27 April 2022

Scientists have shed light on why certain immune disorders sometimes only affect one of identical twins. New research led by the Wellcome Sanger Institute and the Josep Carreras Leukaemia Research Institute in Spain, suggests the answer lies in both alterations in immune cell-to-cell communication and the epigenome.

The study, published last week in Nature Communications, also provides the first cell atlas to categorise common variable immunodeficiency (CVID) at the single-cell resolution, the researchers say.

Communication problems resulting from defects in B cells and other immune cell types were found to impair immune response, and this revealed a number of pathways that are promising targets for treatments. The researchers also identified major defects in the epigenome – the range of biological processes that control how our genes function.

Although identical twins share the same genome, most are born with a small number of genetic and epigenetic differences. However, if one twin experiences a health problem and their sibling does not, genetic differences alone cannot explain why this has occurred in most cases.

About 20% of CVID cases are attributed to a defect in a gene associated with the condition, but scientists believe other factors must be involved. This was confirmed by a recent study that linked CVID to DNA methylation.

In this new study, researchers 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 twins found the sibling with CVID had fewer B cells, and that B cell defects resulted in epigenetic problems with DNA methylation, chromatin accessibility and transcriptional defects in memory B cells themselves.

Massive defects in the cell-to-cell communication required for the immune system to function normally were also found.

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 the problems were the same, providing a solid model for characterising the disease.

The challenge, they say, will be to use these insights to develop new treatments.

Senior author Dr Esteban Ballestar, 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.”

Source: Rodríguez-Ubreva J, Arutyunyan A, Bonder MJ, Del Pino-Molina L, Clark SJ, de la Calle-Fabregat C, Garcia-Alonso L, Handfield L-F, Ciudad L, Andrés-León E, Krueger F, Català-Moll F, Rodríguez-Cortez VC, Polanski K, Mamanova L, van Dongen S, Kiselev VY, Martínez-Saavedra MT, Heyn H, Martín J, Warnatz K, López-Granados E, Rodríguez-Gallego C, Stegle O, Kelsey G, Vento-Tormo R & Ballestar E (2022) “Single-Cell Atlas of Common Variable Immunodeficiency reveals germinal center-associated epigenetic dysregulation in B cell responses.” Nature Communications, doi: 10.1038/s41467-022-29450-x

Link: https://www.nature.com/articles/s41467-022-29450-x

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