A new study led by Newcastle University scientists has uncovered a new genetic cause for rare childhood immune disorders, opening the door to early diagnosis and treatment.
The effects of Severe Combined Immunodeficiency (SCID) and Omenn Syndrome (OS) are inevitably fatal if left untreated. It is hoped that these new discoveries can assist with early detection, giving children with these conditions the best chance at life. Read on to find out more.
Contents:
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Severe Combined Immunodeficiency and Omenn Syndrome
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Studying rare childhood immune disorders
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The importance of early diagnosis
Severe Combined Immunodeficiency and Omenn Syndrome
Severe Combined Immunodeficiency is a type of primary immune deficiency that affects the lymphocytes – a type of white blood cell responsible for defending the body against infections, and especially for immune memory. Children with SCID don’t make enough T lymphocytes, leaving them unable to fight off viruses, bacteria and some fungal infections. Though they often appear healthy at birth, babies with SCID can very quickly show symptoms of the disorder, such as frequent respiratory infections, bacterial infections and failure to thrive.
The related disorder called Omenn Syndrome happens when a very few T lymphocytes develop – not enough to do a useful job protecting against infection, but enough to cause extra, inflammatory problems such as skin redness (erythroderma), peeling (desquamation), hair loss (alopecia) and swelling of the liver and spleen.
Without urgent treatment, such as stem cell transplantation to replace the faulty immune system, these disorders are fatal in infancy. This is why newborn screening for severe T cell deficiency is being piloted in many countries.
Newborn screening is a vital step in the early identification of rare childhood immune disorders.
Studying rare childhood immune disorders
Published in Science Immunology, the study was a combined effort between experts from Newcastle University, the Great North Children’s Hospital in Newcastle, the Wellcome Sanger Institute, and their collaborators in the UK, Norway and the Netherlands.
The team studied 11 children across four different families: two of these children had SCID, while the other nine had Omenn syndrome. Our researchers found that all 11 children had inherited mutations that disrupted the function of the NUDCD3 protein. These mutations prevented the normal development of both T and B lymphocytes needed to combat different pathogens.
The team used detailed studies of patient-derived cells and mouse models to show that NUDCD3 mutations impair a vital gene-rearranging process called V(D)J recombination. This process is essential for generating the diverse T cell receptors and antibodies needed to recognise and fight different pathogens. They found that human patients faced severe, life-threatening consequences compared to mice engineered with the same NUDCD3 mutations, who experienced milder immune problems. Two patients survived after receiving a stem cell transplant, reinforcing the importance of early diagnosis and intervention.
Professor Sophie Hambleton, senior author of the study at Newcastle University and a practising paediatric immunologist at the Great North Children's Hospital, is pleased with the findings.
“SCID and Omenn syndrome are devastating disorders, requiring complex and timely treatments,” says Hambleton. “The more we can understand about its underlying causes, the better we can look after affected babies. Our research is aimed at filling in the gaps so that families can achieve a molecular diagnosis while we continue learning more about how the immune system works in health and disease.
“We are deeply grateful to the families whose invaluable participation in this study will help future generations.”
The importance of early diagnosis
“For babies born with high-risk immunodeficiencies, early detection can mean the difference between life and death,” says Dr Gosia Trynka, one of the authors of the study.
The findings from this study open opportunities for early diagnosis and intervention for SCID and OS, as well as genetic counselling for affected families.
While newborn screening methods can flag T cell deficiency, knowledge of the specific genetic cause increases confidence in the diagnosis of SCID and informs the choice of curative therapy. However, this currently remains out of reach for at least one in 10 families affected by SCID and OS.
According to Dr Trynka: “These diseases leave newborns essentially defenceless against pathogens that most of us can easily fend off. The identification of this new disease gene will help clinicians to make a prompt molecular diagnosis in affected patients, meaning they can receive life-saving treatments more quickly.”
You might also like:
- read the study: R. Chen, E. Lukianova et al. (2024) ‘NUDCD3 deficiency disrupts V(D)J recombination to cause SCID/Omenn syndrome.’ Science Immunology. DOI: 10.1126/sciimmunol.ade5705
- find out more about Dr Sophie Hambleton, Professor of Paediatrics & Immunology at Newcastle University
- learn about the work of Dr Gosia Trynka, Group Leader at the Sanger Institute and Experimental Science Director at Open Targets
- discover more about our Ageing and Health research community at Newcastle University
