Nature's major discovery: Why immunodeficiency affects only one of identical twins

New research from the Wellcome Sanger Institute, the Jose Pucarreras Leukemia Institute in Spain and their collaborators finds that the answer lies in altered immune cell-cell communication and changes in the epigenome, which regulates key to the biological process of our gene function

The study, published today (April 1, 2022) in the journal Nature Communications, is the first cellular atlas to classify common variable immunodeficiency (CVID) at single-cell resolution

Common variable immunodeficiencies (CVIDs) include a range of immune disorders caused by a reduced ability to produce protective antibodies, which leaves individuals vulnerable to persistent or repeated infection

Although identical twins share the same genome, most are born with a small number of genetic and epigenetic differences, and the number of variants increases throughout their lives

About 20% of CVID cases can be attributed to genetic defects associated with the disease

In the new study, researchers from the Wellcome Sanger Institute and the Josep Carreras Leukemia Institute generated single-cell data to investigate epigenetic factors associated with CVID

Analysis of identical twin participants found that siblings with CVID not only had fewer B cells, but that B cell defects led to epigenetic problems in DNA methylation, chromatin accessibility, and transcriptional defects in memory B cells themselves

"The human immune system is not a static entity, and communication between immune cells is critical for it to work effectively," said Javier Rodríguez-Ubreva, Ph.

The researchers compared epigenetic changes and cell-to-cell communication problems in twins with CVID with a broader cohort of CVID and found that these problems were identical, providing a solid model for the characteristics of the disease

Dr Esteban Ballestar, the study's senior author from the Jose Carreras Leukemia Institute, said: "This is the first of many studies looking at Common Variable Immunodeficiency (CVID) and other major immune deficiencies to try to find treatments for these diseases.

In addition to immunoglobulin replacement therapy, epigenetic drugs can also be used to treat immune disorders, and the findings of this study highlight some biological avenues worthy of further investigation to find new drug targets

Dr Roser Vento-Tormo, senior author of the study from the Wellcome Sanger Institute, said: "This is the first study of a common primary immunodeficiency A sorted cell atlas will be an invaluable contribution to the Human cell atlas initiative, which maps every cell type in the body

article title

Single-Cell Atlas of Common Variable Immunodeficiency reveals germinal center-associated epigenetic dysregulation in B cell responses