Dimitrios C. Mastellos
Molecular Immunology Laboratory, Division of Biodiagnostic Sciences and Technologies, INRASTES, National Center for Scientific Research Demokritos, Aghia Paraskevi, Athens, Greece.
The complement system constitutes a key innate immune sentinel that mediates host immunosurveillance and tissue homeostasis. Through a tightly regulated proteolytic cascade, complement elicits a rapid response against pathogens, involving microbial pattern recognition, release of proinflammatory mediators and recruitment of phagocytes to the site of infection (1). However, when regulatory control is lost, imbalanced complement can lead to detrimental proinflammatory consequences that fuel tissue damage and pathology. Over the last decade, our knowledge of this system has expanded considerably. Besides acting in the intravascular space, complement has been recognized to act intracellularly via crosstalk with the autophagosomal compartment, the NLRP3 inflammasome and other signaling pathways (1-2). Notably, intracellular complement activation impacts T-cell homeostasis and survival and skews T-cell polarization towards a Th1 phenotype. Furthermore, intracellular C3 is involved in tagging microbial pathogens for autophagosomal degradation, while upregulation of C3 in pancreatic islets triggers cytoprotective autophagy with important implications for type-II diabetes. Moreover, chronic complement dysregulation has been linked to an insidious inflammatory response that exacerbates synaptic loss and neurodegeneration in CNS pathologies (1,4).
For decades the role of complement in cancer immunity was perceived as that of an augmenter of the cytolytic activity of anti-tumor antibodies (3). Accumulating evidence now supports a protumorigenic role of complement whereby various complement effectors promote tumor-associated inflammation and immunosuppression (3). In this regard, promising results from preclinical cancer models have sparked translational efforts to develop combinatorial cancer immunotherapies that exploit targeted complement inhibition (4). Complement activation is physiologically regulated by an array of endogenous regulatory proteins. By binding to polyanionic surfaces, such as the proteoglycan-rich glycocalyx that overlays the vascular endothelium, these regulators shield our vessels from complement-mediated injury. However, genetic alterations or acquired defects (autoantibodies) that render these regulatory proteins inactive have been linked to many pathologies, including renal glomerular diseases (4). The unique anatomy of the kidney and the lack of complement regulators in the glomerular basement membrane make this organ highly susceptible to complement-mediated injury. To this end, a wide spectrum of complement-targeted therapeutics are currently in clinical development as treatment options for acute or chronic renal indications, including kidney allograft rejection, C3 glomerulopathy, lupus nephritis and IgA nephropathy (4).
References:
- Hajishengallis G, Reis ES, Mastellos DC, Ricklin D, Lambris JD. Novel mechanisms and functions of complement. Nat Immunol. 2017 Nov 16;18(12):1288-1298. doi: 10.1038/ni.3858
- Reis ES, Mastellos DC, Hajishengallis G, Lambris JD. New insights into the immune functions of complement. Nat Rev Immunol. 2019 Aug;19(8):503-516. doi: 10.1038/s41577-019-0168-x. Review.
- Reis ES, Mastellos DC, Ricklin D, Mantovani A, Lambris JD. Complement in cancer: untangling an intricate relationship. Nat Rev Immunol. 2018 Jan;18(1):5-18. doi: 10.1038/nri.2017.97.
- Mastellos DC, Ricklin D, Lambris JD. Clinical promise of next-generation complement therapeutics. Nat Rev Drug Discov. 2019 Sep;18(9):707-729. doi: 10.1038/s41573-019-0031-6. Epub 2019 Jul 19. Review.