We have recently reviewed current knowledge on the mechanisms that underlie immunogenic cell death (ICD) in the context of cancer and infectious diseases, the capacity of ICD to elicit an adaptive immune response in the absence of exogenous adjuvants, and the pathophysiological relevance of this process (Nat. Rev. Immunol. doi: 10.1038/nri.2016.107 (2016))1.
In their Correspondence (Nat. Rev. Immunol. doi: 10.1038/nri.2016.142 (2016)), Jin and He evoked the importance of the complement system for ICD, pointing to the role of complement activation in the efficient uptake of dead cells by phagocytes coupled to the delivery of robust anti-inflammatory signals. Activation of the complement system has indeed been linked to the capacity of phagocytes to engulf dead cells, while preserving tolerance2. Moreover, defects in the complement system in humans are associated with autoimmune disorders such as systemic lupus erythematosus (SLE)3. However, C3-deficient mice (which lack a convertase involved in both classical and alternative complement activation)4 are viable and fertile, do not spontaneously develop autoimmune disorders, and only display mildly impaired B cell and T cell responses5,6. These findings suggest that systems other than complement have an even more important role in the maintenance of peripheral tolerance to dying cells7. Consistent with this interpretation, Jmjd6−/− mice (which lack the phagocytic receptor for phosphatidylserine externalized by dying cells) die at birth owing to the accumulation of dead cells in the brain and lung8,9. Along similar lines, Rubcn−/− mice (which are deficient in LC3-associated phagocytosis — a specialized phagocytic pathway relying on elements of the autophagic machinery)10,11 spontaneously develop an SLE-like disorder owing to an intrinsic defect in efferocytosis12. Taken together, these observations point to complement activation as a process that supports, but is not crucial for, the removal of dying cells in physiological and pathological conditions. Irrespectively, our Review has a specific focus on the mechanisms of immunogenic, not tolerogenic, cell death.
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Galluzzi, L., Buqué, A., Kepp, O. et al. The complement system is also important in immunogenic cell death. Nat Rev Immunol 17, 143 (2017). https://doi.org/10.1038/nri.2016.143
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DOI: https://doi.org/10.1038/nri.2016.143
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