Absence of FcγRIII results in increased proinflammatory response in FcγRIII-KO cardiac recipients

Melek M. Erdinc Sunay, Karen Fox-Talbot, Ergun Velidedeoglu, William M. Baldwin, Barbara A. Wasowska

Research output: Contribution to journalArticle

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-2) hearts were transplanted into wild-type (WT) or FcγRIII-knockout (KO) C57BL/6 (H-2) 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.

Original languageEnglish (US)
Pages (from-to)601-608
Number of pages8
JournalTransplantation
Volume96
Issue number7
DOIs
StatePublished - Oct 15 2013

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Keywords

  • Alloantibody
  • Apoptosis
  • Complement
  • Fc receptor
  • Heart transplantation
  • Serum amyloid P component (SAP)

ASJC Scopus subject areas

  • Transplantation

Cite this

Erdinc Sunay, M. M., Fox-Talbot, K., Velidedeoglu, E., Baldwin, W. M., & Wasowska, B. A. (2013). Absence of FcγRIII results in increased proinflammatory response in FcγRIII-KO cardiac recipients. Transplantation, 96(7), 601-608. https://doi.org/10.1097/TP.0b013e31829c2455