title: Blockade of self-reactive IgM significantly reduces injury in a murine model of acute myocardial infarction.
abstract: OBJECTIVE
  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.
  
  
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: DecImmune Therapeutics, Inc., Boston, MA, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Haas
authors.forename: Elisabeth M
authors.initials: EM
authors.lastname: Alicot
authors.forename: Franziska
authors.initials: F
authors.lastname: Schuerpf
authors.forename: Isaac
authors.initials: I
authors.lastname: Chiu
authors.forename: Jinan
authors.initials: J
authors.lastname: Li
authors.forename: Francis D
authors.initials: FD
authors.lastname: Moore
authors.forename: Michael C
authors.initials: MC
authors.lastname: Carroll
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000918:Antibody Specificity; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D000939:Epitopes; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007075:Immunoglobulin M / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018716:Molecular Mimicry; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D009203:Myocardial Infarction / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000276:immunology* / Q000473:pathology; D018995:Myosin Heavy Chains / Q000276:immunology*; D020556:Neutrophil Infiltration / Q000187:drug effects; D010455:Peptides / Q000494:pharmacology*; D013997:Time Factors; D019210:Troponin I / Q000097:blood
chemical_list: D000911:Antibodies, Monoclonal; D000939:Epitopes; D018398:Homeodomain Proteins; D007075:Immunoglobulin M; D010455:Peptides; D019210:Troponin I; C064658:RAG-1 protein; D003094:Collagen; D018995:Myosin Heavy Chains
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