Goodpasture disease. Characterization of a single conformational epitope as the target of pathogenic autoantibodies
Hellmark, Thomas LU
; Burkhardt, H
and Wieslander, Jörgen
LU
(1999)
In Journal of Biological Chemistry
274(36).
p.25862-25868
- Abstract
- Goodpasture disease is a prototype autoimmune disease characterized by the formation of autoantibodies against the heterotrimeric basement membrane collagen type IV, which causes a rapidly progressive glomerulonephritis. The pathogenic antibody response is directed to the non-collagenous (NC1) domain of the alpha3 chain of type IV collagen (alpha3(IV)NC1), but not to the homologous region of the alpha1(IV)NC1. To identify the conformation-dependent immunodominant epitope on the alpha3(IV)NC1, a variety of recombinant NC1 domains were constructed by replacing single residues of alpha3(IV) with the corresponding amino acids from the nonreactive alpha1(IV) chain. Replacement mutations were identified that completely destroyed the Goodpasture... (More)
- Goodpasture disease is a prototype autoimmune disease characterized by the formation of autoantibodies against the heterotrimeric basement membrane collagen type IV, which causes a rapidly progressive glomerulonephritis. The pathogenic antibody response is directed to the non-collagenous (NC1) domain of the alpha3 chain of type IV collagen (alpha3(IV)NC1), but not to the homologous region of the alpha1(IV)NC1. To identify the conformation-dependent immunodominant epitope on the alpha3(IV)NC1, a variety of recombinant NC1 domains were constructed by replacing single residues of alpha3(IV) with the corresponding amino acids from the nonreactive alpha1(IV) chain. Replacement mutations were identified that completely destroyed the Goodpasture epitope in the alpha3(IV) chain. Based on the identification of these critical positions, the epitope was finally reconstructed within the frame of the alpha1(IV) chain. The substitution of nine discontinuous positions in the alpha1(IV)NC1 with amino acid residues from the alpha3 chain resulted in a recombinant construct that was recognized by all patients' sera (n = 20) but by none of the sera from healthy controls (n = 10). This provides, for the first time, the molecular characterization of a single immunodominant conformational epitope recognized by pathogenic autoantibodies in a human autoimmune disease, representing the basis for the development of new epitope-specific strategies in the treatment of Goodpasture disease. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/1114292
- author
- Hellmark, Thomas
LU
; Burkhardt, H
and Wieslander, Jörgen
LU
- organization
- publishing date
- 1999
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Journal of Biological Chemistry
- volume
- 274
- issue
- 36
- pages
- 25862 - 25868
- publisher
- American Society for Biochemistry and Molecular Biology
- external identifiers
-
- pmid:10464328
- scopus:0033520320
- ISSN
- 1083-351X
- language
- English
- LU publication?
- yes
- id
- 1e8fb786-8922-4696-a33c-d0cce7ac43d5 (old id 1114292)
- alternative location
- http://www.jbc.org/cgi/content/full/274/36/25862
- date added to LUP
- 2016-04-01 11:45:39
- date last changed
- 2025-04-04 15:29:13
@article{1e8fb786-8922-4696-a33c-d0cce7ac43d5,
abstract = {{Goodpasture disease is a prototype autoimmune disease characterized by the formation of autoantibodies against the heterotrimeric basement membrane collagen type IV, which causes a rapidly progressive glomerulonephritis. The pathogenic antibody response is directed to the non-collagenous (NC1) domain of the alpha3 chain of type IV collagen (alpha3(IV)NC1), but not to the homologous region of the alpha1(IV)NC1. To identify the conformation-dependent immunodominant epitope on the alpha3(IV)NC1, a variety of recombinant NC1 domains were constructed by replacing single residues of alpha3(IV) with the corresponding amino acids from the nonreactive alpha1(IV) chain. Replacement mutations were identified that completely destroyed the Goodpasture epitope in the alpha3(IV) chain. Based on the identification of these critical positions, the epitope was finally reconstructed within the frame of the alpha1(IV) chain. The substitution of nine discontinuous positions in the alpha1(IV)NC1 with amino acid residues from the alpha3 chain resulted in a recombinant construct that was recognized by all patients' sera (n = 20) but by none of the sera from healthy controls (n = 10). This provides, for the first time, the molecular characterization of a single immunodominant conformational epitope recognized by pathogenic autoantibodies in a human autoimmune disease, representing the basis for the development of new epitope-specific strategies in the treatment of Goodpasture disease.}},
author = {{Hellmark, Thomas and Burkhardt, H and Wieslander, Jörgen}},
issn = {{1083-351X}},
language = {{eng}},
number = {{36}},
pages = {{25862--25868}},
publisher = {{American Society for Biochemistry and Molecular Biology}},
series = {{Journal of Biological Chemistry}},
title = {{Goodpasture disease. Characterization of a single conformational epitope as the target of pathogenic autoantibodies}},
url = {{http://www.jbc.org/cgi/content/full/274/36/25862}},
volume = {{274}},
year = {{1999}},
}