Barbro Persson: Exploring the pathophysiology of COVID-19 using biomarkers of the contact and complement systems

Abstract

The immune system protects against disease, injury, and mortality, with the intravascular innate immune system (IIIS) playing a central role. It consists of plasma cascade systems and circulating blood cells that enable rapid and amplified responses through interconnected pathways. While normally well regulated, dysregulation—whether hereditary, congenital, or acquired—can cause excessive activation and lead to thromboinflammation, ie interconnected activation of coagulation and complement system. Components and activation products of these cascades can serve as biomarkers for diagnosis, disease monitoring, and treatment evaluation.

In Paper I, a magnetic bead-based immunoassay was developed to measure complement factor C1q in plasma and cerebrospinal fluid, showing reduced levels in systemic lupus erythematosus (SLE), especially patients with nephritis, and correlating with disease activity.

In Papers II-IV, we examined the thromboinflammatory response in the first 66 critically ill COVID-19 patient admitted to the ICU at Uppsala University Hospital, using newly developed assays targeting IIIS functions.

Paper II linked elevated mannose-binding lectin (MBL) to thromboembolic events (TE). 

Paper III found that blood groups A and AB were associated with increased risk of severe COVID-19.

In Paper IV we analyzed samples both cross-sectionally on day 1 and longitudinally for up to one month. The assessed IIIS biomarkers were compared with biochemical parameters, clinical outcome and death. Longitudinal analyses showed widespread activation of cascade systems, associated with multi-organ damage and predictive of clinical outcomes, highlighting potential therapeutic targets.

In Paper V, we conducted longitudinal analyses of Swedish and Norwegian COVID-19 cohorts, with milder disease, demonstrated early, sustained activation of innate immune pathways, including the complement and contact systems, supporting their role in disease progression and prognosis. Our findings corroborate previous reports demonstrating concurrent activation of innate inflammatory pathways.

Taken together, the studies in this thesis highlight the importance of having a broad panel of assays to monitor IIIS activation markers, both to improve understanding of disease mechanisms and to support the development of targeted therapies. They also leave us better prepared to refine and expand our analytical toolkit for investigating and monitoring IIIS responses in the next pandemic.