Identification of post-transplant anti-{alpha}5(IV) collagen alloantibodies in X-linked Alport syndrome

X-linked Alport syndrome (AS) is a heritable disorder whichis associated with mutations in the type IV collagen 5(IV) chaingene (COL4AS) located on chromosome X. Following renal transplantation,an average of 6% of male AS patients develop anti-GBM nephritis.We studied the specificity of the antibodies against type IVcollagen in the serum of a patient with COL4A5 partial deletion.The specificity of these alloantibodies was determined againstcollagenasedigested GBM, as well as against recombinant noncollagenous(NCl) domains of the type IV collagen 1(IV)—6(IV) chainsexpressed in Escherichia coli. Immunoblotting and ELISA demonstratedthat these antibodies bound specifically to the NCl domain of5(IV) collagen. There was no binding to the NCl domain of theother chains, including the Goodpasture antigen. CompetitiveELISA confirmed the results obtained by ELISA and immunoblotting.This patient developed alloantibodies directed against antigenspresent in the grafted kidney, but absent from his Alport kidney.The pathogenesis of post-transplantation glomerulonephritisin the Alport patient studied is thus similar to that of Goodpasturesyndrome, with the exception that the pathogenic antibodiesare targeted to another chain of type IV collagen.