Goodpasture disease - Characterization of a single conformational epitope as the target of pathogenic autoantibodies

被引:75
作者
Hellmark, T
Burkhardt, H
Wieslander, J
机构
[1] Univ Lund, Dept Nephrol, S-22185 Lund, Sweden
[2] Univ Erlangen Nurnberg, Dept Internal Med 3, D-91054 Erlangen, Germany
[3] Wieslab AB, S-22370 Lund, Sweden
关键词
D O I
10.1074/jbc.274.36.25862
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 alpha 3 chain of type IV collagen (alpha 3(IV)NC1), but not to the homologous region of the alpha 1(IV)NC1, To identify the conformation-dependent immunodominant epitope on the alpha 3(IV)NC1, a variety of recombinant NC1 domains were constructed by replacing single residues of alpha 3(IV) with the corresponding amino acids from the nonreactive alpha 1(IV) chain. Replacement mutations were identified that completely destroyed the Goodpasture epitope in the alpha 3(IV) chain. Based on the identification of these critical positions, the epitope was finally reconstructed within the frame of the alpha 1(IV) chain. The substitution of nine discontinuous positions in the alpha 1(IV)NC1 with amino acid residues from the alpha 3 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.
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页码:25862 / 25868
页数:7
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