A novel rationale for inhibition of gelatinase B in multiple sclerosis: MMP-9 destroys alpha B-crystallin and generates a promiscuous T cell epitope.
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.
Starckx
Sofie
S
Rega Institute for Medical Research, University of Leuven, 3000 Leuven, Belgium.
Van den Steen
Philippe E
PE
Verbeek
Richard
R
van Noort
Johannes M
JM
Opdenakker
Ghislain
G
D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D018984:Epitopes, T-Lymphocyte / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D006868:Hydrolysis; D007276:Injections, Intraventricular; D008213:Lymphocyte Activation / Q000276:immunology; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism / Q000502:physiology*; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009103:Multiple Sclerosis / Q000201:enzymology* / Q000276:immunology*; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D011994:Recombinant Proteins / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology; D038203:alpha-Crystallin B Chain / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology
D018984:Epitopes, T-Lymphocyte; D061965:Matrix Metalloproteinase Inhibitors; D010446:Peptide Fragments; D011994:Recombinant Proteins; D038203:alpha-Crystallin B Chain; D020780:Matrix Metalloproteinase 9