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A Nephritogenic Peptide Induces Intermolecular Epitope Spreading on Collagen IV in Experimental Autoimmune Glomerulonephritis

Lanlin Chen^*, Thomas Hellmark, Vadim Pedchenko, Billy G. Hudson, Charles D. Pusey, Jay W. Fox^* and W. Kline Bolton^*

^* Department of Medicine, Division of Nephrology, University of Virginia Health System, Charlottesville, Virginia; Department of Nephrology, Lund University Hospital, Lund, Sweden; Department of Medicine, Division of Nephrology, Vanderbilt University School of Medicine, Medical Center, Nashville, Tennessee; and Department of Medicine Renal Section, Imperial College, London, Hammersmith Hospital, London, United Kingdom

Address correspondence to: Dr. W. Kline Bolton, PO Box 800133, University of Virginia Health System, Charlottesville, VA 22908-0133. Phone: 434-924-5125; Fax: 434-924-5848; E-mail: wkb5s{at}virginia.edu

Received for publication July 3, 2006. Accepted for publication August 16, 2006.

This group previously identified a peptide p13 of 3(IV)NC1 domain of type IV collagen that induces experimental autoimmune glomerulonephritis (EAG) in rats with generation of antibodies to sites on 3(IV)NC1 external to the peptide as a result of intramolecular epitope spreading. It was hypothesized that intermolecular epitope spreading to other collagen IV chains also was induced. Rats were immunized with nephritogenic peptide that was derived from the amino terminal part of rat 3(IV)NC1 domain, and serum and kidney eluate were examined for antibodies to both native and recombinant NC1 domains of collagen IV. Peptide induced EAG with proteinuria and decreased renal function and glomerular basement membrane IgG deposits. Sera from these rats were examined by ELISA, which revealed reactivity not only to immunizing peptide but also to human and rat 3(IV)NC1 and to human 4(IV)NC1 domains. Kidney eluate that was depleted of 3(IV)NC1 antibodies still reacted to 4(IV)NC1, and 3(IV)NC1 column-bound antibody reacted with 3(IV)NC1. There was minimal reactivity to other collagen chains. Eluate that was adsorbed to NC1 hexamer from rat glomerular basement membrane lost all reactivity to glomerular constituents, and the eluted antibodies reacted to 3(IV)NC1 and 4(IV)NC1 domains. These studies show that a T cell epitope of 3(IV)NC1 induces EAG, intramolecular epitope spreading along 3(IV)NC1, and intermolecular epitope spreading to 4(IV)NC1 domain with minimal or no reactivity to other collagen chains or glomerular constituents. This is the first demonstration in EAG of intermolecular epitope spreading and identification of the spread epitopes.

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J. Am. Soc. Nephrol. 2006 17: 2947-2948. [Full Text] [PDF]

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