Blockade of self-reactive IgM significantly reduces injury in a murine model of acute myocardial infarction.
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.
Haas
Michael S
MS
DecImmune Therapeutics, Inc., Boston, MA, USA.
Alicot
Elisabeth M
EM
Schuerpf
Franziska
F
Chiu
Isaac
I
Li
Jinan
J
Moore
Francis D
FD
Carroll
Michael C
MC
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
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
Circ Res. 2004 Jul 23;95(2):125-34
15271864
J Biol Chem. 2005 Aug 12;280(32):29080-7
15955802
N Engl J Med. 2008 Jul 31;359(5):518-20
18669431
Nature. 2006 Apr 27;440(7088):1217-21
16642000
J Thorac Cardiovasc Surg. 2008 Oct;136(4):884-93
18954626
J Clin Invest. 1985 Nov;76(5):1713-9
4056048
Mol Immunol. 2008 Sep;45(15):4036-9
18672288
Am J Physiol Heart Circ Physiol. 2009 Nov;297(5):H1853-9
19749170
J Immunol. 2006 Oct 1;177(7):4727-34
16982912
J Immunol. 2006 Dec 1;177(11):8080-5
17114482
J Exp Med. 1996 May 1;183(5):2343-8
8642343
Surgery. 2006 Feb;139(2):236-43
16455333
Proc Natl Acad Sci U S A. 1997 Jan 21;94(2):679-83
9012844
Transplantation. 2003 Feb 15;75(3):375-82
12589162
Antioxid Redox Signal. 2006 Nov-Dec;8(11-12):1907-39
17034340
Immunogenetics. 1983;18(3):229-39
6618532
Am J Physiol Cell Physiol. 2002 Feb;282(2):C227-41
11788333
J Exp Med. 1971 Apr 1;133(4):885-900
4993831
Circulation. 1995 Mar 15;91(6):1872-85
7882499
N Engl J Med. 2008 Jul 31;359(5):473-81
18669426
J Exp Med. 2007 Nov 26;204(12):3037-47
18025128
J Invest Dermatol. 1994 May;102(5):803-6
7513741
Circulation. 2010 Feb 23;121(7):e46-e215
20019324
Circulation. 2003 Nov 11;108(19):2304-7
14597593
Am J Physiol. 1995 Dec;269(6 Pt 2):H2147-54
8594926
J Immunol. 2005 May 15;174(10):6373-80
15879138
Am J Physiol Gastrointest Liver Physiol. 2004 Apr;286(4):G580-7
15010362
Physiol Rev. 2008 Apr;88(2):581-609
18391174
J Immunol. 1992 Sep 1;149(5):1723-8
1387151
Immunology. 1975 Jun;28(6):1067-80
48505
J Exp Med. 2006 Jan 23;203(1):141-52
16390934
J Am Coll Cardiol. 2002 Oct 2;40(7):1199-204
12383565
Circulation. 1993 Oct;88(4 Pt 1):1779-87
8104739
J Mol Cell Cardiol. 2006 Jul;41(1):62-7
16781728
J Invest Dermatol. 1991 Aug;97(2):305-11
1712820
J Immunol. 2002 Nov 15;169(10):5433-40
12421918
Ann Surg. 1992 Dec;216(6):677-83
1334645
J Appl Physiol (1985). 1999 Mar;86(3):938-42
10066708
Proc Natl Acad Sci U S A. 2004 Mar 16;101(11):3886-91
14999103
Science. 1990 Jul 13;249(4965):146-51
2371562
N Engl J Med. 2007 Sep 13;357(11):1121-35
17855673
Science. 1999 Jul 23;285(5427):595-9
10417391
Science. 2009 Jul 31;325(5940):612-6
19644120