Updated:
Keep
Scientists have long wondered what causes immunological disorders in only one of two identical twins, with identical genes. Now, research by the Josep Carreras Leukemia Research Institute, the Wellcome Sanger Institute (United Kingdom) and their collaborators has discovered that the answer lies both in alterations in immune cell-cell communication and in the epigenome, the set of biological processes that regulate the functioning of our genes.
The study, published in Nature Communications, is the first cell atlas to classify 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 impaired the immune response, highlighting a number of pathways that are promising targets for epigenetic therapies.
In addition, they also identified important defects in the epigenome.
The common variable immunodeficiency (CVID) encompasses a series of immune disorders caused by a reduced ability to produce protective antibodies, leaving the individual vulnerable to persistent or repeated infections. These individuals often have low levels of immunoglobulins, better known as 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 throughout their lives. But when a twin experiences a health problem that her brother doesn’t, in most cases genetic differences alone can’t explain why it happened.
About 20% of IDCV cases can be attributed to a defect in a gene associated with the disease. But since four out of five cases remain largely unexplained, scientists have predicted that other factors must be at play. This is confirmed by a recent study, which relates IDCV to DNA methylation, an epigenetic process that increases or decreases the level of activation of a certain gene.
In this new study, researchers generated cell-resolution data to investigate the epigenetic factors involved in CVD. Samples were taken from a pair of identical twins, only one of whom had the disease, as well as from a larger group of disease patients and healthy individuals.
Analysis of identical twin participants found that not only did the sibling with CVID have fewer B cells, but the B cell defects led to epigenetic problems of DNA methylation, chromatin accessibility, and transcriptional defects in the B cells themselves memory In addition, the researchers discovered massive defects in the cell-to-cell communication necessary for the immune system to function normally.
Javier Rodriguez-Ubreva, first author of the study, points out that “the human immune system is not a static entity and communication between immune cells is vital for it to function effectively. We can see in healthy individuals how cells communicate with each other and, from there, identify where communication breaks down in individuals with CVID common variable immunodeficiency. In the immune system, this cell-to-cell communication is critical in defining the ability of B cells to mature and produce antibodies.”
The researchers compared the epigenetic changes and cell-to-cell communication problems detected in the twin suffering from CVID with a larger cohort of CVID and found that the problems were the same, providing a robust model for characterizing the disease. The challenge now will be to use this knowledge to develop new treatments.
For Esteban Ballestar, lead author of the study, “this is the first of many studies that will analyze IDCV and other primary immunodeficiencies in an attempt to identify new therapies to treat these disorders. We already have viable options, such as immunoglobulin replacement therapy, that I hope can be tailored to treat the specific B-cell defects we’ve identified here.”
Besides the immunoglobulin replacement therapy, epigenetic drugs can also be used to treat immune disordersand the results of this study highlight a series of biological pathways that deserve to be investigated in search of new pharmacological targets.
“This is the first cell atlas to classify common variable primary immunodeficiencies and will be a valuable contribution to the Human Cell Atlas initiative to map all cell types in the human body. What this study shows in particular is how quickly data from the cell atlas can be applied to better understand specific health problems and open up new avenues of treatment,” concludes Roser Vento-Tormo, lead author of the study from the Wellcome Sanger Institute. .
See them
comments