A novel rationale for inhibition of gelatinase B in multiple sclerosis: MMP-9 destroys alpha B-crystallin and generates a promiscuous T cell epitope.

Abstract	The small heat shock protein alphaB-crystallin is considered as a candidate autoantigen in multiple sclerosis (MS) lesions. Gelatinase B or matrix metalloproteinase (MMP)-9 is a proteinase establishing various disease-promoting feedback loops in autoimmune diseases. Human alphaB-crystallin was digested with natural gelatinase B and all cleavage sites were identified by a combined approach of mass spectrometry and peptide sequencing analysis. Previously identified immunodominant and cryptic epitopes of alphaB-crystallin in mice and rats were generated and largely left intact by MMP-9 processing. The alphaB-crystallin peptide 1-16, generated as a remnant epitope, provoked a significant T cell response in alphaB-crystallin knockout mice. None of the remnant peptides was encephalitogenic when injected intracerebrally into mice or induced MMP-9 in vitro. Gelatinase B is thus able to release T cell epitopes from intact alphaB-crystallin, but their pathogenic role remains unclear.
Authors	Sofie Starckx, Philippe E Van den Steen, Richard Verbeek, Johannes M van Noort, Ghislain Opdenakker
Journal	Journal of neuroimmunology (J Neuroimmunol) Vol. 141 Issue 1-2 Pg. 47-57 (Aug 2003) ISSN: 0165-5728 [Print] Netherlands
PMID	12965253 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Epitopes, T-Lymphocyte Matrix Metalloproteinase Inhibitors Peptide Fragments Recombinant Proteins alpha-Crystallin B Chain Matrix Metalloproteinase 9
Topics	Amino Acid Sequence Animals Cell Line, Tumor Epitopes, T-Lymphocyte (metabolism, pharmacology) Humans Hydrolysis Injections, Intraventricular Lymphocyte Activation (immunology) Matrix Metalloproteinase 9 (metabolism, physiology) Matrix Metalloproteinase Inhibitors Mice Mice, Inbred C57BL Mice, Knockout Molecular Sequence Data Multiple Sclerosis (enzymology, immunology) Peptide Fragments (metabolism, pharmacology) Rats Rats, Inbred Lew Recombinant Proteins (metabolism) T-Lymphocytes (cytology, immunology) alpha-Crystallin B Chain (administration & dosage, genetics, metabolism, pharmacology)

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