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

J Neuroimmunol. 2003 Aug;141(1-2):47-57. doi: 10.1016/s0165-5728(03)00217-0.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cell Line, Tumor
  • Epitopes, T-Lymphocyte / metabolism*
  • Epitopes, T-Lymphocyte / pharmacology
  • Humans
  • Hydrolysis
  • Injections, Intraventricular
  • Lymphocyte Activation / immunology
  • Matrix Metalloproteinase 9 / metabolism
  • Matrix Metalloproteinase 9 / physiology*
  • Matrix Metalloproteinase Inhibitors*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Molecular Sequence Data
  • Multiple Sclerosis / enzymology*
  • Multiple Sclerosis / immunology*
  • Peptide Fragments / metabolism
  • Peptide Fragments / pharmacology
  • Rats
  • Rats, Inbred Lew
  • Recombinant Proteins / metabolism
  • T-Lymphocytes / cytology
  • T-Lymphocytes / immunology
  • alpha-Crystallin B Chain / administration & dosage
  • alpha-Crystallin B Chain / genetics
  • alpha-Crystallin B Chain / metabolism*
  • alpha-Crystallin B Chain / pharmacology

Substances

  • Epitopes, T-Lymphocyte
  • Matrix Metalloproteinase Inhibitors
  • Peptide Fragments
  • Recombinant Proteins
  • alpha-Crystallin B Chain
  • Matrix Metalloproteinase 9