Inborn
immunodeficiencies are rare and often vary in severity.
“Immunodeficient children frequently contract infections of the upper
airways,” says an author. The illnesses are often caused by Epstein-Barr
virus, cytomegalovirus, or Pneumocystis jirovecii,
a pathogen that causes pneumonia. These are all infections that
physicians regularly see in other patients with immunodeficiencies.
The
seven patients in this study also suffer from these infections. When
the researchers delved deeper, they found that the children’s immune
systems shared some similarities: “All the children have too few
antibodies in their blood and very few B cells, which normally produce
the antibodies. They also have fewer T cells than healthy individuals,
and the T cells they do have function less well,” says the author.
Alongside B cells and antibodies, T cells are an important pillar of the
immune system.
In
many children who are born with an immunodeficiency, the cause of the
condition is unknown. Today, though, genome sequencing can help shed
light on it. This was how the study’s authors discovered the T95R
mutation in IRF4. By collaborating closely in international networks,
the researchers traced the genetic cause of the disease in these
children from unrelated families to the same point mutation. This makes
them the index patients – the first described cases – for this
deficiency. The consortium was also able to produce the same syndrome in
mice by specifically mutating the Irf4 gene. This allowed the researchers to gain a more detailed understanding of the errors of immunity caused by IRF4.
The
T95R mutation is only ever found on one of the two copies of the
genome. And although the patients also always produce healthy IRF4, they
all develop the immunodeficiency. “The biology of the mutation
effectively beats the biology of the healthy form,” says the author.
Genome analysis of the families revealed that the index patients didn’t
inherit the mutation from their parents. Rather, it occurred
spontaneously (de novo) in the germline or during early embryonic development.
The
mutation in transcription factor IRF4 occurs at the precise location
where the protein binds to DNA. Usually, the amino acid threonine (T) is
found here, but in the mutation it is replaced by arginine. “In
conjunction with other factors, the mutation changes IRF4’s affinity for
DNA,” says the author. This means that, as well as binding to known DNA
binding sites with varying degrees of strength depending on the
context, the mutated IRF4 protein also binds to parts of the genome that
it shouldn’t be involved in at all – sites that the normal variant of
the protein (the wild type) would never bind to. Bioinformatics analyses
allowed the researchers to identify these new binding sites. They
describe the mutation in their paper as “multimorphic” because as well
as blocking certain genes, it also activates others – and even new ones.
Depending
on the type and severity of an inborn immunodeficiency, patients might
undergo stem cell transplants or receive regular antibody injections
throughout their lives. “Now our study suggests that it would be
possible to change a mutated transcription factor’s binding sites
without affecting the healthy variant,” says the author.
The
T95R mutation in IRF4 will now be added to the catalogue of genes used
to diagnose inborn immunodeficiency. Interestingly, IRF4 also plays an
important role in the development of certain types of blood cancer,
which the lab is also investigating.
https://www.science.org/doi/10.1126/sciimmunol.ade7953
http://sciencemission.com/site/index.php?page=news&type=view&id=publications%2Fa-multimorphic-mutation&filter=22