̽��ֱ�� of Cambridge - Medical Research Foundation

‘Ageing’ immune cell levels could predict how well we respond to vaccines

cjb250 — Tue, 27 Jun 2023 09:00:30 +0000

During the COVID-19 pandemic, it has become clear that some patients are better protected by vaccination than others. Many studies have shown that SARS-CoV-2 vaccines are less effective in people with weakened immune systems, but also that this effect is not uniform.

Vaccination involves priming the immune system to look for – and get rid of – invading pathogens, such as viruses and bacteria. In part, this involves stimulating the production of antibodies uniquely programmed to identify a particular invader. These antibodies are themselves produced by a type of immune cell known as a B cell.

One specific subset of B cells is known as age-associated B cells (ABCs). While, on average, less than one in 20 of a healthy individual’s B cells is an ABC, the proportion gradually increases as we get older. ̽��ֱ��reasons for this increase are not yet fully understood, but may include previous infections. Certain people with weakened immune systems accumulate ABCs still faster.

A team from the Medical Research Council (MRC) Toxicology Unit at the ̽��ֱ�� of Cambridge, led by Dr James Thaventhiran, examined ABCs from two very different patient groups – one comprised of people with an inherited condition that impairs the activity of their immune systems and a second group comprised of cancer patients taking immunotherapy drugs – as well as from healthy individuals.

Emily Horner, from Thaventhiran’s lab, explained the aim of this research: “By looking at patients’ B cells, we hoped to learn how we could stratify vulnerable patients – in other words, work out whether some patients were at greater risk from infection, even after vaccination, than others.”

̽��ֱ��researchers measured the relative proportion of ABCs compared to healthy B cells, and used a technique known as single cell RNA sequencing to look in detail at the activity of cells. They also teamed up with Dr Nicholas Matheson, from the Cambridge Institute of Therapeutic Immunology and Infectious Disease, to test how these factors influenced the ability of a vaccinated individual’s immune system to neutralise live SARS-CoV-2 virus.

Dr Juan Carlos Yam-Puc, also from the MRC Toxicology Unit, said: “What we found, much to our surprise, was that the age-associated B cells in these very different groups looked the same. ̽��ֱ��key difference was in the amount of these cells – the greater the proportion of ABCs in an individual’s blood, the less effective that individual was post-vaccination at neutralising the virus.”

This could help explain the variability seen within particular patient groups in responses to the vaccine: people with fewer ABCs are likely to respond better to vaccines.

Although the researchers examined ABCs in the context of responses to the SARS-CoV-2 vaccine, they believe that this phenomenon will almost certainly apply more widely, for example to the annual influenza vaccine.

Dr Pehuén Pereyra Gerber, who performed the experiments with live SARS-CoV-2 virus in Matheson’s lab, added: “Looking at blood levels of ABCs could tell us that person A should respond well to a vaccine, while person B might need a stronger vaccine or to be prioritised to receive a booster.”

Thaventhiran added: “Ultimately, this research could lead to the development of a clinical test to predict vaccine efficacy for immunodeficient patients, and for the population more generally.”

̽��ֱ��research was funded by the Medical Research Council, the Medical Research Foundation, and ̽��ֱ��Evelyn Trust.

Reference
Yam-Puc, JC et al. Age-Associated B cells predict impaired humoral immunity after COVID-19 vaccination in patients receiving immune checkpoint blockade. Nat Comms; 27 June 2023; DOI: 10.1038/s41467-023-38810-0

Cambridge scientists have identified a signature in the blood that could help predict how well an individual will respond to vaccines. ̽��ֱ��discovery, published today in Nature Communications, may explain why, even among vulnerable patient groups, some individuals have better responses to vaccines than others.

By looking at patients’ B cells, we hoped to learn how we could stratify vulnerable patients – in other words, work out whether some patients were at greater risk from infection, even after vaccination, than others

Emily Horner

Ed Us

Vaccination

̽��ֱ��text in this work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

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Children with rare genetic disorders more likely to be diagnosed with developmental, behavioural and mental health problems

cjb250 — Wed, 03 Aug 2022 22:30:47 +0000

With the advent of rapid whole genome sequencing, children presenting with an intellectual disability or developmental delay are recommended to have their DNA sequenced to identify the underlying genetic cause.

To capitalise on this recent NHS development, researchers at the ̽��ֱ�� of Cambridge, ̽��ֱ�� College London and Cardiff ̽��ֱ�� established IMAGINE ID, a national UK cohort study that aims to discover how genetic changes affect children and young people’s behaviour, in order to inform better care of families and children now and in the future.

Writing in ̽��ֱ��Lancet Psychiatry today, the researchers have published the results of an analysis of data from almost 2,800 young people with rare genomic variants – changes to their DNA – that are associated with intellectual disability.

Professor Lucy Raymond from the ̽��ֱ�� of Cambridge, the study’s senior author, said: “Thanks to all the families that have taken part in our research, we’ve been able to conduct the largest study to date of the impact of rare genetic variants associated with intellectual disability. What we’ve found from parents is that these children are extremely likely to develop other neurodevelopmental or mental health conditions, which can present additional challenges both to the children and their families.”

