Complement interaction with other inflammatory pathways and potential concurrent interventions
Complement system dysregulation is one of the major endothelial injury pathways. While complement blockade improves TMA, not all patients respond to therapy, prompting a search for additional targetable pathways of endothelial injury. Emerging data on COVID-19 affected population indicate that multiple inflammatory pathways are likely to interplay, and novel strategies personalized to each individual or combination therapies might be required to effectively fight the hyperinflammatory storm (Figure 2) (Barnes et al., 2020; Giamarellos-Bourboulis et al., 2020; Gloude et al., 2017; Zhao, 2020). In support of this view, proteomic and metabolomic profiling of sera from healthy controls, non-severe and severe COVID-19 patients identified changes in complement pathways in concert with platelet degranulation and macrophage function as the main variables to predict progression to severe COVID-19 disease(Shen et al., 2020). All of these pathways have formerly been associated with the development of TMA. Of note, the authors found strong increase in CRP in severely ill COVID-19 patients, which is strong non-canonical activator of complement by the CP (Biro et al., 2007). Recent data in HSCT recipients with TA-TMA suggests a key relationship between complement activation and increased interferon (IFN) signaling, NETs, and chemokines/cytokines like IL-8 and IL-6 forming an “IFN-complement loop” that can perpetuate endothelial injury and TMA. Recent RNAseq data in HSCT recipients with TMA showed that IFNs promote expression of complement genes, such as C1Q, which initiates the classical complement pathway and ultimately leads to formation of the lytic membrane attack complex (MAC or C5b-9) and endothelial injury presenting as TMA (Jodele et al., 2020b). Intracellular complement C5 production, cleavage into C5a and intracellular C5aR1 activation after T cell activation results in NLRP3 inflammasome activation, Th1 differentiation and production of IFN-γ which could fuel the inflammatory scenario and sustain endothelial cell damage (Arbore et al., 2016).
Injured endothelial cells release IL-8, causing neutrophil activation and formation of NETs. In response, NET formation promotes complement system activation via the AP and FP (properdin) binding (Yuen et al., 2016). NET production can be further stimulated by IFN-γ (Gloude et al., 2017). IFN-α and -β increase differentiation of B cells into plasma cells that can produce anti-FH antibodies, preventing inhibition of the AP. NETs can activate plasmacytoid dendritic cells to produce high levels of IFN-α that can directly activate complement via C5b-9, resulting in vascular endothelial injury (Umemura et al., 2015).
Therapeutic administration of IFNs has been shown to cause TMA (Garcia-Romo et al., 2011). Viral pathogens that can trigger high IFN-γ production may also lead to development of complement mediated TMA (Zareei et al., 2019). In addition, viruses can directly injure endothelial cells and promote release of IFN-γ (An, Saenz Robles, Duray, Cantalupo & Pipas, 2019). Inflammatory chemokines/cytokines like IL-6, IL-8, and IFN-γ are also released from circulating activated T cells, NK cells, monocytes, and tissue macrophages as a response to viral infection, again contributing to TMA development.
Improved understanding in key cytokines roles in the “IFN-complement loop” provides us with new opportunities to combine therapies that might be used as personalized treatment options for selected patients. One clinical example is hemophagocytic lymphohistiocytosis (HLH), a rare clinical syndrome of excessive immune activation, characterized by signs and symptoms of extreme inflammation, driven mainly by IFN-γ and other pro-inflammatory cytokines with good response to emapalumab (Lounder, Bin, de Min & Jordan, 2019; Vallurupalli & Berliner, 2019), a human monoclonal antibody to IFN-γ, which blocks its binding to cell surface receptors and activation of inflammatory signals. It is approved for treatment of severe HLH. Patients with HLH, who simultaneously present with complement-mediated TMA have high incidence of multi-organ injury and poor outcomes. Case series in children suggest that co-administration of both, an IFN-γ blocker and a complement blocker targeting both pathways in TMA might provide faster disease control and recovery from organ injury (Gloude et al., 2020). Taking into consideration that COVID-19 affected subjects may preferentially have one of the other inflammatory pathways overactivated, monitoring blood sC5b-9 and CXCL9 (indicates activated IFN-γ ) and IL-6 level will have immediate clinical implication in proposing care algorithms for patient risk stratification and targeted interventions, like implementation of complement, interferon, IL-6 modulating therapy using currently available drugs to halt COVID-19 progression to multi-organ failure and improve outcome.