Key interests

Main methods

Overview of the complement system

Key interests

Current challenges that we are tackling include:
  • Characterisation of how complement opsonisation is regulated and what communicative signals complement opsonins send out to bystander cells
  • Development and testing of novel biopharmaceutical complement inhibitors 
  • Characterisation of inflammatory complement activiation on bio- and nanomaterials
  • Investigation of complement's influence on shaping an inflammatory or a tolerogenic immune response

  • Characterisation of the interactions between complement proteins with the malaria parasite Plasmodium falciparum

Main methods

We specialise in characterising protein-protein, protein-ligand and protein-cell interactions and furthermore engineer, produce and test novel immunmodulatory biopharmaceutical candidates.  To achieve this we use a wide range of protein biochemical and immunological techniques ranging from recombinant protein technology (protein expression in bacterial, yeast and mammalian hosts followed by protein purification), knowledge-based protein engineering, protein chemistry, biophysical interaction analysis (e.g. SPR), fluorescent cell microscopy, fluorescence-activated cell sorting (FACS), protein and cell-based immunological assays (e.g. ELISPOT analysis).  

Overview of the complement system

The complement system is the main soluble effector arm of innate immunity and is found ubiquitously in the human body. Its omnipresence warrants fast and efficient immune surveillance and additionally maintains vital host homeostasis. More than 30 soluble and cell-surface anchored complement proteins cooperate to manage the central element of the complement system, the complement cascade. The liver supplies the blood stream with large amounts of complement components, but a huge number of cells and tissues add to the systemically provided components through local production. 

Owing to its phylogenetically long and ubiquitous presence at high concentrations, complement’s role expanded from an originally old, self-sufficient protection mechanism to an interconnected player managing global immune surveillance and tissue homeostasis with such diverse effects and influence on as:

defense against microbial invaders, removal of cellular waste and debris (e.g. apoptotic cells), crosstalk with Toll-like receptors, interplay with coagulation, enhancing humoral immunity, regulating T-cell responses, inflammatory diseases and acute phase disorders (for a detailed compendium see (Ricklin et. al., Nature Immunology, 2010)). 

Three distinct pathways - the classical, the lectin and the alternative pathway – trigger the complement cascade intrinsically. Extracellular, soluble complement pattern recognition molecules (of the classical and lectin pathway) serve as sentinels for danger signals, and upon recognition of pathogen associated molecular patterns (PAMPs) or endogenous danger associated molecular patterns (DAMPs) trigger distinct complement activation profiles. In contrast, the alternative pathway (AP) is not specifically activated by PAMPs or DAMPs, but is active at all time at a very low level. However, host-specific regulator molecules control AP-activation on self-cells, thus protecting from the AP via “missing-self recognition”. Complement activation cumulates in the central step of the complement cascade, the enzymatic activation of the pivotal complement protein C3 via convertase enzymes into the small anaphylatoxin C3a and the 175 kDa opsonin C3b, which indiscriminatingly attaches to nucleophils in its vicinity through its reactive thioester forming a covalent bond. C3b-opsonised molecules, particles and surfaces act, if not held in check by surface associated regulators,  as germination centres for the auto-amplification of further C3b opsonins through newly formed C3-convertases, thus auto-amplifying the initial trigger, irrespective of its origin, by a multifold.

Scheme of the major complement pathways:


Tight regulation of the pivotal C3-convertases – and in particular of the AP-amplification loop C3-convertase – is of crucial importance and under-regulation of this central step leads to severe tissue damage and is the underlying and/or aggravating factor of many rare and common disease conditions such as e.g. paroxysmal nocturnal hemoglubinuria (PNH), atypical haemolytic uremic sundrom (aHUS), age related macuar degeneration (AMD), asthma, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, Alzheimer’s disease, ischemia-reperfusion injury, transplant rejection.

Complement activation must be spatially and temporarily limited in order to avoid damage to normal self as a consequence of excessive widespread, and prolonged activation (which also leads to exhaustion of complement proteins in one event and consequently to unresponsiveness to later events).  

Under normal, physiological conditions the level of complement activation and associated immunological outcome ideally is dependent on the nature of the initiating stimulus.

A) On pathogens complement acts as the first responder of the immune system in a robust and unrestricted activation profile promoting clearance, inflammation and consequently immunity:

Insufficient regulation of the C3-convertases on pathogens leads to massive C3-opsonisation, followed by the assembly of C5-convertases, which process the complement C5 protein into the very potent anaphylatoxin C5a and C5b. While C5a promotes inflammation, mast cell degranulation and leucocyte migration to alert all branches of the immune system, C5b associates with the complement components C6, C7, C8 and multiple copies of C9 to form the membrane attach complex (MAC) which punches holes into cells eventually resulting in lytic cell death. (i.e. raising alarm within the entire immune system).

B) On altered self (e.g. apoptotic and injured cells, debris) complement promotes a limited, more regulated activation profile resulting in mild inflammation, but preventing immunity and thus supports house-keeping functions:

Intense regulation of the C3-convertases stops the complement cascade from progression into the detrimental lytic pathway, but allows – to varying extent - particles and molecules to be coated with opsonin C3b and Factor I-processed inactivation products of C3b: iC3b, C3dg, C3d. Coating with opsonins facilitates clearance and uptake of antigens by professional phagocytotic cells, enhanced antigen presentation, lowering of thresholds for B-cell activation (T-cell dependent and independent B-cell activation).

C)  On normal self (e.g. healthy cells) complement activation is limited to the baseline activation of the alternative pathway. In the presence of regulators this low level surveillance-activation is insufficient to raise inflammation and immunity.

2020 Christoph Schmidt, all rights reserved