Traumatic brain injury is the leading cause of death and disability of young adults in the developed world.
There is evidence that the body’s immune response to a severe traumatic brain injury compounds the initial damage in some patients, leading to a worse outcome. In this project, the team set out to improve understanding of this immune response, how it might impact recovery, and how it could be prevented or treated to improve outcomes for patients.
Traumatic brain injury (TBI) is damage to the brain that is caused by an external physical force – most commonly the result of an accident, assault or fall. It is the leading cause of death and disability of young adults in the developed world.
On top of the initial injury, subsequent brain swelling in the days after the injury causes further damage to the brain. Additionally, one in three brain-injured patients develop progressive neurodegeneration over the years following the injury.
Although little except prevention can influence the initial injury, these two secondary phenomena could theoretically be prevented with medication, thereby improving outcomes for patients.
Whilst the underlying causes of these two phenomena are not understood, there is some evidence that the body's immune system is contributing to both the acute swelling and the long-term brain cell loss.
Read more: Brain and spinal cord injury
The University of Cambridge hosts leading groups in the fields of TBI, neurocritical care and neuroinflammation, and Addenbrooke’s Hospital in Cambridge has one of the very few dedicated trauma/ neurocritical care units in the UK. Additionally, Cambridge is one of two co-ordinating centres for ‘CENTER-TBI’ – a pan-European initiative that aims to improve care for patients with TBI, bringing many of the world’s leading TBI experts together in an international and multi-disciplinary effort to revolutionise treatment.
This project was a collaboration between Professor David Menon, a world-leader in TBI research, and co-chair of CENTER-TBI; Dr Edward Needham, who was instrumental in delivering the pilot study and bringing the research this far; Professor Alasdair Coles, an expert in the mechanisms of autoimmunity in the brain; and Dr Virginia Newcombe, an expert in neuro-imaging and TBI. With our funding, the team set out to understand the role of the immune system in TBI recovery.
Whilst the immune system usually protects the body from harm, fighting infection and healing damage, in certain circumstances, it can mistake the body’s own cells for invaders and attack them as if they were an infection. This process is called autoimmunity.
In a previous pilot study, the team had found evidence that some TBI patients develop an autoimmune response against brain cells, producing ‘autoantibodies’ that attacked the brain cells. The patients who developed these autoantibodies appeared to have a worse-than-predicted outcome. This suggested that the autoantibodies might be contributing to brain damage.
Our funding enabled the team to carry out a larger study to confirm and further explore these results. With a cohort of 470 patients with TBI, they used blood samples, brain scans and memory tests to find out more about the autoantibody response, and how it relates to outcomes after TBI over time.
Their results confirmed the findings of their pilot study - that TBI triggers a significant autoantibody response, and this was found to be associated with an increase in the levels of certain immune cells in the first week after injury.
There was no relationship between this autoimmune response and the severity of injury but there was a clear association with age, whereby younger patients had more marked responses.
Patients with high levels of a certain type of autoantibody were found to have worse than expected outcomes six months later.
By analysing blood samples taken at different points post-injury, the team showed that the autoantibodies remained elevated months after the injury and they looked to see whether they related to markers of ongoing brain damage, or other later consequences of TBI. The autoantibodies did not appear to be associated with late brain damage but, interestingly, patients who went on to develop epilepsy after their head injury had lower levels of certain autoantibodies, despite having higher general levels of inflammation in their blood. This suggests that the autoantibodies might play a useful role later after the injury.
There is great and inexplicable variability in outcome between individuals with overtly similar brain injuries and, despite significant advances in technology, it remains difficult to predict outcomes.
Secondary injury, from inflammation in the brain, compounds the original brain damage and this research has shed some light on this process, helping to clarify the effect of the autoimmune response on outcome after TBI.
This has been the most comprehensive study of the inflammatory response in human TBI. It has created a rich dataset across multiple time points post-injury and has confirmed pilot findings that there are distinct immunological processes that predict outcome after TBI, shedding light on the underlying biological mechanisms. This gives a deeper understanding of how to target the immune system with drugs that could prevent the development of autoimmunity and promote its healing role.
On the back of this study, the team has received a £2.3 million grant from UKRI to run an experimental medicine trial of an immunotherapy drug that is already used to treat autoimmune diseases such as rheumatoid arthritis, with the hope that this will improve patient outcomes. They have also received funding from other sources to explore further outputs from the project, including post-traumatic epilepsy.
Acquired brain and spinal cord injury (including stroke) is one of our current research priorities, reflecting the large unmet need in this area. Our aim is to fund research to advance understanding of how to promote repair of the brain and spinal cord following injury.
Read about our other research projects under this theme:
Find out about our other research in this area:
