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(American Journal of Pathology. 2007;170:1629-1639.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.060772

Emergence of Anti-Red Blood Cell Antibodies Triggers Red Cell Phagocytosis by Activated Macrophages in a Rabbit Model of Epstein-Barr Virus-Associated Hemophagocytic Syndrome

Wen-Chuan Hsieh*, Yao Chang*, Mei-Chi Hsu*, Bau-Shin Lan{dagger}, Guan-Chung Hsiao{dagger}, Huai-Chia Chuang{ddagger} and Ih-Jen Su*{dagger}

From the Division of Clinical Research,* National Health Research Institutes, Tainan; and the Graduate Institutes of Microbiology{dagger} and Basic Medicine,{ddagger} National Cheng Kung University College of Medicine, Tainan, Taiwan

Hemophagocytic syndrome (HPS) is a fatal complication frequently associated with viral infections. In childhood HPS, Epstein-Barr virus (EBV) is the major causative agent, and red blood cells (RBCs) are predominantly phagocytosed by macrophages. To investigate the mechanism of RBC phagocytosis triggered by EBV infection, we adopted a rabbit model of EBV-associated HPS previously established by using Herpesvirus papio (HVP). The kinetics of virus-host interaction was studied. Using flow cytometry, we detected the emergence of antibody-coated RBCs, as well as anti-platelet antibodies, at peak virus load period at weeks 3 to 4 after HVP injection, and the titers increased thereafter. The presence of anti-RBCs preceded RBC phagocytosis in tissues and predicted the full-blown development of HPS. The anti-RBC antibodies showed cross-reactivity with Paul-Bunnell heterophile antibodies. Preabsorption of the HVP-infected serum with control RBCs removed the majority of anti-RBC activities and remarkably reduced RBC phagocytosis. The RBC phagocytosis was specifically mediated via an Fc fragment of antibodies in the presence of macrophage activation. Therefore, the emergence of anti-RBC antibodies and the presence of macrophage activation are both essential in the development of HPS. Our observations in this animal model provide a potential mechanism for hemophagocytosis in EBV infection.






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Copyright © 2007 by the American Society for Investigative Pathology.