IgM Antibodies to Apoptosis-Associated Determinants Recruit C1q and Enhance Dendritic Cell Phagocytosis of Apoptotic Cells

Abstract

Natural Abs, which arise without known immune exposure, have been described that specifically recognize cells dying from apoptosis, but their role in innate immunity remains poorly understood. Herein, we show that the immune response to neoantigenic determinants on apoptotic thymocytes is dominated by Abs to oxidation-associated Ags, phosphorylcholine (PC), a head group that becomes exposed during programmed cell death, and malondialdehyde (MDA), a reactive aldehyde degradation product of polyunsaturated lipids produced following exposure to reactive oxidation species. While natural Abs to apoptotic cells in naive adult mice were dominated by PC and MDA specificities, the amounts of these Abs were substantially boosted by treatment of mice with apoptotic cells. Moreover, the relative amounts of PC and MDA Abs was affected by VH gene inheritance. Ab interactions with apoptotic cells also mediated the recruitment of C1q, which enhanced apoptotic cell phagocytosis by immature dendritic cells. Significantly, IgM Abs to both PC and MDA were primary factors in determining the efficiency of serum-dependent apoptotic cell phagocytosis. Hence, we demonstrate a mechanism by which certain natural Abs that recognize neoantigens on apoptotic cells, in naive mice and those induced by immune exposure to apoptotic cells, can enhance the functional capabilities of immature dendritic cells for phagocytic engulfment of apoptotic cells.

Annexin A2 and A5 Serve as New Ligands for C1q on Apoptotic Cells

“…C1q has been shown to interact with apoptotic cells both directly (7), which is the subject of this study, and indirectly via C-reactive protein (34), serum amyloid P, pentraxin 3 (35), and natural IgM (36). DNA has long been known as a ligand for C1q and here we further characterized the interaction by determining the K D value using surface plasmon resonance, confirming a very strong interaction.…”

Naturally Occurring Human Phosphorylcholine Antibodies Are Predominantly Products of Affinity-Matured B Cells in the Adult

“…The realization that the classic PC-reactive T15 clone recognizes oxidation specific epitopes (1) has opened up a whole new aspect of investigation. Subsequent research has demonstrated that anti-PC aids in clearance of apoptotic cells (6,30) and prevents the formation of pathogenic foam cells in atherosclerosis by clearing oxidized low density lipoprotein (1). Murine studies with PC vaccination have shown strong beneficial effects on experimental atherosclerosis in vivo (11)(12)(13), and human epidemiology has consistently linked anti-PC insufficiency to cardiovascular events (14)(15)(16)(17).…”

Apoptotic lymphocytes treated with IgG from Trypanosoma cruzi infection increase TNF‐α secretion and reduce parasite replication in macrophages

“…On the other hand, lymphocytes treated with chagasic IgM failed to reduce parasite load, and did not elicit TNF-a production by macrophages (not shown). IgM mediates clearance through deposition of C1q and iC3b on apoptotic cells [16,30,31]. Opsonization by C1q or iC3b leads to silent, non-inflammatory removal of dead cells [32][33][34].…”