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

Identification of a clinically relevant immunodominant region out lung hemorrhage. The pathogenic process is driven of type IV collagen in Goodpasture disease. by antibodies to type IV collagen, one of the main struc- Background. The characteristic feature of Goodpasture dis- tural components of basement membranes. These auto- ease is the occurrence of an autoantibody response to the antibodies can be detected as circulating antibodies or noncollagenous domain of the a3 chain of type IV collagen as linear deposits of IgG in the affected basement mem- (a3(IV)NC1) in the alveolar and glomerular basement mem- brane. These antibodies are associated with the development branes. Studies have revealed that the major antigenic of a rapidly progressive glomerulonephritis, with or without epitopes are located in the C-terminal region of the lung hemorrhage, whereas autoantibodies specific for the other a3(IV) chain (1, 2), one of the six known a(IV) chains a chains of the heterotrimeric type IV collagen probably do (3). In this region, each chain is folded into a globular not cause disease. In this study, we have investigated whether domain (4), called the NC1 domain. The limited distribu- differences in fine specificity of autoimmune recognition of the tion of the a3(IV) chain (5), mainly in glomerular and a3(IV)NC1 correlate with clinical outcome. Methods. For mapping of antibody binding to type IV colla- alveolar basement membranes, correlates well with the gen, chimeric collagen constructs were generated in which parts organ involvement in Goodpasture disease. of the a3(IV)NC1 domain were replaced by the corresponding There are several reports discussing specificity of the sequences of homologous nonreactive a1(IV). The different Goodpasture autoantibodies and their epitopes. The epi- recombinant collagen chimeras allowed the analysis of anti- tope has been shown to be a conformational epitope