All the participants were aged between four and 19 years. Just under three-quarters (74%) had an intellectual disability caused by a duplication or deletion of sections of DNA – a so-called copy number variant (CNV). ̽��ֱ��remaining young people had a disability caused by a single ‘spelling error’ in their DNA – a change in the A, C, G or T nucleotides – referred to as a single nucleotide variant (SNV).

Compared to the English national population, children in the study were almost 30 times as likely to have been diagnosed as autistic. In the general population, 1.2% of people are diagnosed with the condition compared to 36% of the study participants. Similarly, 22% of the study population were diagnosed with ADHD, compared to 1.6% of the general population, meaning that they were more than 13 times more likely to have the condition.

Around one in eight children (12%) had been diagnosed with oppositional defiant disorder, in which children are uncooperative, defiant, and hostile toward others – a rate 4.4 times higher than in the general population.

One in ten (11%) had an anxiety disorder, a 1.5 times increased risk. Rates of childhood depression were significantly lower, at just 0.4% compared with 2.1% of the general population, but this may increase over the next few years as some mental health disorders do not start until later adolescence or early adult life. Almost all of the children (94%) were reported to have at least one significant physical health problem, including disturbed sleep (65%), motor or movement disorders (64%) or seizures (30%).

Dr Jeanne Wolstencroft from Great Ormond Street Institute of Child Health, ̽��ֱ�� College London, said: “Routine genomic testing now allows parents to understand the genetic cause of intellectual disabilities in an increasing number of children but, because so many of these conditions are rare, we still lack information on the impact this has on their children’s future mental health.

“We already know that intellectual disabilities tend to be associated with an increased likelihood of neurodevelopmental conditions, as well as emotional and behavioural difficulties, but we found that where there is an identifiable genetic cause, the likelihood is amplified considerably. This suggests that these children should be provided with early assessment and help where appropriate.”

̽��ֱ��team has also shown for the first time that children with intellectual disability caused by a genetic variant inherited from a family member, are more likely to come from a more deprived socioeconomic background. This suggests that some parents or family members with the same variant may also have unrecognised difficulties that placed them at a social and educational disadvantage. These children were more likely to be diagnosed with a neuropsychiatric condition and were also more likely to exhibit behavioural difficulties.

Professor David Skuse from Great Ormond Street Institute of Child Health, ̽��ֱ�� College London, said: “We hope this work helps improve the targeting of assessments and interventions to support families at the earliest opportunity. We’d like to see better training for health care providers about the wider use and utility of genetic testing. We have identified its potential value in terms of prioritising children with mental health needs for child mental health services, who are currently hugely limited in the UK.”

̽��ֱ��research was funded by the Medical Research Council (part of UK Research & Innovation) and the Medical Research Foundation. Additional support was provided by the NIHR Cambridge Biomedical Resource Centre and the NIHR GOSH BRC.

Reference
Wolstencroft, J et al. Neuropsychiatric risk in children with intellectual disability of genetic origin: IMAGINE - ̽��ֱ��UK National Cohort Study. Lancet Psychiatry; 4 Aug 2022; DOI: 10.1016/PIIS2215-0366(22)00207-3

A major study of children with intellectual disabilities has highlighted the additional challenges that they often face, including a much-increased likelihood of being diagnosed as autistic, as well as Attention Deficit Hyperactivity Disorder (ADHD) and other mental health difficulties.

Thanks to all the families that have taken part in our research, we’ve been able to conduct the largest study to date of the impact of rare genetic variants associated with intellectual disability

Lucy Raymond

PhotoAlto/Laurence Mouton (Getty Images)

Toddler's hands touching tree bark

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

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Experts call for more mental health support for parents of children with genetic learning disabilities

cjb250 — Wed, 11 Mar 2020 00:02:58 +0000

As many as one in 20 families worldwide is thought to include a child with a learning disability, but little is known about how this affects the parents’ mental health and wellbeing. Although some parents experience depression and anxiety, it is not clear why some are at greater risk than others.

Professor Claire Hughes from the ̽��ֱ�� of Cambridge Centre for Family Research, said: “It’s important that we understand why some parents are at greater risk of mental health problems than others. If a parent experiences long-term mental health problems, this could have a knock-on effect on the whole family, affecting partner relationships, the wellbeing of their child with disability, and the experiences of siblings. That’s why interventions are often more successful when they are designed to help parents in order to help children.”

To address this question, Professor Hughes assembled an interdisciplinary team of researchers from the Universities of Cambridge and Birmingham to analyse information from 888 families taking part in the IMAGINE-ID study – a UK-wide project examining the links between genetic diagnoses, learning disabilities and mental health. Parents were asked to rate their everyday feelings and the nature and impact of their child’s difficulties, as well as to provide information about their family’s social circumstances.

One parent who participated in IMAGINE-ID said that professionals tended to focus on the child’s needs and did not consider the wider needs of families: “It’s very much about getting support for your child. At no point were we ever offered any mental health support, even though we have such a massive role to play in bringing up our children. We need support as well.”

