Faculty of Medical Sciences

Staff Profile

Professor Sophie Hambleton

Professor of Paediatrics & Immunology

Background

From bedside to bench and back again - my research is all about what children with inherited immunodeficiencies can teach us about the normal immune system, and how that knowledge can help us look after patients better. I am a clinical paediatric immunologist at the Great North Children's Hospital, which is home to a supra-regional service for children with primary immunodeficiencies. My work is aimed at understanding the cellular and molecular basis of novel primary immunodeficiencies, and how this informs our knowledge of the normal immune system.

The human immune system has evolved to protect us from a bewildering array of germs, a job it usually performs unnoticed. We can think of the immune system as a network of armed forces that cooperate to defend us. When one element of these defences is weakened, it can leave us critically exposed to certain threats. Unusual or severe infections in young children can indicate a problem with the genes that determine how our immune system works. If affected children survive, they may suffer ongoing ill-health owing to chronic infection, stunted growth and lung damage. Sometimes this is accompanied by other problems such as the "friendly fire" of autoimmune disease or blood cancers. This type of immunodeficiency tends to run in families and is commoner in children whose parents are related to each other.

 

At the Great North Children's Hospital (GNCH), we care for hundreds of patients with inherited immunodeficiency, but the faulty gene can be pinpointed in fewer than half. Making a genetic diagnosis is important for two main reasons, one medical and one scientific:

(1) An accurate diagnosis can help doctors and families make the right treatment decisions. Many immunodeficiencies can now be cured by replacing the immune system with a bone marrow transplant. Unfortunately, this is an unpleasant and risky procedure. Scientists continue to work on smarter methods to replace or repair just the faulty gene. Where cure is not possible we can take steps to prevent and treat complications if we know what to expect.

(2) Linking the faulty gene to the resulting pattern of disease tells us about its normal function. By studying individuals with inherited immunodeficiency, we can learn a great deal about what is important for human immunity. This knowledge can also help us understand the ways germs get round our immune system to cause disease.

 

My research addresses both these priorities by searching for the underlying cause of unexplained immunodeficiencies. The children we study are past and present patients of the GNCH, many of whom generously contribute small samples of blood and other tissues for research. First, we carefully review the patient's medical and laboratory information and make sure known causes of immunodeficiency have been ruled out. Then we use a variety of modern DNA sequencing methods to look for genetic changes that may link with disease. We test the strength of that link within the family and the wider population. We try to find out how the genetic change interferes with normal immune function by experiments in the test tube.

 

As soon as a linked genetic change is confirmed, this can be fed back to the clinical team and inform patient care. Families can then benefit from genetic counselling and the possibility of early diagnosis for other affected family members. We share our research findings with the medical community at large so that patients with a similar disease pattern can be screened for the same genetic problem. We believe our work will lead to improved scientific understanding of human immunity, which is fundamentally important to health and disease.



Research

Group members:

Angela Grainger

Karin Engelhardt

Joe Willet

David Swan

Jarmila Spegarova

Nic Robertson

Chris Duncan

Meghan Acres

Becky Payne

Rui Chen

Ben Thompson


Our research

Primary immunodeficiencies (PIDs) represent a rich resource for hypothesis-generating research on the human immune system. My aim is to elucidate disease mechanism in novel inherited disorders of cellular immunity. My group studies well-characterised patients presenting in childhood with otherwise unexplained susceptibility to intracellular pathogens and/or immune dysregulation. A variety of methods are used to identify candidate disease-causing gene variants, including whole exome sequencing and homozygosity mapping. Selected variants are taken forward for biochemical and functional validation by tailored analyses of biobanked material. In recent years we have identified novel defects of T cells, antigen-presenting cells and innate antiviral immunity that have each contributed important mechanistic insights into human immunobiology.  


By comparison with genetically engineered mouse models, a forward genetic approach to human PID offers inherent scientific advantages such as (1) increased relevance of findings to human immunity in the natural environment, (2) a definite and clinically important phenotype, (3) freedom from preconceptions as to candidate genes. PIDs thus represent critically important human models in which to discover and explore the function of individual genes and pathways. A major advantage of our work is its direct relevance to patient care by extending the possibility of molecular diagnosis, with attendant benefits in terms of timely and tailored treatment and genetic counselling.


Postgraduate Supervision

I welcome postgraduate students who are interested in translational immunology research.


Funding

Sir Jules Thorn Charitable Trust Biomedical award 2013-2017

MRC clinician scientist award 2008-2012

Academy of Medical Sciences

Bubble Foundation

Teaching

Undergraduate Teaching

Extensive experience of mentoring, teaching and assessing students of medicine and biomedical sciences.

Postgraduate Teaching

I play an active role in postgraduate education within my clinical subspecialty including delivery of registrar training and running study days. I teach on two masters programmes (MRes Immunobiology module, MSc Genomics) and supervise students carrying out research projects at all levels.

Publications