Antibodies to ?5 chain of collagen IV are pathogenic in Goodpasture's disease.

ABSTRACT: Autoantibody against glomerular basement membrane (GBM) plays a direct role in the initiation and development of Goodpasture's (GP) disease. The principal autoantigen is the non-collagenous domain 1 (NC1) of ?3 chain of collagen IV, with two immunodominant epitopes, EA-?3 and EB-?3. We recently demonstrated that antibodies targeting ?5NC1 are bound to kidneys in GP patients, suggesting their pathogenic relevance. In the present study, we sought to assess the pathogenicity of the ?5 autoantibody with clinical and animal studies. Herein, we present a special case of GP disease with circulating autoantibody reactive exclusively to the ?5NC1 domain. This autoantibody reacted with conformational epitopes within GBM collagen IV hexamer and produced a linear IgG staining on frozen sections of human kidney. The antibody binds to the two regions within ?5NC1 domain, EA and EB, and inhibition ELISA indicates that they are targeted by distinct sub-populations of autoantibodies. Sequence analysis highlights five residues that determine specificity of antibody targeting EA and EB epitopes of ?5NC1 over homologous regions in ?3NC1. Furthermore, immunization with recombinant ?5NC1 domain induced crescentic glomerulonephritis and alveolar hemorrhage in Wistar-Kyoto rats. Thus, patient data and animal studies together reveal the pathogenicity of ?5 antibodies. Given previously documented cases of GP disease with antibodies selectively targeting ?3NC1 domain, our data presents a conundrum of why ?3-specific antibodies developing in majority of GP patients, with ?5-specific antibodies emerged in isolated cases, the answer for which is critical for understanding of etiology and progression of the GP disease.

SUBMITTER: Cui Z 

PROVIDER: S-EPMC5600521 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature