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J. Biol. Chem., Vol. 280, Issue 29, 27147-27154, July 22, 2005
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From the
Division of Nephrology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, 37232 and ¶Shigei Medical Research Institute, Okayama 701, Japan
Rapidly progressive glomerulonephritis in Goodpasture disease is mediated by autoantibodies binding to the non-collagenous NC1 domain of 
3(IV) collagen in the glomerular basement membrane. Goodpasture epitopes in the native autoantigen are cryptic (sequestered) within the NC1 hexamers of the 345(IV) collagen network. The biochemical mechanism for crypticity and exposure for autoantibody binding is not known. We now report that crypticity is a feature of the quaternary structure of two distinct subsets of 345(IV) NC1 hexamers: autoantibody-reactive M-hexamers containing only monomer subunits and autoantibody-impenetrable D-hexamers composed of both dimer and monomer subunits. Goodpasture antibodies only breach the quaternary structure of M-hexamers, unmasking the cryptic epitopes, whereas D-hexamers are resistant to autoantibodies under native conditions. The epitopes of D-hexamers are structurally sequestered by dimer reinforcement of the quaternary complex, which represents a new molecular solution for conferring immunologic privilege to a potential autoantigen. Dissociation of non-reinforced M-345(IV) hexamers by Goodpasture antibodies is a novel mechanism whereby pathogenic autoantibodies gain access to cryptic B cell epitopes. These findings provide fundamental new insights into immune privilege and the molecular mechanisms underlying the pathogenesis of human autoimmune Goodpasture disease.
Received for publication, April 13, 2005 , and in revised form, May 19, 2005.
* This work was supported by Grants P01 DK65123 (to D.-B. B.), R01 DK46282 (to E. G. N.), and R37 DK18381 (to B. G. H.) from the National Institutes of Health and by the Carl W. Gottschalk Research Scholar Award (to. D.-B. B.) from the American Society of Nephrology. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
To whom correspondence should be addressed: Div. of Nephrology, Dept. of Medicine, Vanderbilt University School of Medicine, S-3223 MCN, Nashville, TN 37232. Tel.: 615-322-7298; Fax: 615-343-7156; E-mail: Dorin-Bogdan.Borza{at}vanderbilt.edu.
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