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.
1. Milk Sprague-Dawley rats were allocated at 100 g into either an adlib.-fed control group or a food-restricted group. The restricted group was fed for 9 d at 25% of ad lib. intake. Controls were killed at a body-weight of 100 g and 29 d of age and the restricted animals were killed at 70 g and 38 d of age.2. The effects of food restriction on muscle weight, fibre number, fibre diameter, DNA, and protein were examined in three skeletal muscles, the soleus, plantaris and extensor digitorurn longus (EDL).3. Acute dietary restriction caused body-and muscle-weight loss and a decrease in both the number and cross-sectional area of muscle fibres in each of the muscles.4. The restriction halted growth-related increases in DNA in all muscles and decreased the protein: DNA value in the plantaris and EDL.5. These results indicate that present theories describing cellular development are not adequate to define growth potential or growth retardation of skeletal muscle.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.