| 1. |
- Yang, Rui, et al.
(författare)
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Antigen and epitope specificity of anti-glomerular basement membrane antibodies in patients with Goodpasture disease with or without anti-neutrophil cytoplasmic antibodies
- 2007
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Ingår i: Journal of the American Society of Nephrology. - 1046-6673. ; 18:4, s. 1338-1343
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Tidskriftsartikel (refereegranskat)abstract
- Goodpasture disease (GP) is defined by the presence of anti-glomerular basement membrane (anti-GBM) antibodies and rapidly progressive glomerulonephritis. Besides anti-GBM, many patients with GP produce anti-neutrophil cytoplasmic antibodies (ANCA). For elucidation of the pathophysiologic significance of ANCA in this setting, epitope and antigen specificity of the anti-GBM antibodies and antigen specificity of ANCA were studied. Bovine testis a(IV)NC1 (tNC1); recombinant human alpha 1, alpha 3, alpha 4, and alpha 5(IV)NC1 (r alpha 1 through r alpha 5); and three chimeric proteins that contain previously defined epitope regions designated E-A, E-B, and S2 were used to examine the anti-GBM antibodies by ELISA in 205 Chinese patients with GP with or without ANCA. In the 205 anti-GBM antibody-positive sera, 63 (30.7%) were also ANCA positive (61 myeloperoxidase-ANCA and six proteinase 3-ANCA, four being triple positive). All 205 sera recognized tNC1 and r alpha 3(IV)NC1. In the double-positive group, 54.0, 66.7, 71.4% of the sera could recognize r alpha 1, r alpha 4, and r alpha 5, respectively, compared with 49.3, 60.6, and 55.6% for patients with anti-GBM antibodies alone. The levels of the antibodies to r alpha 3, tNC1, and the alpha 3/alpha 1 ratio were lower in the double-positive group than that in patients with anti-GBM antibody alone (P < 0.05). Most of the sera could recognize the epitope regions E-A,E-B, and S2, but the absorbance values to EA, EB, and S2 were lower in double-positive group (P < 0.05). Double-positive patients had a broader spectrum of anti-GBM antibodies and lower levels of antibodies against alpha 3(IV)NC1 compared with that of patients with anti-GBM antibodies alone.
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| 2. |
- Yang, Rui, et al.
(författare)
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Levels of epitope-specific autoantibodies correlate with renal damage in anti-GBM disease
- 2009
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Ingår i: Nephrology Dialysis Transplantation. - Oxford, UK : Oxford University Press (OUP). - 1460-2385 .- 0931-0509. ; 24:6, s. 1838-1844
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Tidskriftsartikel (refereegranskat)abstract
- Background. Although the clinical importance of demonstrating the presence of anti-glomerular basement membrane (anti-GBM) antibodies is well established, less is known concerning the clinical utility of measuring the levels of autoantibodies. Two conformational epitopes of anti-GBM antibodies have been defined at residues 17-31 and 127-141 of the alpha 3(IV)NC1 domain of type IV collagen [alpha 3(IV)NC1], which were named as EA and EB, respectively. In order to elucidate the importance of such antibodies, we studied the levels and the epitope specificities of anti-GBM antibodies in a large cohort of Chinese patients with anti-GBM disease. Methods. All patients, with anti-GBM disease and available clinical data, diagnosed at Peking University First Hospital from 1996 to 2005 were included in the present study. Recombinant chimeric proteins containing previously defined epitope regions designated as EA and EB were used to detect anti-GBM antibodies by ELISA. Results were compared and correlated with clinical data collected at the time of diagnosis, biopsy findings and outcome after 1 year of follow-up. Results. A retrospective diagnosis of anti-GBM disease was made in 147 patients. Haemoptysis was recorded for 47% of these cases while 53.5% cases had oliguria or anuria at the time of diagnosis. Among these patients, the levels of anti-GBM antibodies correlated with serum creatinine at diagnosis (P < 0.05 for anti EA, EB and alpha 3(IV)NC1). Oliguric patients had higher levels of autoantibodies than non-oliguric patients, however, the difference being statistically significant only for EB (P < 0.05). Renal biopsies were performed in 66 patients, and it was found that 50 (75.8%) had cresent formation in > 85% of the glomeruli. There was a correlation between the percentage of crescents and levels of antibodies, but it was significant only for anti-EA antibodies (P < 0.05). Clinical data regarding the follow-up were available for 102 patients; at the end of 1 year, 88 (86.3%) were either dead or dialysis dependent. The absorbance values of anti-GBM antibodies against both EA and EB were also associated with the subsequent development, death or terminal renal insufficiency (P < 0.05). Conclusion. In this study, patients with high levels of circulating antibodies against the specific epitopes EA and EB had a more severe renal disease at diagnosis as well as a worse prognosis.
