title: Absence of FcγRIII results in increased proinflammatory response in FcγRIII-KO cardiac recipients.
abstract: BACKGROUND
  Alloantibody can contribute significantly to rejection of heart transplants by activation of complement and interactions with a variety of effector cells, including macrophages and monocytes through activating FcγRI, FcγRIII, FcγRIV, the inhibitory FcγRIIB and complement receptors. These receptors link cellular and humoral immunity by bridging the antibody specificity to effector cells. Activating FcγRs are also involved in serum amyloid P component (SAP)-mediated clearance of apoptotic bodies.
  
  
  METHODS
  B10.A (H-2a) hearts were transplanted into wild-type (WT) or FcγRIII-knockout (KO) C57BL/6 (H-2b) mouse recipients. Levels of alloantibodies and SAP in the circulation were determined by flow cytometry and enzyme-linked immunosorbent assay, respectively. Intragraft cytokine mRNA expression was measured by real-time polymerase chain reaction. Intragraft deposition of C4d, von Willebrand factor, SAP, and activated caspase 3 was visualized by immunochemistry.
  
  
  RESULTS
  B10.A hearts in C57BL/6 FcγRIII-KO recipients were rejected acutely within 6 to 8 days compared with 10 to 14 days in WT. The rejection in FcγRIII-KO was accompanied by higher levels of circulating IgM/IgG alloantibodies and SAP than in WT recipients. Histology in FcγRIII-KO cardiac allograft recipients indicated perivascular margination of monocytes and neutrophils, vascular endothelial cell injury, and intense vasculocentric infiltrates with extensive apoptosis. Higher numbers of apoptotic cells, stronger C4d and SAP deposition, and extensive activated caspase 3 were found in areas of dense pockets of apoptotic blebs in FcγRIII-KO.
  
  
  CONCLUSIONS
  We propose that absence of FcγRIII is associated with the lack of efficient SAP-mediated clearance of apoptotic cells through FcγRs. Apoptotic cells become immunogenic and induce enhanced inflammation, alloantibody production, and complement activation leading to accelerated cardiac allograft rejection.
authors.affiliation: 1 Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD. 2 Currently, Division of Special Pathogen and Transplant Products, Food and Drug Administration, Silver Spring, MD. 3 Currently, Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH. 4 Address correspondence to: Barbara A. Wasowska, Ph.D., 720 Rutland Avenue, Ross Building, #664B, Baltimore, MD 21205.
authors.forename: Melek M
authors.initials: MM
authors.lastname: Erdinc Sunay
authors.forename: Karen
authors.initials: K
authors.lastname: Fox-Talbot
authors.forename: Ergun
authors.initials: E
authors.lastname: Velidedeoglu
authors.forename: William M
authors.initials: WM
authors.lastname: Baldwin
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Wasowska
mesh_terms: D000818:Animals; D017209:Apoptosis; D003167:Complement Activation; D016207:Cytokines / Q000378:metabolism; D006084:Graft Rejection / Q000097:blood / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D006085:Graft Survival; D016027:Heart Transplantation / Q000009:adverse effects*; D007249:Inflammation / Q000097:blood / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D018836:Inflammation Mediators / Q000097:blood / Q000378:metabolism*; D007518:Isoantibodies / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000276:immunology* / Q000473:pathology; D017452:Receptors, IgG / Q000172:deficiency* / Q000235:genetics; D000683:Serum Amyloid P-Component / Q000378:metabolism; D013997:Time Factors
chemical_list: D016207:Cytokines; C485700:Fcgr3 protein, mouse; D018836:Inflammation Mediators; D007518:Isoantibodies; D017452:Receptors, IgG; D000683:Serum Amyloid P-Component
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