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The University of Southampton
BRAIN UK

Lay Summaries of studies supported by BRAIN UK by category: Inflammation

BRAIN UK Ref: 11/001
Role of neutrophils in the pathogenesis of neuromyelitis optica
Mr M C Papadopoulos, St. George’s University of London 

Neuromyelitis optica (NMO, Devic’s disease) is an autoimmune inflammatory disorder of the central nervous system which results in the loss of the conducting sheath of nerve fibres located preferentially in the optic nerve and spinal cord resulting in weakness, paralysis and loss of sensation (including blindness). NMO is related to multiple sclerosis (MS) which tends to affect the brain preferentially. NMO is associated with circulating autoimmune antibodies which bind to a particular molecule (aquaporin-4, AQP4) present on the surface of astrocytes which are diagnostic of NMO. The researcher’s team has developed an animal model of NMO by introducing these autoimmune antibodies into mouse brain and have discovered that inflammatory tissue damage is mediated by a particular type of cell called a neutrophil that is a normal constituent of the immune system. A molecule called neutrophil elastase can be detected in tissue using specific staining procedures and is specific for neutrophils and this study aims to test the hypothesis that tissue damage in NMO (but not MS) is mediated by neutrophils in support of data from previous mouse studies.

Project Status: Closed

BRAIN UK Ref: 11/002
Pilot study comparing microglial markers in different neurological diseases known to be associated with inflammation
Dr D Boche, University of Southampton

A particular cell type in the central nervous system called microglia are involved in the normal immune response to inflammation caused by processes such as infection, traumatic injury and inflammatory diseases such as multiple sclerosis (MS). However, microglia may exhibit different forms of activation which can be characterized by the types of ‘marker’ molecules this cell type expresses which is called its phenotype. This study aims to identify specific ”markers” of microglia in different neuroinflammatory conditions in order to both determine their phenotypes as well as to ensure that the staining methods used are optimised for extension to other related studies.

Project Status: Active

Research Outputs: Publication x 6; Grant Application x 11; Presentation x 12; Poster x 9

DatePublication title
2013 Inflammatory Components in Human Alzheimer's Disease and After Active amyloid-β42 Immunization
2015 Effect of Amyloid-β (Aβ) Immunization on Hyperphosphorylated Tau: A Potential Role for Glycogen Synthase Kinase (GSK)-3β
2015 Effect of Active Aβ Immunotherapy on Neurons in Human Alzheimer's Disease
2015 Novel Association Between Microglia and Stem Cells in Human Gliomas: A Contributor to Tumour Proliferation?
2018 TREM2 Expression in the Human Brain: A Marker of Monocyte Recruitment?
2018 Systemic Infection Modifies the Neuroinflammatory Response in Late Stage Alzheimer's Disease
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BRAIN UK Ref: 11/003
Pilot study – Microglia profile in schizophrenia
Dr D Boche, University of Southampton

Schizophrenia is a disorder affecting normal cognition resulting in a breakdown of coherent thought and speech processes and social and behavioural dysfunction. There appear to be a number of contributory factors including genetics and early environmental influences. Inflammation is an important component of a number of disease processes but it relevance to schizophrenia remains uncertain as evidence is contradictory. A type of cell called microglia, which are an integral part of the immune system, may exhibit different levels of activation which can be characterized by the expression of ‘marker’ molecules (the cell’s ‘phenotype’) which can be demonstrated using specific staining techniques. This study aims to use specific staining methods in order to determine the phenotypes of microglia in schizophrenia brain tissue and to determine whether such cells play a role in this particular disease.

Project Status: Closed

Research Outputs: Grant Application x 5; Poster x 2

BRAIN UK Ref: 12/001
Pilot study to identify mast cells and basophils in brain
Dr D Boche, University of Southampton 

Particular cell types in the central nervous system called mast cells and basophils are involved in the normal immune response to inflammation caused by processes such as infection, traumatic injury and inflammatory diseases processes such as multiple sclerosis (MS). Mast cells act at the interface between two arms of the immune system (the simple innate system and more complex acquired system) and act by co-ordinating and directing a normal immune response. Basophils are involved in the immune response to allergens and parasites and again aid in the co-ordination of an immune response by increasing blood flow to an affected area of the body.
This study aims to apply specific staining methods of mast cells and basophils in different neuroinflammatory conditions to compare their distribution with those of microglia as well as to ensure that the staining methods used are optimised for extension to other related studies.

