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

Background. The characteristic feature of Goodpasture disease is the occurr ence of an autoantibody response to the noncollagenous domain of the alpha 3 chain of type IV collagen [alpha 3(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 alpha chains of the heterotr imeric type IV collagen probably do not cause disease. In this study, we ha ve investigated whether differences in fine specificity of autoimmune recog nition of the alpha 3(IV)NC1 correlate with clinical outcome. Methods. For mapping of antibody binding to type IV collagen, chimeric coll agen constructs were generated in which parts of the alpha 3(IV)NC1 domain were replaced by the corresponding sequences of homologous nonreactive alph a 1(IV). The different recombinant collagen chimeras allowed the analysis o f antibody specificities in 77 sera from well-documented patients. Results. One construct that harbors the aminoterminal third of the alpha 3( IV)NC1 was recognized by all sera, indicating that it represents the domina nt 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 alpha 3(TV)NC1 correlated with prognosi s, that is, kidney survival after six months of follow-up. Conclusion. The results indicate the crucial importance of antibody recogni tion of this particular domain for the pathogenesis of Goodpasture disease, thereby opening new avenues for the development of better diagnostic and t herapeutic procedures.