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Presentation of the Goodpasture Autoantigen Requires Proteolytic Unlocking Steps That Destroy Prominent T Cell Epitopes

MRC Centre for Inflammation Research (Renal Autoimmunity), University of Edinburgh, Edinburgh, United Kingdom

Address correspondence to: Dr. Richard G. Phelps, MRC Centre for Inflammation Research (Renal Autoimmunity), The Queens Medical Research Institute, 47 Little France Crescent, EH16 4TJ, UK. Phone: +44-131-242-9164; Fax: +44-131-242-9168; E-mail: richard.phelps{at}ed.ac.uk

Received for publication September 27, 2006. Accepted for publication December 29, 2006.

The most abundant autoreactive T cells in patients with Goodpasture’s disease are specific for peptides in the autoantigen that have high affinity for the disease-associated HLA class II molecule, DR15. How can such T cells escape self-tolerance mechanisms? This study showed that these peptides are highly susceptible to destruction in the earliest stages of antigen processing, and some must be cleaved for antigen digestion to be possible ("unlocking"). Goodpasture autoantigen [collagen 3(IV)NC1; approximately 31 kD] that was incubated with B cell lysosomes was cleaved within a few minutes to form approximately 9- and approximately 22-kD fragments, then increasing quantities of smaller peptides. The processing was completely abrogated by pepstatin A, a specific inhibitor of cathepsin D/E, even though lysosomal extracts contain a rich array of proteases. Purified cathepsin D generated the same major 3(IV)NC1 fragments as entire lysosomes, suggesting that cathepsin D cleavages are required to initiate 3(IV)NC1 processing. The initial unlocking cleavages destroyed two major self-epitopes, and subsequent preferred cleavages destroyed all of the other T cell epitopes that are recognized by most patients’ autoreactive T cells. The responses of T cell clones that are specific for a major disease-associated peptide to antigen-pulsed intact antigen-presenting cells were substantially enhanced by pepstatin A treatment. Therefore, cathepsin D activity significantly diminishes presentation of 3(IV)NC1 peptides that are recognized by patients’ T cells by destroying the peptides in early processing. These observations can explain why the mature T cell repertoire includes reactivity toward these self-peptides and suggests that a key factor in disease initiation is likely to be a shift in antigen processing.

This article has been cited by other articles:

				J. Zou, S. Hannier, L. S. Cairns, R. N. Barker, A. J. Rees, A. N. Turner, and R. G. Phelps Healthy Individuals Have Goodpasture Autoantigen-Reactive T Cells J. Am. Soc. Nephrol., February 1, 2008; 19(2): 396 - 404. [Abstract] [Full Text] [PDF]

Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673