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IgM and C1q function in the same pathway to promote the clearance of apoptotic cells in vivo
Arthritis Res Ther volume 5, Article number: 153 (2003)
Dying cells may be the source of the autoantigens that initiate and/or perpetuate systemic autoimmunity. C1q-deficient mice develop a lupus-like disease and accumulate apoptotic cells in their kidneys, and our studies  suggested that classical complement components facilitate the clearance of apoptotic cells. Mice deficient in serum IgM (sIgM) also develop a lupus-like disease.
Since IgM binds to apoptotic cells and activates the classical complement on the apoptotic cells in vitro , we asked whether sIgM was required for complement activation and rapid removal of dying cells by phagocytic cells in vivo.
Apoptotic thymocytes were injected into the peritoneum of mice that had received thioglycollate 3 days previously. Thirty minutes after intraperitoneal injection, apoptotic cell uptake by elicited peritoneal macrophages was determined by light microscopy.
The percentages of peritoneal macrophages that ingested apoptotic cells were (mean ± standard error): wild type (WT) (n = 12), 31.2 ± 4.7%; C1q-/- (n = 4), 9.4 ± 1.8%; sIgM-/-(n = 16), 8.5 ± 0.9%. The differences between C1q-deficient and WT mice as well as between sIgM deficient and WT mice were highly significant (P = 0.0036 and P = 0.0003, respectively). Mice heterozygous for sIgM showed an intermediate result (17.9 ± 1.8%). To determine whether the clearance defect in the sIgM-deficient mice could solely be attributed to IgM deficiency, apoptotic thymocytes were preincubated with purified murine IgM prior to intraperitoneal injection into sIgM-deficient mice. IgM completely restored the ability of sIgM-deficient mice to ingest apoptotic cells. Finally, to prove that IgM and C1q function in the same pathway to facilitate clearance of apoptotic cells, we created C1q/IgM double knockout mice. In contrast to the IgM single knockout mice, addition of IgM to the double knockout mice failed to restore phagocytosis of apoptotic cells.
These findings indicate that IgM plays a pivotal role in clearance of apoptotic cells, and that this occurs through activation of the classical pathway of complement. IgM upstream of complement-mediated opsonization of dying cells provides a unifying mechanism explaining why mice with either early complement component or sIgM deficiency develop lupus-like diseases. These findings have important implications for understanding the pathogenesis of lupus in humans.
Mevorach D, Mascarenhas J, Gershov DA, Elkon KB: Complement-dependent clearance of apoptotic cells by human macrophages. J Exp Med. 1998, 188: 2313-2320. 10.1084/jem.188.12.2313.
Kim SJ, Gershov D, Ma X, Brot N, Elkon KB: I-PLA(2) activation during apoptosis promotes the exposure of membrane lysophosphatidylcholine leading to binding by natural immunoglobulin M antibodies and complement activation. J Exp Med. 2002, 196: 655-665. 10.1084/jem.20020542.
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Elkon, K., Kowaleski, R., Montenegro, V. et al. IgM and C1q function in the same pathway to promote the clearance of apoptotic cells in vivo. Arthritis Res Ther 5, 153 (2003) doi:10.1186/ar954
- Apoptotic Cell
- Wild Type Mouse
- Peritoneal Macrophage
- Complement Component
- Classical Pathway