Project Status: Closed

Research Outputs: Presentation; Poster

BRAIN UK Ref: 12/002
Neuropathology of autoimmune/limbic encephalitis associated with antibodies against voltage-gated potassium channels
Dr A Shivane, Plymouth Hospitals NHS Trust

Autoimmune encephalitis is a relatively uncommon disorder typically associated with an underlying cancer. A number of sub-types have been described associated with molecules called antibodies directing inappropriate immune responses against cellular targets within the body. One particular sub-type involves an autoimmune response against molecules in cells specific for potassium ions that are sensitive to voltage changes and are important in the normal conduction of nerve impulses.
This study will examine cases of autoimmune encephalitis where antibodies against voltage-gated potassium channels are demonstrated and compare them to other cases of autoimmune encephalitis. Analysis will involve the description of microscopic pathological changes in different areas of the brain with particular reference to the intensity of the immune response which will be assessed with the use of specific staining techniques.

Project Status: Closed

Research Outputs: Abstract

BRAIN UK Ref: 12/007
Regulation of microglial proliferation and its contribution to chronic neurodegeneration
Dr D Gomez-Nicola, University of Southampton

Lay Summary not available.

Project Status: Closed.

BRAIN UK Ref: 12/009
Investigation into the impact of systemic inflammation due to infection on microglial phenotype and its contribution to Alzheimer's disease neuropathology
Dr D Boche, University of Southampton 

When we have an infection we feel sick and uninterested in things. This is known as “sickness behaviour” and is temporary. Studies have shown that this occurs because certain brain cells (microglia) are switched on by inflammatory chemicals produced during the infection.
In Alzheimer’s disease (AD), the microglia are already switched on by the disease, and animal models of dementia have shown that infection modifies microglia to be more aggressive, adding to the brain damage.
We propose that common infections (e.g. urinary or lung infections) play an important role in accelerating AD. Using human post-mortem brain tissue from people who died either with or without an infection, both non-demented and AD people, we will investigate whether:
(i) Infection has a more marked effect on microglia in AD.
(ii) APOE ε4, the main genetic risk factor for AD, modulates the damaging response.
(iii) Microglia switched on by infection add to the brain damage in AD.
(iv) Infection is associated with the presence in the brain of other inflammatory cells (T-lymphocytes) which may accelerate the disease.
This concept has readily applicable implications, suggesting that prevention and management of episodes of infection in the elderly population may slow the progression of dementia.

Project Status: Active

Research Outputs: Publication; Grant Application; Abstract x 1; Presentation x 10; Poster x 7

DatePublication title
2018 Systemic Infection Modifies the Neuroinflammatory Response in Late Stage Alzheimer's Disease
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BRAIN UK Ref: 13/002
Investigating inflammation of the normal appearing brain in patients with low-grade glioma
Dr F Roncaroli, Imperial College, London

