Table 4 NAbs-dependent clearance of apoptotic cells

NAbs are well-known to bind to oxidation-associated neo-determinants that become exposed on the membrane of apoptotic cells. Phosphorylcholine (PC) is an example of neo-determinant present in the plasma membrane of apoptotic cells. It is a head group of neutral lipids such as phosphatidylcholine, but it is kept in a conformation that hides it from recognition by antibodies. When cells undergo apoptosis, oxidative alterations change lipid conformations, exposing PC [92]. Despite the variety of neo-epitopes exposed on the plasma membrane of apoptotic cells, around 50% of splenic B-1 cells recognize PC and malondialdehyde after immunization with apoptotic cells [93]. However, as B-1 cells rapidly divide and downregulate CD5 expression upon exposure to antigens, this percentage of B-1 cells binding to AC after immunization does not reflect the frequency of AC-binding B-1 cells in unimmunized mice. However, it highlights the ability of these cells to sense and react to common neoepitopes exposed upon apoptotic cell death.” In fact, the prototypical NAb, T15, is recognized by its ability to bind to PC-containing antigens [94]

Binding of natural IgM anti-PC to apoptotic cells leads to further opsonization with the eat-me signals C1q and MBL, subsequently triggering complement activation. [93]. Opsonization of apoptotic cells with NAbs also allows recognition by FcRs on professional phagocytes, which will ultimately result in phagocytosis of dead cells. Interestingly, natural IgM and IgG do not bind to PS [68], thus, NAbs may act as a complementary mechanism, together with PS, in the clearance of apoptotic cells. The role of natural IgM in the clearance of apoptotic cells is well stablished in vitro and in vivo by pioneering studies. Incubation of apoptotic bodies with polyclonal IgM increases their clearance [95]. Natural IgM was also demonstrated to increase the phagocytosis of apoptotic cells by alveolar macrophages [96]. Mice that cannot secret IgM have impaired clearance of apoptotic cells, making them susceptible to develop lupus and produce autoimmune IgG against nucleic acids [97]. NAbs are also required for the removal of senescent red blood cells (RBCs), which cannot undergo apoptosis. As RBCs lack nuclei and mitochondria, the death of RBCs is not associated with energy-consuming events including the cleavage of intracellular content and alterations in membrane composition during apoptotic death. Some NAbs bind to senescent RBCs by recognizing determinants that involve the whole PtC molecule instead of only recognizing the PC-containing antigens [98]