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Distinct Epitopes for Anti–Glomerular Basement Membrane Alport Alloantibodies and Goodpasture Autoantibodies within the Noncollagenous Domain of 3(IV) Collagen: A Janus-Faced Antigen

Xu-Ping Wang^*, Agnes B. Fogo, Selene Colon^*, Giovanna Giannico, Sameh R. Abul-Ezz, Jeffrey H. Miner and Dorin-Bogdan Borza^*

^* Division of Nephrology, Department of Medicine, and Department of Pathology, Vanderbilt University School of Medicine, Nashville, Tennessee; Division of Nephrology, University of Arkansas, Little Rock, Arkansas; and Renal Division, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri

Address correspondence to: Dr. Dorin-Bogdan Borza, S-3223 Medical Center North, Division of Nephrology, Vanderbilt University Medical Center, Nashville, TN 37232-2372. Phone: 615-322-2089; Fax: 615-343-7156; E-mail: dorin-bogdan.borza{at}vanderbilt.edu

Received for publication June 29, 2005. Accepted for publication August 27, 2005.

Alport posttransplantation anti–glomerular basement membrane (GBM) nephritis is mediated by alloantibodies against the noncollagenous (NC1) domains of the 345(IV) collagen network, which is present in the GBM of the allograft but absent from Alport kidneys. The specificity of kidney-bound anti-GBM alloantibodies from a patient who had autosomal recessive Alport syndrome (ARAS) and developed posttransplantation nephritis was compared with that of Goodpasture autoantibodies from patients with autoimmune anti-GBM disease. Allograft-eluted alloantibodies reacted specifically with 345 NC1 hexamers, targeting their 3NC1 and 4NC1 subunits, and recognized a noncontiguous alloepitope formed jointly by the E_A and E_B regions of 3NC1 domain. In contrast, human Goodpasture autoantibodies recognized the separate E_A and E_B autoepitopes of 3NC1 but not the composite alloepitope. Molecular modeling of 3NC1 revealed that the alloepitope is more accessible within the NC1 hexamers than the partially sequestered Goodpasture autoepitopes. Overall, the specificity of alloantibodies indicated a selective lack of immune tolerance toward the 3 and 4(IV) collagen chains not expressed in patients with ARAS. Using COL4A3 knockout mice, a model of ARAS, it was shown further that acid-dissociated rather than native 345 NC1 hexamers elicited murine anti-GBM antibodies most closely resembling human ARAS alloantibodies. In contrast, 3NC1 monomers elicited Goodpasture-like murine antibodies, targeting the E_A and E_B autoepitopes. Thus, the identity of 3NC1 epitopes targeted by anti-GBM antibodies is strongly influenced by the molecular organization of the immunogen. These findings suggest that different isoforms of 3(IV) collagen may be implicated in the pathogenesis of ARAS posttransplantation anti-GBM nephritis and Goodpasture disease.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673