Autologous inflammation is induced by reperfusion of ischemic tissues and follows acute burn. Ageneralizable mechanism to explain this sterile inflammation is that induction of ischemia via trauma orcontraction of blood flow due to burn induces shedding of intracellular antigen (non-muscle myosin heavychain). Binding of ischemia antigen by circulating natural IgM activates the complement system via the lectinpathway resulting in acute inflammation mediated by mast cell activation. In order to further dissect thispathway and to determine if a similar mechanism is involved in human tissues three aims are proposed incollaboration with the Moore and Austen groups.
The first aim will identify and characterize the source of pathogenic IR natural antibody using a knock-inmouse developed during the last period. There are three sub-aims: (i) characterize development andregulation of the self-reactive B cells expressing a heavy chain knock-in bearing lgM-cm22 specificity (cm22IgHi); (ii) characterize IR and burn injury in the knock-in mice; (iii) construct cm22 Ig-light chain (Lc) knock-inmice.
The second aim will develop blocking antibodies to pathogenic IgM cm22 and test for protection against IRand 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 burninjury in human tissues in three sub-aims: (i) develop human:mouse chimeric engraftment model; (ii) testhuman IgM in hu:mo chimeras for induction of burn injury; (iii) test antibodies to N2 peptide in hu:mochimeras for protection from burn injury.The overall significance of this project is that it will lead to a better understanding of autologous inflammationin animal models and identify a possible novel therapy for inhibition of IgM specific injury. Moreover, theidentification of a similar pathway of injury in human tissues following burn will provide novel approaches forprotection.
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