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Prepublished online as a Blood First Edition Paper on August 1, 2002; DOI 10.1182/blood-2002-06-1875.
Submitted June 26, 2002
Accepted July 17, 2002
Complement-mediated clearance of erythrocytes: mechanism and delineation of the regulatory roles of Crry and DAF
Hector Molina, Takashi Miwa, Lin Zhou, Brendan Hilliard, Dimetrios Mastellos, Michael A Maldonado, John D Lambris, and Wen-Chao Song*
Department of Medicine, Washington University School of Medicine, St Louis, MO, USA
Center for Experimental Therapeutics and Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
* Corresponding author; email: song{at}spirit.gcrc.upenn.edu.
The role of complement in the pathogenesis of autoimmune hemolytic anemia (AIHA) has been controversial and may depend on a number of factors including the affinity and isotype of the pathogenic antibodies involved. We have recently shown that mouse erythrocytes deficient in the membrane C3 regulatory protein Crry, but not DAF, were spontaneously eliminated in vivo by complement. Here, by generating a mouse deficient in both DAF and Crry, we further delineated the roles of Crry and DAF in regulating alternative and classical pathway C3 activation. By using Ig-, Fc R-, C3-, C4- and C5-deficient mice, we also determined the mechanism by which membrane C3 regulator-deficient erythrocytes are cleared from the circulation. Finally, we evaluated the relative importance of the Fc receptor versus the complement pathway in disposing antibody-opsonized DAF/Crry-deficient erythrocytes. We conclude that: a) Crry plays a more dominant role than DAF in regulating the alternative pathway of complement, whereas DAF and Crry are equally effective in preventing antibody-induced runaway complement activation on mouse erythrocytes; b) DAF/Crry-deficient erythrocytes are eliminated by the alternative pathway of complement via complement receptor-mediated erythrophagocytosis in the spleen; c) when opsonized with an IgG2a autoantibody, Crry/DAF-deficient erythrocytes are eliminated more rapidly by complement than by the Fc receptor pathway. These results shed new light on the relative activities of Crry and DAF, and underscore the critical roles of membrane C3 regulators in preventing spontaneous and antibody-induced erythrocyte damage in vivo.
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