Bo Nilsson – The intravascular innate immune system and thromboinflammation

Our research focuses on the intravascular innate immune system (IIIS), with the aim to develop combined diagnostic and therapeutic strategies that modulate IIIS as a whole.

The intravascular innate immune system (IIIS) comprises the blood cascade systems together with circulating and endothelial cells and underlies a broad spectrum of thromboinflammatory reactions in disease and during medical treatments. Its physiological role is an evolutionarily old waste‑handling and repair system that eliminates pathogens, removes apoptotic and necrotic cells, clears foreign particles, and prepares for tissue repair.

The cascade proteins share common evolutionary origins, giving rise to families such as C3/C4/C5 (macroglobulins) and related regulators (SCRs, serpins). These molecules enable complex amplification and regulatory loops, and in most animal species that lack adaptive immunity, IIIS provides the primary defence against infection and tissue damage.

IIIS components

The core of IIIS consists of the plasma cascade systems: complement (classical, lectin, and alternative pathways), coagulation (tissue factor– and factor XII–driven activation), the kallikrein–kinin system, and fibrinolysis. It also includes pattern‑recognition molecules such as FXII, collectins, ficolins and pentraxins and effector cells including granulocytes, monocytes, and platelets. Extensive cross‑talk means that activation of one system can rapidly spread to the others, resulting in a coordinated thromboinflammatory response.

Thromboinflammation

Thromboinflammation is the tightly linked combination of clotting and inflammation which normally helps seal vascular injury, recruit leukocytes, clear damaged tissue, and support healing. However, when excessive or dysregulated, it can cause tissue injury, microvascular thrombosis and organ dysfunction. Because IIIS distinguishes self from non‑self mainly at the species level, it may also attack altered host cells during infection, hypoxia, or mechanical stress.

Experimental models

Historically, research on these systems has been fragmented, with complement studied mainly in serum and coagulation and the kallikrein–kinin system in re‑calcified citrated plasma, which has hampered analysis of genuine interactions.

We have developed in vitro models with antithrombotic surfaces (heparin, specialised polymer) that allow experiments in whole blood with minimal artificial activation. This has revealed previously unrecognised interactions within IIIS, shifting the focus from isolated cascades to a unified intravascular innate immune network.

IIIS as an integrated system

Our overall aim is to investigate IIIS as an integrated system and to develop combined diagnostic and therapeutic strategies that modulate IIIS as a whole. This can be illustrated by conditions such as COVID‑19, extracorporeal circulation and ischaemia–reperfusion injury, where the same fundamental mechanisms drive quite different clinical syndromes.

Papers linked to our research:

Dangerous liaisons: complement, coagulation, and kallikrein/kinin cross-talk act as a linchpin in the events leading to thromboinflammation. Ekdahl KN, Teramura Y, Hamad OA, Asif S, Duehrkop C, Fromell K, Gustafson E, Hong J, Kozarcanin H, Magnusson PU, Huber-Lang M, Garred P, Nilsson B. Immunol Rev. 2016 Nov;274(1):245-269. doi: 10.1111/imr.12471.

Cardiovascular disease in haemodialysis: role of the intravascular innate immune system. Ekdahl KN, Soveri I, Hilborn J, Fellström B, Nilsson B. Nat Rev Nephrol. 2017 May;13(5):285-296. doi: 10.1038/nrneph.2017.17.