Innate Immunity and Ischemia / Reperfusion Injury
Recent advance in autoimmunity research reveals that innate immune system is able to recognize self-targets and initiate inflammatory response in a similar way as with pathogens. Studies of ischemia/reperfusion (I/R) models showed that reperfusion of ischemic tissues elicits an acute inflammatory response involving complement system which is activated by natural IgM. The recent identification of a monoclonal natural IgM that initiates I/R led to the identification of nonmuscle myosin heavy chain type II as the self-targets. New evidence further suggests that IgM binds initially to ischemic antigen providing a binding site for mannan binding lectin (MBL) which subsequently leads to activation of complement and results in tissue injury. Therefore, natural IgM mediated innate autoimmunity is likely responsible for the detrimental consequences in ischemic diseases. To target this early event of I/R pathogenesis, short peptides were screened from phage-displayed-peptide library and showed encouraging results to reduce I/R injury in animal models. This discovery of innate autoimmunity in I/R injury may provide a new avenue of therapy for ischemic diseases.
Our laboratory is devoted to the basic science research of I/R injury and have ongoing collaborations with scientists around the nation as well as internationally. Besides exploring the animal models of I/R injury, we team up with anesthesiologists, cardiac surgeons, cardiologists, and pathologists to develop clinical research projects studying cardiovascular diseases.
PUBLICATIONS
1. Zhang M and Carroll MC. Natural antibody mediated innate autoimmune response. Mol Immunol. 2007;44(1-3):103-10. [PubMed]
2. Zhang M, Takahashi K, Alicot EM, Vorup-Jensen T, Kessler B, Thiel S, Jensenius JC, R. Ezekowitz AB, Moore FD, and Carroll MC. Activation of the lectin pathway by natural IgM in a model of ischemia/reperfusion Injury. J Immunol. 2006;177(7):4727-34. [PubMed]
3. Zhang M, Michael LH, Grosjean SA, Kelly RA, Carroll MC, and Entman ML. The role of natural IgM in myocardial ischemia-reperfusion injury. J Mol Cell Cardiol. 2006; 41:62-7. [PubMed]
4. Zhang M, Alicot E, Chiu I, Li J, Verna N, Vorup-Jensen T, Kessler B, Shimaoka M, Chan R, Friend D, Mahmood U, Weissleder R, Moore FD and Carroll MC. Identification of the Target Self-antigens in Reperfusion Injury. J Exp Med. 2006; 203:141-52. [Full Text]
5. Chan RK, Verna N, Afnan J, Zhang M, Ibrahim S, Carroll MC, Moore FD, Jr. Attenuation of skeletal muscle reperfusion injury with intravenous 12 amino acid peptides that bind to pathogenic IgM. Surgery. 2006;139:236-43. [PubMed]
6. Barrington RA, Zhang M, Zhong X, Jonsson H, Holodick N, Cherukuri A, Pierce SK, Rothstein TL, Carroll MC. CD21/CD19 coreceptor signaling promotes B cell survival during primary immune responses. J Immunol. 2005;175(5):2859-67.[PubMed]
7. Zhang M, Austen WG, Jr., Chiu I, Alicot EM, Hung R, Ma M, Verna N, Xu M, Hechtman HB, Moore FD, Jr., Carroll MC. Identification of a specific self-reactive IgM antibody that initiates intestinal ischemia/reperfusion injury. PNAS. 2004;101:3886-91. [Full Text]
8. Gadjeva M, Tomczak MF, Zhang M, Wang YY, Dull K, Rogers AB, Erdman SE, Fox JG, Carroll M, Horwitz BH. A role for NF-kappaB subunits p50 and p65 in the inhibition of lipopolysaccharide-induced shock. J Immunol. 2004;173:5786-93. [PubMed]
9. Austen WG, Jr., Zhang M, Chan R, Friend D, Hechtman HB, Carroll MC, Moore FD, Jr. Murine hindlimb reperfusion injury can be initiated by a self-reactive monoclonal IgM. Surgery. 2004;136:401-6. [PubMed]
10. Reid RR, Woodcock S, Shimabukuro-Vornhagen A, Austen WG, Jr., Kobzik L, Zhang M, Hechtman HB, Moore FD, Jr., Carroll MC. Functional activity of natural antibody is altered in Cr2-deficient mice. J Immunol. 2002;169:5433-40. [Full Text]
11. Barrington R, Zhang M, Fischer M, Carroll MC. The role of complement in inflammation and adaptive immunity. Immunol Rev. 2001;180:5-15. [PubMed]
12. McCarthy B. A., Chong SY, Parker G, Meramo M, Zhang M, Czarneski J, Mansour A, Raveche ES. In Vivo and In Vitro Analysis of IL-10 in the NZB Leukemic Model. 2004; Cancer Genomics & Proteomics 1: 407-418 [link to journal]
13. Chong SY, Zhang M, Lin YC, Coffman F, Garcia Z, Ponzio N, Raveche ES. The growth-regulatory role of B-cell-specific activator protein in NZB malignant B-1 cells. Cancer Immunol Immunother. 2001;50:41-50. [PubMed]
14. Yen Chong S, Lin YC, Czarneski J, Zhang M, Coffman F, Kashanchi F, Raveche E. Cell cycle effects of IL-10 on malignant B-1 cells. Genes Immun. 2001;2:239-47. [PubMed]
15. Zhang M, Chong SY, Raveche ES. The role of B-cell-specific activator protein in the response of malignant B-1 cells to LPS. Exp Cell Res. 2001;264:233-43. [PubMed]
16. Peng B, Zhang M, Sun R, Lin YC, Chong SY, Lai H, Stein D, Raveche ES. The correlation of telomerase and IL-10 with leukemia transformation in a mouse model of chronic lymphocytic leukemia (CLL). Leuk Res. 1998;22:509-16. [PubMed]
17. Zhang M, Raveche ES. Apoptosis induction in fludarabine resistant malignant B-1 cells by G2- M cell cycle arrest. Oncol Rep. 1998;5:23-30. [PubMed]