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| 3. |
- Yang, Rui, et al.
(författare)
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Natural anti-GBM antibodies from normal human sera recognize alpha 3(IV)NC1 restrictively and recognize the same epitopes as anti-GBM antibodies from patients with anti-GBM disease
- 2007
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Ingår i: Clinical Immunology. - : Elsevier BV. - 1521-6616. ; 124:2, s. 207-212
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Tidskriftsartikel (refereegranskat)abstract
- Anti-GBM disease is a rare autoimmune condition characterized by autoantibodies targeting the alpha 3 chain non-collagen 1 domain of type IV collagen (alpha 3(IV)NC1). Recently, we isolated IgG reacting with alpha 3(IV)NC1 from normal healthy human sera. The current study examined the antigen and epitope specificity of these natural autoantibodies (NAA) using recombinant human alpha 1, 3, 5(IV)NC1 and three constructs expressing, previously defined epitope regions designated E-A, E-B and S2, in the alpha 1(IV)NC1 background. The NAA preparations reacted with recombinant human alpha 3(IV) NC1 to the same extent as with purified bovine alpha(IV)NC1, but not with recombinant human alpha 1 and alpha 5 (IV)NC1. NAA preparations recognized the three chimeric proteins (E-A, E-B and S2) yielding similar absorbance values. We conclude that anti-GBM NAA recognize the same major epitopes as anti-GBM antibodies from patients with Goodpasture's disease.
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| 4. |
- Yang, Rui, et al.
(författare)
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Successful treatment of experimental glomerulonephritis with IdeS and EndoS, IgG-degrading streptococcal enzymes
- 2010
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Ingår i: Nephrology Dialysis Transplantation. - Oxford, UK : Oxford University Press (OUP). - 1460-2385 .- 0931-0509. ; 25:8, s. 2479-2486
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Tidskriftsartikel (refereegranskat)abstract
- Background. Anti-glomerular basement membrane (anti-GBM) disease often results in end-stage renal failure despite therapy with plasma exchange and immunosuppressive drugs. The newly discovered streptococcal enzymes IgG-degrading enzyme of S.pyogenes (IdeS) and endoglycosidase S (EndoS) act with remarkable specificity on circulating IgG. In this study, we investigate their ability in vivo to prevent damage mediated by kidney-bound antibodies in a mouse model of anti-GBM disease. Methods. Anti-GBM disease was induced in mice by injection of subnephritogenic doses of rabbit anti-mouse GBM, followed a week later by injection of monoclonal mouse anti-rabbit IgG antibodies. By administrating IdeS or EndoS as fusion partners with GST between these antibody injections, we tested their ability to prevent damage by acting on kidney-bound rabbit anti-GBM. Control animals received placebo injections. Results. All animals in the positive control groups developed severe albuminuria immediately after the second antibody injection (mean, 2.51 mg/24 h; range, 0.13-8.20). This was significantly diminished by EndoS (1.3 +/- 1.3 mg/24 h) and completely prevented by IdeS (0.017 +/- 0.014 mg/24 h). Immunofluorescence studies showed that IdeS treatment effectively removed the Fc fragments of the rabbit IgG. This was accompanied by a significant reduction of the deposition of the complement components C3 and C1q, and this diminished the recruitment of leukocytes to the glomeruli. Conclusion. IdeS degrades IgG bound to the GBM in vivo, thereby preventing renal damage in this animal model. Most likely, IdeS would degrade both circulating and kidney-bound anti-GBM in patients with Goodpasture's disease. Whether this would lead to a halt in disease progression and a better prognosis remains to be determined.
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