A brain tumour can be defined as a mass lesion that is composed mostly of abnormal cells that grow in the brain. The cells can come from the brain itself or from its coverings (primary brain tumours) or from other organs in the body, this latter being defined as secondary or metastatic brain tumours. Primary brain tumours can be benign or malignant while secondary tumours are always aggressive (www.brainstrust.org.uk). There are over a hundred types of primary brain tumour each of which shows different behaviour.
Gliomas are between the commonest types of brain tumour in adults. The way the spread in the normal brain and their growth varies from type to case. Astrocytomas and oligodendrogliomas account for the vast majority of gliomas and they typically invade the surrounding tissue. In order to better define the behaviour of gliomas and guide their treatment, The World Health Organisation has devised a grading system from 1 to 4, grade 4 being those fast growing and therefore most aggressive.
Grade II gliomas are generally defined as low grade (LGG). They account for about 15% of primary brain tumours in adults. Approximately 80% of patients with a LGG present with fits, which progress with time from focal to generalised to eventually become unresponsive to medications. In addition, patients with LGG often develop memory problems and personality changes that impact on the quality of their lives.
In a previous study using imaging techniques, we observed that the brain of patients with LGG is diffusely inflamed compared to normal individuals of the same age. Because inflammation is known to cause damage to the brain, we have decided to study this problem more in depth using tissue supplied by Brain UK.
Our aims are to i) prove that results obtained with imaging reflect the reality; ii) understand the mechanism of brain damage caused by inflammation; iii) understand if treatment to reduce inflammation can help to controlling epilepsy and reduce the burden of memory and intellectual problems.

Project Status: Closed

Research Outputs: Presentation x 2

BRAIN UK Ref: 16/003
Activation of the type 1 interferon response by nucleic acids.
Dr David Hunt, University of Edinburgh 

Neurolupus is a serious brain disease which affects most patients who suffer from the autoimmune disease systemic lupus erythematosus (SLE). It can be very disabling, the cause is not known and treatment options are limited. We want to understand the molecular basis of this condition so we can develop effective markers of the disease and effective treatments. We want to study how the innate immune system, which usually protects the body from viral attack, might “accidentally” damage the brain in neurolupus. We will be looking in neurolupus brains to identify activation of innate immune pathways to try and find drug targets.

Project Status: Active

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BRAIN UK Ref: 16/014 
Effect of Hypothermia Treatment on Brain inflammation and Development in Neonatal Hypoxic Ischemia Encephalopathy
Dr D Boche, University of Southampton 

Neonatal Hypoxic Ischaemic Encephalopathy (HIE) is a significant worldwide problem that affects 1.3 to 1.7 per 1000 live births in UK. It occurs in babies who have been starved of oxygen around the time of birth and is associated with a high risk of brain injury and long-term neurological and neurodevelopmental problems. Body cooling treatment, where the body temperature is decreased from 37oC to 33.5oC for 72 hours, has dramatically improved the survival of the HIE babies without major side-effects. However, in the long-term, these children developed a number of neurological problems impacting on their daily life. It is thought that this is due to abnormal behaviour of the microglia during this time of oxygen starvation. Microglia is a brain cell which is an integral part of the immune system in the brain. Several studies suggest that the increased survival rates is driven by blocking this microglia. However, it has been observed in animal studies that microglia are an important component of the brain development in normal conditions. Therefore we hypothesize that the cooling treatment causes microglia to behave in a way that leads to brain development malfunction.

To explore this hypothesis, we will perform a study on post-mortem brain tissue investigating microglia and brain dysfunction.

Project status: Active

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BRAIN UK Ref: 19/018
Somatic mutation in human macrophages: defining ontogeny and mechanisms of inflammatory disease
Prof Matthew Collin, University of Newcastle and Dr Desmond Kidd, Royal Free Hospital

Not yet available 

Project Status: Active

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BRAIN UK Ref: 20/002
Validation of microglial receptor TREM2 expression and function in human patients following ischaemic stroke
Dr Barry McColl, University of Edinburgh

Lay Summary not yet available.

Project Status: Awaiting Approval

 

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BRAIN UK Ref: 20/007
Investigation of neuropathological changes in COVID-19
Professor Sebastian Brandner, University College London

COVID-19 is a disease caused by a virus called SARS-CoV-2 which was first reported in China at the end of 2019, but soon after the virus spread across the world causing a pandemic. The most common health problems of patients with COVID-19 are caused by a viral infection of lung tissue (so-called viral pneumonia). However, a small number of patients also develop symptoms as a result of brain damage.
In this large study to which many hospitals will contribute brain tissue, we want to find out more about the brain damage caused by this virus. We will look at cells that cause the brain tissue damage (so-called inflammatory cells) and we will use a technique that can detect the virus in brain cells.

Project status: Active

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