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.