̽��ֱ��study data shows that rates of negative symptoms such as worry, anxiety and stress were much higher in the IMAGINE-ID group of parents than in the general population of parents. Mothers in the IMAGINE-ID study – who were more likely to be the main caregiver – were particularly affected. Contrary to evidence from previous studies, social factors did not predict a parent’s risk of low mood and stress: more important were the type of genetic disorder that affected their child, their child’s physical and medical needs, and their child’s behaviour.

For the first time, the researchers were able to demonstrate that the cause of a child’s disabilities is one factor that predicts the emotional wellbeing of parents. A subgroup of genetic disorders is caused by short missing or duplicated sections of DNA (known as ‘copy number variants’). Parents within this subgroup reported that their child’s difficulties had a high level of impact on family life as well as restricting their child’s activities and friendships, and these impacts were the source of their own distress.

̽��ֱ��researchers say there could be a number of explanations for these findings, varying from the complex effects of chromosomal differences on children’s development through to the availability of support for these families. They have called for more multi-disciplinary, family-focused research to determine how genetic diagnoses are linked to parents’ mental health, so that support for families can be improved in future.

Dr Kate Baker, lead author of the research paper, based at the MRC Cognition and Brain Sciences Unit, ̽��ֱ�� of Cambridge, said: “These results suggest that we need to start looking at genetic diagnoses as useful not just for predicting a child’s needs and informing the support that they might receive, but also for predicting the broader impact that the diagnosis will have on their family.”

Francesca Wicks, former research coordinator for IMAGINE-ID and now Family Support and Information Officer for Unique, the rare chromosome and single gene disorder support charity, said: “It’s clear that not enough care and support is being offered to parents before, during and after their child’s diagnosis. ̽��ֱ��help and support offered by organisations such as Unique is incredibly valuable, but much more needs to be done within health and statutory services. Many of the families I have met have expressed feelings of anxiety and depression over the years, which is why we have produced our Carers Wellbeing guide.”

̽��ֱ��IMAGINE-ID study is funded by the UK Medical Research Council and Medical Research Foundation.

Reference
Baker, K et al. Childhood intellectual disability and parents’ mental health: integrating social, psychological and genetic influences. BJPsych; 11 March 2020; DOI: 10.1192/bjp.2020.38

Parents of children with genetic conditions that cause learning disabilities are at risk of mental health problems, suggests new research published today in the British Journal of Psychiatry. ̽��ֱ��teams behind the study have called for greater support for parents whose child receives a genetic diagnosis for their learning disability.

If a parent experiences long-term mental health problems, this could have a knock-on effect on the whole family, affecting partner relationships, the wellbeing of their child with disability, and the experiences of siblings

Claire Hughes

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Parent and child

Researcher profile: Dr Kate Baker

Image: Kate Baker (centre) with research assistant Elise Ng-Cordell (left) and post-doctoral research associate Diandra Brkic (right) on Rare Disease Day

Dr Kate Baker, a researcher at the MRC Cognition and Brain Sciences Unit, decided early on that she wanted to be a scientist as well as a doctor. At the time, she was a medical student and helping out in a brain research laboratory.

“There are just too many unanswered questions about genes, brains, and mental health, and patients deserve better answers and better treatments,” she says. “Initially I learned to study slices of post-mortem brain tissue – then I discovered that doing research with whole people is a lot more fun, even if they are more noisy and complicated.”

Kate says she has been extremely lucky to work with “fantastic” colleagues and research participants who share the same curiosities and motivations – “We want to understand brain development and improve care for children with neurodevelopmental disorders and their families. It’s a slow process but it is also very exciting and rewarding.”

Her research looks at the genetic differences that can affect children’s development by changing the way that their brain grows and functions. “ ̽��ֱ��most surprising aspect is how an extremely tiny change in one gene can have a devastating impact, whilst sometimes much larger genetic changes have only subtle effects which vary a lot from one person to another.”

Kate leads a small research team of psychologists and neuroscientists, but particularly enjoys joining forces with scientists from different research fields who use very different approaches to understand the same core problem, “working together to join the dots and build up a more complete answer”.

One such collaboration is with Professor Claire Hughes from the Centre for Family Research. Cambridge collaborations can begin in unlikely places. “Claire and I started discussing the research questions we have addressed in our new paper after a Sunday morning yoga class, not knowing we would be able to work together to actually find some answers!”

Kate hopes her research will make a difference for children and families affected by severe neurodevelopmental disorders, by changing the way we understand these conditions, and also by improving the treatments and support they can receive.

“Until now, treatments have been mainly ‘symptom-focused’, which don’t always work because the same problems, such as limited communication skills or impulsive behaviours, can come about because of many different underlying reasons. If we had a better understanding of each child’s disorder ‘under the surface’, I hope we can improve their quality of life, even for a small number of patients and families.”

As if this wasn’t enough, Kate and her family have embarked on a challenging project. “My husband, children and I have recently built our own home, on the outskirts of Cambridge. So you’re likely to find me nailing plasterboard, wheelbarrowing mud, making curtains, or (more likely) feeding all the friends and family who have come to help us with the project.”

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