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Prepublished online as a Blood First Edition Paper on August 1, 2002; DOI 10.1182/blood-2002-06-1875.
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Blood, 15 December 2002, Vol. 100, No. 13, pp. 4544-4549
IMMUNOBIOLOGY
Complement-mediated clearance of erythrocytes: mechanism and
delineation of the regulatory roles of Crry and DAF
Hector Molina,
Takashi Miwa,
Lin Zhou,
Brendan Hilliard,
Dimitrios Mastellos,
Michael A. Maldonado,
John D. Lambris, and
Wen-Chao Song
From the Center for Experimental Therapeutics,
Department of Pharmacology, Department of Pathology and Laboratory
Medicine, and Department of Medicine, University of Pennsylvania School
of Medicine, Philadelphia; and the Department of Medicine,
Washington University School of Medicine, St Louis, MO.
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, complement receptor
1-related gene/protein y (Crry), but not decay-accelerating factor (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
immunoglobulin-, Fc receptor (FcR)-,
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 (1) 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;
(2) DAF/Crry-deficient erythrocytes are eliminated by the alternative
pathway of complement via complement receptor-mediated
erythrophagocytosis in the spleen; and (3) when opsonized with an
immunoglobulin G2a (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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