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Identification of a clinically relevant immunodominant region of collagen IV in Goodpasture disease

1999; Elsevier BV; Volume: 55; Issue: 3 Linguagem: Inglês

10.1046/j.1523-1755.1999.055003936.x

1523-1755

Thomas Hellmark, Mårten Segelmark, Christine Unger, Harald Burkhardt, Juan Saus, J. Wieslander,

Coagulation, Bradykinin, Polyphosphates, and Angioedema

Identification of a clinically relevant immunodominant region of type IV collagen in Goodpasture disease.BackgroundThe characteristic feature of Goodpasture disease is the occurrence of an autoantibody response to the noncollagenous domain of the α3 chain of type IV collagen [α3(IV)NC1] in the alveolar and glomerular basement membrane. These antibodies are associated with the development of a rapidly progressive glomerulonephritis, with or without lung hemorrhage, whereas autoantibodies specific for the other α chains of the heterotrimeric type IV collagen probably do not cause disease. In this study, we have investigated whether differences in fine specificity of autoimmune recognition of the α3(IV)NC1 correlate with clinical outcome.MethodsFor mapping of antibody binding to type IV collagen, chimeric collagen constructs were generated in which parts of the α3(IV)NC1 domain were replaced by the corresponding sequences of homologous nonreactive α1(IV). The different recombinant collagen chimeras allowed the analysis of antibody specificities in 77 sera from well-documented patients.ResultsOne construct that harbors the aminoterminal third of the α3(IV)NC1 was recognized by all sera, indicating that it represents the dominant target of the B-cell response in Goodpasture disease. Seventy percent of the samples recognized other parts of the molecule as well. However, only reactivity to the N-terminus of the α3(IV)NC1 correlated with prognosis, that is, kidney survival after six months of follow-up.ConclusionThe results indicate the crucial importance of antibody recognition of this particular domain for the pathogenesis of Goodpasture disease, thereby opening new avenues for the development of better diagnostic and therapeutic procedures. Identification of a clinically relevant immunodominant region of type IV collagen in Goodpasture disease. The characteristic feature of Goodpasture disease is the occurrence of an autoantibody response to the noncollagenous domain of the α3 chain of type IV collagen [α3(IV)NC1] in the alveolar and glomerular basement membrane. These antibodies are associated with the development of a rapidly progressive glomerulonephritis, with or without lung hemorrhage, whereas autoantibodies specific for the other α chains of the heterotrimeric type IV collagen probably do not cause disease. In this study, we have investigated whether differences in fine specificity of autoimmune recognition of the α3(IV)NC1 correlate with clinical outcome. For mapping of antibody binding to type IV collagen, chimeric collagen constructs were generated in which parts of the α3(IV)NC1 domain were replaced by the corresponding sequences of homologous nonreactive α1(IV). The different recombinant collagen chimeras allowed the analysis of antibody specificities in 77 sera from well-documented patients. One construct that harbors the aminoterminal third of the α3(IV)NC1 was recognized by all sera, indicating that it represents the dominant target of the B-cell response in Goodpasture disease. Seventy percent of the samples recognized other parts of the molecule as well. However, only reactivity to the N-terminus of the α3(IV)NC1 correlated with prognosis, that is, kidney survival after six months of follow-up. The results indicate the crucial importance of antibody recognition of this particular domain for the pathogenesis of Goodpasture disease, thereby opening new avenues for the development of better diagnostic and therapeutic procedures.