20 Apr 2018

Journey into new field complements blood research

High praise from Professor Beverley Hunt! See her tweet
by Anne Crawford

An exploratory review of literature about an ancient immune system has taken researchers in the Australian Centre for Blood Disorders (ACBD) into what is for them a new and fascinating world. It has yielded insights into links to their own research into haematological processes, suggested exciting new avenues of investigation and provided fuel for thought about new drugs on the market.

As a researcher focusing on blood clots, Professor Robert Medcalf rarely came across the term ‘complement’ in his usual scientific efforts, as complement is a system of proteins best known for its immunological role fighting infection.

That all changed when PhD student, haematologist Dr Cherry Keragala began a detailed review of the subject. Professor Medcalf, a research group leader in ACBD, was fascinated.

The complement system enhances (complements) the ability of antibodies to fight infection as part of the body’s innate immune system. It has been known for some time, however, that complement drives other processes apparently unrelated to immunological events – and that it interacts with the process of coagulation (clotting).

The term ‘immunothrombosis’ was coined in 2013 to describe this process, which is attracting considerable interest. New drugs using the complement system are also gaining attention. It seemed an opportune time to investigate.

Dr Keragala is first author on the catchily titled ‘Haemostasis and innate immunity – a complementary relationship: A review of the intricate relationship between coagulation and complement pathways’ published recently in the 'British Journal of Haematology'.

The review, which looks at nearly 130 studies, is the first paper to update information about this relationship in some years – despite a number of complement-specific drugs coming onto the market, Professor Medcalf said. Expected to be well cited, it is forming the basis of new research being conducted in Professor Medcalf’s Fibrinolysis and Gene Regulation Laboratory.

One of the most ancient immunological systems, complement dates back many millions of years ago to the first animals. The elegantly refined system orchestrates a cascade of events involving more than 30 proteins, including blood proteins, which seek out infectious microorganisms, foreign and damaged cells in the body, promote inflammation and eliminate unwanted cells.

Coagulation too, acts as an immune response. “Whenever we cut ourselves and bleed, we clott very fast to stop infection setting in, so it’s like a primary immune defense,” Professor Medcalf said. “The natural response is for the body to clot around bacteria to ‘wall off’ the bacteria to stop it disseminating,” he said. Bacteria however retaliate by releasing enzymes to break down clots in order to escape. “It’s like an evolutionary arms race.”

The complement system binds to infected cells and releases enzymes of its own termed the ‘membrane attack complex’ which essentially punches holes in affected cells leading to the cells bursting (lysis).

 “We’re really interested in the relationship between the haematological system and how it interacts with the immune response,” he said. “They’re really dynamic – one influences the other.”

Said Dr Keragala, “For so long we’ve always thought of the way our body clots and the way it fights infection as being separate. The review provides a nice appreciation of how we need to go beyond thinking of them as separate entities and understanding exactly how closely linked they are.”

It was time that research moved on from the traditional separation between different disciplines, she said.

Cross-disciplinary research was vital in working out and forecasting the effects on the body of therapies other than the intended ones. For example, in a related area of research, mice that had been bred so they were missing a clot-busting gene proved to develop more clots, although less than expected, but also lost their memories indicating the clot-busting system has a natural role in the brain unrelated to clot-busting. “Who would have predicated that?”

The researchers are interested in what happens clinically when either system is not functioning properly as seen in many inflammatory and thrombotic disease states, such as sepsis, trauma, atherosclerosis and paroxysmal nocturnal haemoglobinuria (PNH), a rare life-threatening disease of the blood caused when the complement system goes awry and destroys red blood cells and immune cells.

They are looking into the new drugs that ‘dampen down’ the complement system when it is not functioning optimally, such as eculizumab, which has revolutionised the way patients with PNH are managed. Eculizumab is being successfully trialled in other disorders.

“We’re digging into the evolutionary components and drawing on what these anti-complement drugs do, how else they could be used, what are the other unknown benefits or untoward effects they might have because the complement system is involved in so many things,” Professor Medcalf said.

 “We’re really trying to get an idea about what is the most likely new and exciting area we can pursue,” he said.

The laboratory has used the review for example, as a basis for investigating links between the complement system and the blood-brain barrier – an area in which the lab has conducted considerable research – testing whether the system could be involved in permeability of the ‘wall’ that separates blood and brain.

“The evidence is already out there that the system is involved in this process. If complement is opening up the blood-brain barrier it’s letting things into the brain in an untoward way this drug might be useful to stop this process and might be useful in models of head trauma and stroke,” Professor Medcalf said.

To read a complimentary tweet about the paper . . .

Keragala CB, Draxler DF, McQuilten ZK, Medcalf RL. Haemostasis and innate immunity - a complementary relationship: A review of the intricate relationship between coagulation and complement pathways. Br J Haematol. 2018 Mar;180(6):782-798. doi: 10.1111/bjh.15062. Epub 2017 Dec 19.

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