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Quaternary epitopes of ?345(IV) collagen initiate Alport post-transplant anti-GBM nephritis.


ABSTRACT: Alport post-transplant nephritis (APTN) is an aggressive form of anti-glomerular basement membrane disease that targets the allograft in transplanted patients with X-linked Alport syndrome. Alloantibodies develop against the NC1 domain of ?5(IV) collagen, which occurs in normal kidneys, including renal allografts, forming distinct ?345(IV) and ?1256(IV) networks. Here, we studied the roles of these networks as antigens inciting alloimmunity and as targets of nephritogenic alloantibodies in APTN. We found that patients with APTN, but not those without nephritis, produce two kinds of alloantibodies against allogeneic collagen IV. Some alloantibodies targeted alloepitopes within ?5NC1 monomers, shared by ?345NC1 and ?1256NC1 hexamers. Other alloantibodies specifically targeted alloepitopes that depended on the quaternary structure of ?345NC1 hexamers. In Col4a5-null mice, immunization with native forms of allogeneic collagen IV exclusively elicited antibodies to quaternary ?345NC1 alloepitopes, whereas alloimmunogens lacking native quaternary structure elicited antibodies to shared ?5NC1 alloepitopes. These results imply that quaternary epitopes within ?345NC1 hexamers may initiate alloimmune responses after transplant in X-linked Alport patients. Thus, ?345NC1 hexamers are the culprit alloantigen and primary target of all alloantibodies mediating APTN, whereas ?1256NC1 hexamers become secondary targets of anti-?5NC1 alloantibodies. Reliable detection of alloantibodies by immunoassays using ?345NC1 hexamers may improve outcomes by facilitating early, accurate diagnosis.

SUBMITTER: Olaru F 

PROVIDER: S-EPMC3665397 | BioStudies | 2013-01-01

REPOSITORIES: biostudies

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