title: Early complement factors in the local tissue immunocomplex generated during intestinal ischemia/reperfusion injury.
abstract: Recent work reveals that the innate immune system is able to recognize self-targets and initiate an inflammatory response similar to that of pathogens. One novel example of this innate autoimmunity is ischemia/reperfusion (I/R) injury, in which reperfusion of the ischemic tissues elicits an acute inflammatory response activated by natural IgM (nIgM) binding to ischemia-specific self-antigens, which are non-muscle myosin heavy chains type II (NMHC-II) subtype A and C. Subsequently, the complement lectin pathway is activated and eventually tissue injury occurs. Although earlier studies in the intestinal model showed that the classical complement pathway did not initiate I/R injury, C1q deposition was still observed in the local injured tissues by imaging analysis. Moreover, the involvement of the alternative complement pathway became unclear due to conflicting reports using different knockout mice. To explore the immediate downstream pathway following nIgM-ischemic antigen interaction, we isolated the nIgM-ischemic antigen immunocomplexes from the local tissue of animals treated in the intestinal I/R injury model, and examined the presence of initial molecules of three complement pathways. Our results showed that mannan-binding lectin (MBL), the early molecule of the lectin pathway, was present in the nIgM-ischemic Ag immunocomplex. In addition, C1q, the initial molecule of the classical pathway was also detected on the immunocomplex. However, Factor B, the early molecule in the alternative pathway, was not detected in the immunocomplex. To further examine the role of the alternative pathway in I/R injury, we utilized Factor B knockout mice in the intestinal model. Our results showed that Factor B knockout mice were not protected from local tissue injury, and their complement system was activated in the local tissues by nIgM during I/R. These results indicated that the lectin complement pathway operates immediately downstream of the nIgM-ischemic antigen interaction during intestinal I/R. Furthermore, the classical complement pathway also appears to interact with the of nIgM-ischemic antigen immunocomplex. Finally, the alternative complement pathway is not involved in I/R injury induction in the current intestinal model.
authors.affiliation: Department of Anesthesiology, SUNY-Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203, USA.
authors.forename: Haekyung
authors.initials: H
authors.lastname: Lee
authors.forename: Danielle J
authors.initials: DJ
authors.lastname: Green
authors.forename: Lawrence
authors.initials: L
authors.lastname: Lai
authors.forename: Yunfang Joan
authors.initials: YJ
authors.lastname: Hou
authors.forename: Jens C
authors.initials: JC
authors.lastname: Jensenius
authors.forename: David
authors.initials: D
authors.lastname: Liu
authors.forename: Cheolho
authors.initials: C
authors.lastname: Cheong
authors.forename: Chae Gyu
authors.initials: CG
authors.lastname: Park
authors.forename: Ming
authors.initials: M
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000936:Antigen-Antibody Complex / Q000235:genetics / Q000276:immunology*; D001324:Autoantigens / Q000235:genetics / Q000276:immunology; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology; D037582:Complement Pathway, Mannose-Binding Lectin / Q000235:genetics / Q000276:immunology; D003165:Complement System Proteins / Q000235:genetics / Q000276:immunology*; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology; D007075:Immunoglobulin M / Q000235:genetics / Q000276:immunology*; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D007422:Intestines / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D018995:Myosin Heavy Chains / Q000235:genetics / Q000276:immunology; D024462:Myosin Type II / Q000235:genetics / Q000276:immunology; D015427:Reperfusion Injury / Q000235:genetics / Q000276:immunology* / Q000473:pathology
chemical_list: D000936:Antigen-Antibody Complex; D001324:Autoantigens; D007075:Immunoglobulin M; C483905:Myh14 protein, mouse; D003165:Complement System Proteins; D024462:Myosin Type II; D018995:Myosin Heavy Chains