Study sheds light on why immunodeficiency affects only one identical twin

Scientists have long queried the causes of immune disorders in only one of two identical twins with identical genes. New research from the Wellcome Sanger Institute, the Josep Carreras Leukaemia Research Institute in Spain and their collaborators, has found the answer lies in both alterations in immune cell-cell communication and the epigenome, the host of biological processes that regulate how our genes function.

The study, published today (1 April 2022) in Nature Communications, is the first cell atlas to categorise common variable immunodeficiency (CVID) at the single-cell resolution. Researchers found that ‘communication problems’ resulting from defects in B cells and other immune cell types impaired immune response, highlighting a number of pathways that are promising targets for epigenetic treatments. In addition, they also identified major defects in the epigenome.

Common variable immunodeficiency (CVID) encompasses a range of immune disorders caused by a reduced ability to produce protective antibodies, which leaves the individual vulnerable to persistent or repeated infection. These individuals usually have low levels of immunoglobulin, more commonly known as antibodies, due to problems with the B cells that create them.

Though identical twins share the same genome, most will be born with a small number of genetic and epigenetic differences and the number of variations will increase over their lifetime. But where one twin experiences a health problem that their sibling does not, in most cases genetic differences alone cannot explain why this has occurred.

Around 20 per cent of CVID cases can be attributed to a defect in a gene associated with the condition. But with four in five cases remaining largely unexplained, scientists have predicted that other factors must be involved. This was confirmed by a recent study, which linked CVID to DNA methylation, an epigenetic process that turns the level of a particular gene up or down¹.

In this new study, researchers from the Wellcome Sanger Institute and the Josep Carreras Leukaemia Research Institute generated single-cell data to investigate epigenetic factors involved in CVID. Samples were taken from a pair of identical twins, only one of whom suffered from CVID, as well as a wider group of CVID patients and healthy individuals.

Analysis of the identical twin participants found that not only did the sibling with CVID have fewer B cells, but that B cell defects resulted in epigenetic problems with DNA methylation, chromatin accessibility and transcriptional defects in memory B cells themselves². In addition, researchers found massive defects in the cell-to-cell communication required for the immune system to function normally.

Dr Javier Rodríguez-Ubreva, a first author of the study from the Josep Carreras Leukaemia Research Institute, said: “The human immune system is not a static entity and communication between immune cells is vital for it to work effectively. We can see in healthy individuals how cells talk to each other and from there identify where communication breaks down in individuals with common variable immunodeficiency (CVID). In the immune system this cell-to-cell communication is critical to define the ability of B cells to mature and produce antibodies.”

The researchers compared the epigenetic changes and cell-to-cell communication problems found in the twin suffering from CVID against a wider CVID cohort and found that the problems were the same, providing a solid model for characterising the disease. The challenge now will be to use these insights to develop new treatments.

Dr Esteban Ballestar, a senior author of the study from the Josep Carreras Leukaemia Research Institute, said: “This is the first of many studies that will look at common variable immunodeficiency (CVID) and other primary immunodeficiencies in the attempt to identify new therapies for treating these disorders. We already have viable options, such as immunoglobulin replacement therapy, which I would hope can be adapted to address the specific B cell defects that we have identified here.”

As well as immunoglobulin replacement therapy, epigenetic drugs can also be used to treat immune disorders and the findings of this study highlight a number of biological pathways worthy of further investigation for new drug targets.

Dr Roser Vento-Tormo, a senior author of the study from the Wellcome Sanger Institute, said: “This is the first cell atlas to categorise common variable primary immunodeficiencies and will be a valuable contribution to the Human Cell Atlas initiative to map every cell type in the human body. What this study in particular shows is how quickly cell atlas data can be applied to better understand specific health challenges and open up new avenues of treatment.”

ENDS

Contact details:
Dr Matthew Midgley
Press Office
Wellcome Sanger Institute
Cambridge, CB10 1SA
Phone: 01223 494856
Email: press.office@sanger.ac.uk

Notes to Editors:

¹ This previous study is available here: https://www.nature.com/articles/ncomms8335

² Chromatin is a complex of DNA and proteins. It forms the structure in which genetic information is packed.

Publication:

Javier Rodríguez-Ubreva and Anna Arutyunyan et al. (2022). Single-Cell Atlas of Common Variable Immunodeficiency reveals germinal center-associated epigenetic dysregulation in B cell responses. Nature Communications. DOI: https://doi.org/10.1038/s41467-022-29450-x

Funding:

This research was supported by Wellcome; the Josep Carreras Foundation; the Spanish Ministry of Science, Innovation and Universities; UK Biotechnology and Biological Sciences Research Council, the Jeffrey Modell Foundation and the Medical Research Council.

Selected websites:

The Human Cell Atlas (HCA)

The Human Cell Atlas (HCA) is an international collaborative consortium which is creating comprehensive reference maps of all human cells—the fundamental units of life—as a basis for understanding human health and for diagnosing, monitoring, and treating disease. The HCA will impact every aspect of biology and medicine, propelling translational discoveries and applications and ultimately leading to a new era of precision medicine. The HCA was co-founded in 2016 by Dr Sarah Teichmann at the Wellcome Sanger Institute (UK) and Dr Aviv Regev, then at the Broad Institute of MIT and Harvard (USA). A truly global initiative, there are now more than 2,000 HCA members, from 75 countries around the world. https://www.humancellatlas.org

The Josep Carreras Leukaemia Research Institute

The Josep Carreras Leukaemia Research Institute is a public facility belonging to the Generalitat de Catalunya’s CERCA network. It was born in 2010 aimed at fostering biomedical research and personalized medicine in the field of leukaemia and other malignant blood diseases. It is the first European centre exclusively focused on leukaemia and malignant hemopathies, and one of the few existing in the world. The Josep Carreras Institute has five independent but coordinated campus, with its headquarters being at Campus ICO-Germans Trias i Pujol-UAB, in Badalona.

The Wellcome Sanger Institute
The Wellcome Sanger Institute is a world leading genomics research centre. We undertake large-scale research that forms the foundations of knowledge in biology and medicine. We are open and collaborative; our data, results, tools and technologies are shared across the globe to advance science. Our ambition is vast – we take on projects that are not possible anywhere else. We use the power of genome sequencing to understand and harness the information in DNA. Funded by Wellcome, we have the freedom and support to push the boundaries of genomics. Our findings are used to improve health and to understand life on Earth. Find out more at www.sanger.ac.uk or follow us on Twitter, Facebook, LinkedIn and on our Blog.

About Wellcome

Wellcome supports science to solve the urgent health challenges facing everyone. We support discovery research into life, health and wellbeing, and we’re taking on three worldwide health challenges: mental health, global heating and infectious diseases. https://wellcome.org