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This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: ASN.2007111233v1 20/1/123    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Macconi, D. Articles by Benigni, A. Search for Related Content PubMed PubMed Citation Articles by Macconi, D. Articles by Benigni, A. Related Collections Related Articles

Proteasomal Processing of Albumin by Renal Dendritic Cells Generates Antigenic Peptides

Daniela Macconi^*, Chiara Chiabrando, Silvia Schiarea, Sistiana Aiello, Linda Cassis, Elena Gagliardini^*, Marina Noris, Simona Buelli^*, Carla Zoja^*, Daniela Corna^*, Caterina Mele, Roberto Fanelli, Giuseppe Remuzzi^*,, and Ariela Benigni^*

^* Mario Negri Institute for Pharmacological Research, Clinical Research Center for Rare Diseases "Aldo e Cele Daccò," and Unit of Nephrology and Dialysis, Azienda Ospedaliera Ospedali Riuniti di Bergamo, Bergamo, and Mario Negri Institute for Pharmacological Research, Milan, Italy

Correspondence: Dr. Giuseppe Remuzzi, Mario Negri Institute for Pharmacological Research, Via Gavazzeni 11, 24125 Bergamo, Italy. Phone: +39-035-319-888; Fax: +39-035-319-331; E-mail: gremuzzi{at}marionegri.it

Received for publication November 22, 2007. Accepted for publication August 6, 2008.

The role of dendritic cells (DC) that accumulate in the renal parenchyma of non–immune-mediated proteinuric nephropathies is not well understood. Under certain circumstances, DC capture immunologically ignored antigens, including self-antigens, and present them within MHC class I, initiating an autoimmune response. We studied whether DC could generate antigenic peptides from the self-protein albumin. Exposure of rat proximal tubular cells to autologous albumin resulted in its proteolytic cleavage to form an N-terminal 24–amino acid peptide (ALB1-24). This peptide was further processed by the DC proteasome into antigenic peptides that had binding motifs for MHC class I and were capable of activating syngeneic CD8⁺ T cells. In vivo, the rat five-sixths nephrectomy model allowed the localization and activation of renal DC. Accumulation of DC in the renal parenchyma peaked 1 wk after surgery and decreased at 4 wk, concomitant with their appearance in the renal draining lymph nodes. DC from renal lymph nodes, loaded with ALB1-24, activated syngeneic CD8⁺ T cells in primary culture. The response of CD8⁺ T cells of five-sixths nephrectomized rats was amplified with secondary stimulation. In contrast, DC from renal lymph nodes of five-sixths nephrectomized rats treated with the proteasomal inhibitor bortezomib lost their capacity to stimulate CD8⁺ T cells in primary and secondary cultures. These data suggest that albumin can be a source of potentially antigenic peptides upon renal injury and that renal DC play a role in processing self-proteins through a proteasome-dependent pathway.

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Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673