) are recognized by nephritogenic anti-dsDNA antibodies is still controversial. In this study, we determined which glomerular structures are recognized by monoclonal and in vivobound nephritogenic antibodies.Methods.Western blotting was used to analyze the ability of nephritogenic anti-dsDNA antibodies to recognize glomerular and nucleosomal structures. Sera from patients with lupus nephritis, sera from random antinuclear antibody-positive patients, and paired antibodies from sera and kidney eluates from nephritic (NZB ؋ NZW)F 1 mice were analyzed for activity against proteins identified by monoclonal nephritogenic antibodies, and against ␣-actinin, dsDNA, nucleosomes, histone H1, heparan sulfate, DNase I, and type IV collagen. Immunoelectron microscopy was used to determine the glomerular localization of ␣-actinin and in vivo-bound autoantibodies in nephritic (NZB ؋ NZW)F 1 mouse kidneys.Results. Anti-␣-actinin antibodies were observed in human and murine lupus nephritis sera and in sera from patients without systemic lupus erythematosus and were not detected in kidney eluates from nephritic mice. Antibodies to dsDNA and histone H1 were detected in all eluates. Western blot analyses revealed that nephritogenic anti-dsDNA antibodies recognized a 32-kd band, identified as histone H1. Competitive enzyme-linked immunosorbent assay demonstrated that nephritogenic monoclonal antibodies, and dominant antibodies eluted from nephritic kidneys, cross-reacted with dsDNA and H1. This cross-reactive anti-H1 specificity was largely absent in sera from those mice. Immunoelectron microscopic analysis of nephritic (NZB ؋ NZW)F 1 mouse kidneys revealed that antibodies eluted from kidneys, but not anti-␣-actinin antibodies, bound to distinct nephritis-associated electrondense structures linked to glomerular basement membranes. Conclusion.Cross-reactive anti-dsDNA/antihistone H1 antibodies, but not anti-␣-actinin antibodies, are central among those deposited in nephritic glomeruli.

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Section: Discussionsupporting

confidence: 80%

Critical comparative analyses of anti–α‐actinin and glomerulus‐bound antibodies in human and murine lupus nephritis

Kalaaji¹,

Sturfelt²,

Mjelle³

et al. 2006

Arthritis & Rheumatism

102

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“…In fact, we recently observed significant glomerular plasmin activity that reflected the distribution of NAPlr deposition in the early phase of APSGN (T. Oda et al, unpublished data). Circulating immune complexes may readily pass through the altered GBM and accumulate in the subepithelial space (30). Taken together, our findings suggest that NAPlr is a virulence factor for APSGN and that the presence of a high titer of anti-NAPlr antibody should prevent autoimmune sequelae.…”

Section: Discussionmentioning

confidence: 62%

Nephritis-Associated Plasmin Receptor and Acute Poststreptococcal Glomerulonephritis

Yoshizawa¹,

Yamakami²,

Fujino³

et al. 2004

Journal of the American Society of Nephrology

117

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Abstract. The role of nephritis-associated antigen as a virulence factor for acute poststreptococcal glomerulonephritis (APSGN) remains to be fully clarified. Nephritis-associated plasmin receptor (NAPlr) was previously isolated from group A streptococcus (GAS) and shown to bind plasmin(ogen). The nucleotide sequence of the naplr gene from GAS isolates obtained from patients with APSGN was determined. The sequence of the putative open reading frame (1011 bp) showed 99.8% identity among isolated strains. Homology screen revealed an exact match with streptococcal glyceraldehyde-3-phosphate dehydrogenase (GAPDH). NAPlr exhibited GAPDH activity in zymography, and it activated the complement pathway in vitro. In APSGN kidney biopsy specimens, NAPlr was observed mainly in the early stage of the disease (1 to 14 d after onset) but was not colocalized with either C3 or IgG as assessed by double immunofluorescence staining. Sera of patients with APSGN, patients with GAS infection without renal involvement, nonrenal pediatric patients, and healthy adults as controls were assayed for antiNAPlr antibody titers. Anti-NAPlr antibodies were present most frequently in APSGN sera, and antibody titers were also significantly higher than in patients with GAS infection alone or in other control patients. Moreover, antibody titers remained elevated during the entire 10-yr follow-up period.

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“…ETB and its precursor (ETBP) are highly cationic molecules (pI 9 and 8.2, respectively) and have high affinity for the anionic glomerular basement membrane [5, 19, 20]. Binding of ETB/ETBP to glomerular basement membrane after reached circulation may be a rapid event [21,22,23].…”

Section: Discussionmentioning

confidence: 99%

Increased IL-6 in Supernatant of Rat Mesangial Cell Cultures Treated with Erythrogenic Toxin Type B and Its Precursor Isolated from Nephritogenic Streptococci

Pedreáñez

Viera²,

Rincón³

et al. 2006

Am J Nephrol

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Background/Aims: Previous reports have shown the presence of streptococcal erythrogenic toxin type B (ETB), IL-8, transforming growth factor-β (TGF-β) and glomerular proliferation in renal biopsies from patients with acute poststreptococcal glomerulonephritis (APSGN). In addition, increased levels of plasma IL-6 and tumor necrosis factor-α (TNFα) and urinary IL-6 have also been reported in this disease. To determine the effect of ETB in mesangial cell cytokine production and proliferation, the concentration of several cytokines (IL-6, IL-1β, TNFα, IL-10, IL-4, RANTES), soluble TNF receptor I (STNFR-I), soluble TNF receptor II (STNFR-II) and proliferation were measured in rat mesangial cells cultures after treatment with ETB or its precursor (ETBP). Methods: To analyze the levels of cytokines and production of soluble receptors as well as proliferation, rat mesangial cells were cultured with ETB or ETBP (50 µg/ml). After 24, 48 and 96 h of incubation, culture supernatants were assessed for cytokines and receptors by ELISA and for proliferation by incorporation of radioactive thymidine. Results: A significant increase in IL-6 levels was found in mesangial cell cultures treated with either ETBP or ETB when compared with controls. Streptococcal proteins treated mesangial cells also showed elevated levels of proliferation at 96 h. Increased production of IL-6 was not correlated with proliferation. A polyclonal anti-ETB antibody abolished the IL-6 stimulatory effect of ETB on mesangial cells. ETB/ETBP failed to increase the levels of other cytokines and cytokine soluble receptors. Conclusion: Streptococcal ETB/ETBP is capable of inducing increased production of IL-6 and proliferation on mesangial cells. These findings could be relevant in a possible early interaction of streptococcal proteins with mesangial cells and during the course of APSGN.

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The Role of Cationic Proteins in the Pathogenesis of Immune Complex Glomerulonephritis

Cited by 35 publications

References 0 publications

Critical comparative analyses of anti–α‐actinin and glomerulus‐bound antibodies in human and murine lupus nephritis

Critical comparative analyses of anti–α‐actinin and glomerulus‐bound antibodies in human and murine lupus nephritis

Nephritis-Associated Plasmin Receptor and Acute Poststreptococcal Glomerulonephritis

Increased IL-6 in Supernatant of Rat Mesangial Cell Cultures Treated with Erythrogenic Toxin Type B and Its Precursor Isolated from Nephritogenic Streptococci

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