Complement Activation in the Central Nervous System: A Biophysical Model for Immune Dysregulation in the Disease State

Abstract

Complement, a feature of the innate immune system that targets pathogens for phagocytic clearance and promotes inflammation, is tightly regulated to prevent damage to host tissue. This regulation is paramount in the central nervous system (CNS) since complement proteins degrade neuronal synapses during development, homeostasis, and neurodegeneration. We propose that dysregulated complement, particularly C1 or C3b, may errantly target synapses for immune-mediated clearance, therefore highlighting regulatory failure as a major potential mediator of neurological disease. First, we explore the mechanics of molecular neuroimmune relationships for the regulatory proteins: Complement Receptor 1, C1-Inhibitor, Factor H, and the CUB-sushi multiple domain family. We propose that biophysical and chemical principles offer clues for understanding mechanisms of dysregulation. Second, we describe anticipated effects to CNS disease processes (particularly Alzheimer's Disease) and nest our ideas within existing basic science, clinical, and epidemiological findings. Finally, we illustrate how the concepts presented within this manuscript provoke new ways of approaching age-old neurodegenerative processes. Every component of this model is testable by straightforward experimentation and highlights the untapped potential of complement dysregulation as a driver of CNS disease. This includes a putative role for complement-based neurotherapeutic agents and companion biomarkers.

Functional Activity of the Complement System in Hospitalized COVID-19 Patients: A Prospective Cohort Study

“…Given that C1INH is only a very weak regulator of the alternative pathway the lack of its association may support the observed significant association of AP activity with the outcome in our study. As even elevated C1INH concentrations may not be sufficient to inhibit or modulate all potential downstream effectors within the complement and contact activation cascade (47) and due to the detection of an increased amount of modified (cleaved) inactive C1INH in patients with severe sepsis (48) and a decreased expression of C1INH in the lungs of COVID-19 patients (32), results from trials evaluating additional C1INH supplementation treatment (49,50) will be informative if C1INH may influence COVID-19 severity and outcome independent of AP activation (e.g. by inactivating the contact activation system or MASP-2).…”

Targeting thromboinflammation in COVID-19 – A narrative review of the potential of C1 inhibitor to prevent disease progression

“…Consistent with this hypothesis, C1-INH activity correlated negatively with D-dimer levels in COVID-19 patients ( Peerschke et al, 2021 ). Given the formation of 1:1 complexes between C1-INH and respective proteases, C1-INH concentrations are insufficient to inhibit all target proteases in any of the plasmatic cascades even at a resting state ( Peoples and Strang, 2021 ). Given the profound activation of the CAS, CS and KKS during COVID-19, depletion of C1-INH and a relative deficiency despite its acute-phase related increase is very likely and may impact on thromboinflammation and its associated complications.…”

“…Lastly, COVID-19 is characterized by a local activation of plasmatic cascades that progresses to a systemic activation early in the disease ( Busch et al, 2020 ). As such, even two-fold elevated C1-INH concentrations may not be sufficient to significantly inhibit all potential downstream effects of the CS, KKS and CAS ( Peoples and Strang, 2021 , Ravindran et al, 2004 ) given excessive cross-activation and limited inhibition of e.g. the alternative pathway activation.…”

Microglia in Neurodegenerative Events—An Initiator or a Significant Other?

“…A number of downstream effector functions are initiated with complement activation, including surface deposition of opsonin C3b on target cells, recruitment of phagocytic cells, and pathogen lysis [154]. An elevated expression during injury has been proposed as a mechanism to target microglia to degenerating cellular processes, and an association between microglia and active synaptic loss or remodeling has been reported in various brain regions [155][156][157]. A key component to initiate this cascade is the complement protein, C1q, which functions as a recognition component of the macromolecular complex, C1.…”