Abstract
The asparagine-specific endoprotease (AEP) controls lysosomal processing of the potential autoantigen myelin basic protein (MBP) by human B lymphoblastoid cells, a feature implicated in the immunopathogenesis of multiple sclerosis. In this study, we demonstrate that freshly isolated human B lymphocytes lack significant AEP activity and that cleavage by AEP is dispensable for proteolytic processing of MBP in this type of cell. Instead, cathepsin (Cat) G, a serine protease that is not endogenously synthesized by B lymphocytes, is internalized from the plasma membrane and present in lysosomes from human B cells where it represents a major functional constituent of the proteolytic machinery. CatG initialized and dominated the destruction of intact MBP by B cell-derived lysosomal extracts, degrading the immunodominant MBP epitope and eliminating both its binding to MHC class II and a MBP-specific T cell response. Degradation of intact MBP by CatG was not restricted to a lysosomal environment, but was also performed by soluble CatG. Thus, the abundant protease CatG might participate in eliminating the immunodominant determinant of MBP. Internalization of exogenous CatG represents a novel mechanism of professional APC to acquire functionally dominant proteolytic activity that complements the panel of endogenous lysosomal enzymes.
Original language | English |
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Pages (from-to) | 5495-503 |
Number of pages | 9 |
Journal | Journal of Immunology |
Volume | 172 |
Issue number | 9 |
Publication status | Published - May 1 2004 |
Externally published | Yes |
Keywords
- Adult
- Amino Acid Sequence
- Animals
- Antigen-Presenting Cells
- Asparagine
- B-Lymphocyte Subsets
- Cathepsin G
- Cathepsins
- Cell Line
- Cell Line, Transformed
- Cell Separation
- Cysteine Endopeptidases
- Humans
- Hydrolysis
- Lymphocyte Activation
- Lysine
- Lysosomes
- Mice
- Molecular Sequence Data
- Myelin Basic Protein
- Phenylalanine
- Protein Processing, Post-Translational
- Serine
- Serine Endopeptidases
- Comparative Study
- Journal Article
- Research Support, Non-U.S. Gov't