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J. Biol. Chem., Vol. 275, Issue 26, 20027-20032, June 30, 2000
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From the Goodpasture syndrome is an autoimmune
disease of the kidneys and lungs mediated by antibodies and T-cells
directed to cryptic epitopes hidden within basement membrane hexamers
rich in
Reactive Oxygen Species Expose Cryptic Epitopes Associated
with Autoimmune Goodpasture Syndrome*
§¶,,
, and Division of Nephrology, Department of
Medicine, Beth Israel Deaconess Medical Center and Harvard Medical
School, Boston, Massachusetts 02215, the Institute of Clinical
Pathology, University of Vienna, Vienna A1090 Wien, Austria, the
§ Penn Center for Molecular Studies of Kidney Diseases,
Department of Medicine, the Cell and Molecular Biology Graduate Group,
University of Pennsylvania, Philadelphia, Pennsylvania 19104, and the
** Nephrology and Hypertension Division, Vanderbilt University,
Nashville, Tennessee 37240
3 non-collagenous globular (NC1) domains of type IV
collagen. These epitopes are normally invisible to the immune system,
but this privilege can be obviated by chemical modification. Endogenous
drivers of immune activation consequent to the loss of privilege have
long been suspected. We have examined the ability of reactive oxygen
species (ROS) to expose Goodpasture epitopes buried within NC1 hexamers obtained from renal glomeruli abundant in 3(IV) NC1 domains. For
some hexameric epitopes, like the Goodpasture epitopes, exposure to ROS
specifically enhanced recognition by Goodpasture antibodies in a
sequential and time-dependent fashion; control binding of epitopes to 3(IV) alloantibodies from renal transplant recipients with Alport syndrome was decreased, whereas epitope binding to heterologous antibodies recognizing all 3 NC1 epitopes remained the
same. Inhibitors of hydrogen peroxide and hydroxyl radical scavengers
were capable of attenuating the effects of ROS in cells and kidney by
30-50%, respectively, thereby keeping the Goodpasture epitopes
largely concealed when compared with a 70% maximum inhibition by iron
chelators. Hydrogen peroxide administration to rodents was sufficient
to expose Goodpasture epitope in vivo and initiate autoantibody production. Our findings collectively suggest that ROS can
alter the hexameric structure of type IV collagen to expose or destroy
selectively immunologic epitopes embedded in basement membrane. The
reasons for autoimmunity in Goodpasture syndrome may lie in an
age-dependent deterioration in inhibitor function modulating oxidative damage to structural molecules. ROS therefore may
play an important role in shaping post-translational epitope diversity
or neoantigen formation in organ tissues.
*
This work was supported in part by Grants DK-51711 and
DK-55001 from the National Institutes of Health (to R. K.), the 1998 American Society of Nephrology Carl Gottschalk Award, the 1998 National
Kidney Foundation Murry Award (to R. K.), and Grants DK-46282,
DK-07006, DK-30280, and DK-45191 from the National Institutes of Health
(to E. G. N.), Grant DK-48871 from the National Institutes of Health
(to L. G. C.), and the Austrian Fonds Zur Forderung der
Wissenschaftlichen Forschung, Sonderforschungsbereich 5, Project 007 (to D. K.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
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