TY - JOUR
T1 - The alloantigenic sites of α3α4α5(IV) collagen
T2 - Pathogenic X-linked alport alloantibodies target two accessible conformational epitopes in the α5NC1 domain
AU - Jeong, Suk Kang
AU - Kashtan, Clifford E.
AU - Turner, A. Neil
AU - Heidet, Laurence
AU - Hudson, Billy G.
AU - Borza, Dorin Bogdan
PY - 2007/4/6
Y1 - 2007/4/6
N2 - Anti-glomerular basement membrane (GBM) antibody nephritis is caused by an autoimmune or alloimmune reaction to the NC1 domains of α3α4α 5(IV) collagen. Some patients with X-linked Alport syndrome (XLAS) develop post-transplant nephritis mediated by pathogenic anti-GBM alloantibodies to collagen IV chains present in the renal allograft but absent from the tissues of the patient. In this work, the epitopes targeted by alloantibodies from these patients were identified and characterized. All XLAS alloantibodies recognized conformational epitopes in the NC1 domain of α5(IV) collagen, which were mapped using chimeric α1/α5 NC1 domains expressed in mammalian cells. Allograft-eluted alloantibodies mainly targeted two conformational alloepitopes mapping to α5NC1 residues 1-45 and 114-168. These regions also encompassed the major epitopes of circulating XLAS alloantibodies, which in some patients additionally targeted α5NC1 residues 169-229. Both kidney-eluted and circulating alloantibodies to α5NC1 distinctively targeted epitopes accessible in the α3α4α5NC1 hexamers of human GBM, unlike anti-GBM autoantibodies, which targeted sequestered α3NC1 epitopes. The results identify two immunodominant α5NC1 epitopes as major alloantigenic sites of α3α4α5(IV) collagen specifically implicated in the pathogenesis of post-transplant nephritis in XLAS patients. The contrast between the accessibility of these alloepitopes and the crypticity of autoepitopes indicates that distinct molecular forms of antigen may initiate the immunopathogenic processes in the two forms of anti-GBM disease.
AB - Anti-glomerular basement membrane (GBM) antibody nephritis is caused by an autoimmune or alloimmune reaction to the NC1 domains of α3α4α 5(IV) collagen. Some patients with X-linked Alport syndrome (XLAS) develop post-transplant nephritis mediated by pathogenic anti-GBM alloantibodies to collagen IV chains present in the renal allograft but absent from the tissues of the patient. In this work, the epitopes targeted by alloantibodies from these patients were identified and characterized. All XLAS alloantibodies recognized conformational epitopes in the NC1 domain of α5(IV) collagen, which were mapped using chimeric α1/α5 NC1 domains expressed in mammalian cells. Allograft-eluted alloantibodies mainly targeted two conformational alloepitopes mapping to α5NC1 residues 1-45 and 114-168. These regions also encompassed the major epitopes of circulating XLAS alloantibodies, which in some patients additionally targeted α5NC1 residues 169-229. Both kidney-eluted and circulating alloantibodies to α5NC1 distinctively targeted epitopes accessible in the α3α4α5NC1 hexamers of human GBM, unlike anti-GBM autoantibodies, which targeted sequestered α3NC1 epitopes. The results identify two immunodominant α5NC1 epitopes as major alloantigenic sites of α3α4α5(IV) collagen specifically implicated in the pathogenesis of post-transplant nephritis in XLAS patients. The contrast between the accessibility of these alloepitopes and the crypticity of autoepitopes indicates that distinct molecular forms of antigen may initiate the immunopathogenic processes in the two forms of anti-GBM disease.
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U2 - 10.1074/jbc.M611892200
DO - 10.1074/jbc.M611892200
M3 - Article
C2 - 17293596
AN - SCOPUS:34249857120
SN - 0021-9258
VL - 282
SP - 10670
EP - 10677
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 14
ER -