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Abstract
The development of immune tolerance is dependent on the expression of self-peptides in the thymus and bone marrow during lymphocyte development. However, not all self-antigens are expressed in the thymus, particularly for proteins that become post-translationally modified during other biological processes in a cell. We have found that one such post-translational modification, the spontaneous conversion of an aspartic acid to isoaspartic acid (isoAsp), causes ignored self-antigens to become immunogenic. In order to determine the mechanism for this autoimmune response, pigeon cytochrome c peptide 88–104 (PCC p88–104) was synthesized with and without an isoaspartyl residue. Each form was digested with cathepsin D, an enzyme involved in antigen processing. The products of cathepsin digestion were dramatically different between the two forms of self-protein suggesting that cryptic self-peptides may be revealed to the immune system by natural modifications to self-proteins. This observation also held true if whole PCC protein contained isoaspartyl residues was digested with cathespsin D. Additionally, AND transgenic TCR T cells (recognizing PCC 88–104) proliferated to a greater extent in response to isoaspartyl PCC as compared to the normal form of PCC. These finding demonstrate the importance of post‐translational modifications in shaping autoimmune responses in and the development of tolerance to self-proteins.
| Abbreviations | ||
| SLE | = | systemic lupus erythematosus |
| isoAsp | = | isoaspartic acid |
| PCMT | = | protein carboxyl methyltransferase |
| PCC | = | pigeon cytochrome c |
| TCR | = | T cell receptor |
| PBS | = | phosphate buffered saline |
| CFA | = | complete Freund's adjuvant |
| APC | = | antigen presenting cells |
| PDD | = | purified protein derivative of M. tuberculosis HR37 |
| MHC | = | major hisotcompatibility complex |
| AEP | = | asparagine endopeptidase |
| MBP | = | myelin basic protein |
| Cat D | = | cathepsin D |
| Abbreviations | ||
| SLE | = | systemic lupus erythematosus |
| isoAsp | = | isoaspartic acid |
| PCMT | = | protein carboxyl methyltransferase |
| PCC | = | pigeon cytochrome c |
| TCR | = | T cell receptor |
| PBS | = | phosphate buffered saline |
| CFA | = | complete Freund's adjuvant |
| APC | = | antigen presenting cells |
| PDD | = | purified protein derivative of M. tuberculosis HR37 |
| MHC | = | major hisotcompatibility complex |
| AEP | = | asparagine endopeptidase |
| MBP | = | myelin basic protein |
| Cat D | = | cathepsin D |
Acknowledgements
We would like to thank the Promega Corporation for their generous donation of ISOQUANT Isoaspartate Detection kits. We would also like to thank Drs Steven Clarke and Jonathan Lowensen (UCLA) and Dana Aswad (UC, Irvine) for their helpful discussion of these studies. This work was supported by NIH grant AI-48120 to MJM and by an Arthritis Foundation Investigator Award to HAD.