THE ROLE OF NATURAL ANTIBODY IN REPERFUSION INJURY

自体炎症是急性烧伤后缺血组织再灌注引起的。一个

Autologous inflammation is induced by reperfusion of ischemic tissues and follows acute burn. A generalizable mechanism to explain this sterile inflammation is that induction of ischemia via trauma or contraction of blood flow due to burn induces shedding of intracellular antigen (non-muscle myosin heavy chain). Binding of ischemia antigen by circulating natural IgM activates the complement system via the lectin pathway resulting in acute inflammation mediated by mast cell activation. In order to further dissect this pathway and to determine if a similar mechanism is involved in human tissues three aims are proposed in collaboration with the Moore and Austen groups. The first aim will identify and characterize the source of pathogenic IR natural antibody using a knock-in mouse developed during the last period. There are three sub-aims: (i) characterize development and regulation of the self-reactive B cells expressing a heavy chain knock-in bearing lgM-cm22 specificity (cm22 IgHi); (ii) characterize IR and burn injury in the knock-in mice; (iii) construct cm22 Ig-light chain (Lc) knock-in mice. The second aim will develop blocking antibodies to pathogenic IgM cm22 and test for protection against IR and burn injury in collaboration with the Moore and Austen groups. The third aim will test the hypothesis that non-muscle myosin heavy chain is the major target antigen in burn injury in human tissues in three sub-aims: (i) develop human:mouse chimeric engraftment model; (ii) test human IgM in hu:mo chimeras for induction of burn injury; (iii) test antibodies to N2 peptide in hu:mo chimeras for protection from burn injury. The overall significance of this project is that it will lead to a better understanding of autologous inflammation in animal models and identify a possible novel therapy for inhibition of IgM specific injury. Moreover, the identification of a similar pathway of injury in human tissues following burn will provide novel approaches for protection.