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Study sheds light on why immunodeficiency only affects one identical twin

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Scientists have long wondered about 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 Leukemia Research Institute in Spain and their collaborators has found that the answer lies both in alterations in immune cell-cell communication and in the epigenome, the host of biological processes that regulate how our genes work.

The study, published today (April 1, 2022) in Nature Communication, is the first cell atlas to categorize common variable immunodeficiency (CVID) at single-cell resolution. The researchers found that ‘communication problems’ resulting from defects in B cells and other types of immune cells impair the immune response, highlighting a number of pathways that are promising targets for epigenetic treatments. Furthermore, 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 makes the individual vulnerable to persistent or repeated infection. These people usually have low levels of immunoglobulins, more commonly called antibodies, due to problems with the B cells that create them.

Although 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 when a twin experiences a health problem that his sibling does not, in most cases, genetic differences alone cannot explain why it happened.

About 20% of CVID cases can be attributed to a defect in a gene associated with the disease. But with four out of five cases remaining largely unexplained, scientists predicted that other factors must be involved. This was confirmed by a recent study, which linked CVID to DNA methylation, an epigenetic process that ups or downs the level of a particular gene.1.

In this new study, researchers from the Wellcome Sanger Institute and the Josep Carreras Leukemia 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 from a larger group of CVID patients and healthy individuals.

Analysis of identical twin participants revealed that not only did the brother with CVID have fewer B cells, but the B cell defects lead to epigenetic issues with DNA methylation, chromatin accessibility and transcriptional defects in memory B cells themselves.2. Additionally, the researchers discovered massive defects in the intercellular communication necessary for the normal functioning of the immune system.

Dr Javier Rodríguez-Ubreva, first author of the study from the Josep Carreras Leukemia Research Institute, said: “The human immune system is not a static entity and communication between immune cells is vital to that it works efficiently. individuals how cells talk to each other and from there identify where communication breaks down in individuals with Common Variable Immunodeficiency (CVID). B cells to mature and produce antibodies.”

The researchers compared the epigenetic changes and cell-to-cell communication problems found in the twin with CVID with a larger CVID cohort and found that the issues were the same, providing a strong model for characterizing the disease. The challenge now will be to use this knowledge to develop new treatments.

Dr Esteban Ballestar, lead author of the study from the Josep Carreras Leukemia Research Institute, said: “This is the first of many studies that will examine common variable immunodeficiency (CVID) and other primary immunodeficiencies with the aim of identifying new therapies for the treatment of these disorders We already have viable options, such as immunoglobulin replacement therapy, which I hope can be adapted to treat specific defects B lymphocytes that we have identified here.

In addition to immunoglobulin replacement therapy, epigenetic drugs can also be used to treat immune disorders and the results of this study highlight a number of biological pathways meriting further investigation for new drug targets.

Dr Roser Vento-Tormo, lead author of the Wellcome Sanger Institute study, said: “This is the first cell atlas to categorize common primary variable immunodeficiencies and will be a valuable contribution to the Human Cell Atlas initiative to map each 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 conditions and open up new avenues of treatment.

Remarks:

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.

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, Jeffrey Modell Foundation and Medical Research Council.