Study sheds light on why immunodeficiency affects only one identical
twin
Date:
April 1, 2022
Source:
Wellcome Trust Sanger Institute
Summary:
Scientists have long queried the causes of immune disorders in
only one of two identical twins with identical genes. New research
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.
FULL STORY ========================================================================== 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 Rodri'guez-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." Notes: 1This 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, the Jeffrey
Modell Foundation and the Medical Research Council.
========================================================================== Story Source: Materials provided by Wellcome_Trust_Sanger_Institute. Note: Content may be edited for style and length.
========================================================================== Journal Reference:
1. Javier Rodri'guez-Ubreva, Anna Arutyunyan, Marc Jan Bonder,
Luci'a Del
Pino-Molina, Stephen J. Clark, Carlos de la Calle-Fabregat,
Luz Garcia- Alonso, Louis-Franc,ois Handfield, Laura Ciudad,
Eduardo Andre's-Leo'n, Felix Krueger, Francesc Catala`-Moll,
Virginia C. Rodri'guez-Cortez, Krzysztof Polanski, Lira Mamanova,
Stijn van Dongen, Vladimir Yu.
Kiselev, Mari'a T. Marti'nez-Saavedra, Holger Heyn, Javier Marti'n,
Klaus Warnatz, Eduardo Lo'pez-Granados, Carlos Rodri'guez-Gallego,
Oliver Stegle, Gavin Kelsey, Roser Vento-Tormo, Esteban
Ballestar. Single-cell Atlas of common variable immunodeficiency
shows germinal center- associated epigenetic dysregulation
in B-cell responses. Nature Communications, 2022; 13 (1) DOI:
10.1038/s41467-022-29450-x ==========================================================================
Link to news story:
https://www.sciencedaily.com/releases/2022/04/220401094835.htm
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