Blockade of self-reactive IgM significantly reduces injury in a murine model of acute myocardial infarction

Cardiovasc Res. 2010 Sep 1;87(4):618-27. doi: 10.1093/cvr/cvq141. Epub 2010 May 11.


Aims: Coronary artery occlusion resulting in ischaemia/reperfusion (I/R) injury is a major cause of mortality in the western world. Circulating natural IgM has been shown to play a significant role in reperfusion injury, leading to the notion of a pathogenic response against self by the innate immune system. A specific self-antigen (non-muscle myosin heavy chain II) was recently identified as the major target of pathogenic natural IgM. Therefore, we hypothesized that a synthetic peptide mimetope (N2) or monoclonal antibodies directed against the self-antigen would prevent specific IgM binding to the self-antigen and reduce reperfusion injury in the heart.

Methods and results: We find that treatment with N2 peptide reduces infarct size by 47% and serum cardiac troponin-I levels by 69% following 1 h ischaemia and 24 h reperfusion. N2 peptide or an anti-N2 F(ab')(2) (21G6) is also effective at preventing IgM and complement deposition. Additionally, N2 peptide treatment significantly reduces monocyte and neutrophil infiltration at 24 h and collagen deposition at 5 days. Finally, we show that human IgM (hIgM) also includes specificity for the highly conserved self-antigen and that myocardial injury in antibody-deficient mice reconstituted with hIgM is blocked by treatment with N2 peptide or 21G6 F(ab')(2).

Conclusion: The findings in this study identify potential therapeutics [i.e. N2 peptide or 21G6 F(ab')(2)] that prevent specific IgM binding to ischaemic antigens in the heart, resulting in a significant reduction in cardiac I/R injury.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology*
  • Antibody Specificity
  • Collagen / metabolism
  • Disease Models, Animal
  • Epitopes
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Humans
  • Immunoglobulin M / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Molecular Mimicry
  • Monocytes / drug effects
  • Monocytes / immunology
  • Myocardial Infarction / immunology
  • Myocardial Infarction / pathology
  • Myocardial Infarction / prevention & control*
  • Myocardial Reperfusion Injury / immunology
  • Myocardial Reperfusion Injury / pathology
  • Myocardial Reperfusion Injury / prevention & control*
  • Myocardium / immunology*
  • Myocardium / pathology
  • Myosin Heavy Chains / immunology*
  • Neutrophil Infiltration / drug effects
  • Peptides / pharmacology*
  • Time Factors
  • Troponin I / blood


  • Antibodies, Monoclonal
  • Epitopes
  • Homeodomain Proteins
  • Immunoglobulin M
  • Peptides
  • Troponin I
  • RAG-1 protein
  • Collagen
  • Myosin Heavy Chains