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According to research around 80% of all patients
diagnosed with autoimmune diseases are women.
Given women’s needs in healthcare have historically been
underserved or flat out ignored, it’s practically a miracle
that we’ve managed to pick up on this disparity, and it’s very real.
Over the years, a lot of explanations have been proposed,
but scientists still haven’t settled on a definitive one.
Emerging evidence is pointing towards a surprising sleeper option.
And it’s a molecule that prevents your
chromosomes from poisoning you.
Let me explain.
[♪ INTRO]
Autoimmune disorders occur when your immune system sees
its own healthy cells as a threat and starts to attack them.
More than 80 autoimmune disorders have been identified,
and basically all of them occur disproportionately in women.
Sort of – wait for it.
For example, lupus is one of the most common
autoimmune disorders, and it has a 9:1 female to male bias.
In the far less common Hashimoto’s thyroiditis,
95% of patients are female.
But there’s a twist to this, and it might be
the key to understanding this whole thing.
See, autoimmune diseases actually don’t
disproportionately affect women, but very specifically
people with two or more X chromosomes.
Generally, people are born with 23 pairs of chromosomes,
22 pairs of non-sex chromosomes or autosomes,
and 1 pair of sex chromosomes, so XX or XY.
People with Klinefelter syndrome have an extra X chromosome,
making them XXY, and may develop some
typically masculine and feminine traits.
People with trisomy X have three X chromosomes,
and develop typically feminine traits.
And folks in both of these groups are more likely
to have certain autoimmune disorders.
It’s also possible to have one X chromosome and that’s it,
in what’s called Turner’s syndrome.
And these individuals are less likely to develop autoimmune disorders,
even though they also develop typically feminine traits.
This gave scientists a pretty big clue that maybe
it was the “dosage” of chromosome X that was responsible
for the increased susceptibility to autoimmune disorders.
Dosage is an odd choice of words in this case,
but it just refers to how much output you’re getting
from any given gene, or “chromosomeful” of genes, as it were.
To understand why this matters, you only need to know that
duplications of most autosomes are fatal,
with the only real exception being three copies of number 21.
So it follows that for genes on your autosomes,
the typical dosage is two, one from each of your parents.
For most genes, the copy on both chromosomes
needs to be expressed for normal functioning.
But it kind of has to work differently for sex chromosomes, since
people with XY chromosomes have inherited only one copy of X.
Y is much smaller than X.
While most autosomes have matching sets of genes,
most of the genes on X don’t have a partner.
So we’ve evolved to only need one copy of our X genes,
but that creates a new problem – now XX people have one too many!
Fortunately, we’ve developed a way to keep
that extra X in check so no extra genes are expressed.
It’s called X inactivation and it means that in every single cell one X –
or two Xs in XXX individuals – is selected to be locked down.
The X chromosome produces a very long RNA molecule called Xist.
Xist recruits 81 protein partners to make a huge complex
that wraps itself around the extra X and silences it.
It does this by making structural changes to the X chromosome,
as well as through epigenetic modifications to regulate
which genes are turned on or off.
To help regulate which genes get expressed more or less.
Some scientists have proposed that leaky
or inadequate X inactivation could be the problem.
The X chromosome has the largest number
of immune related genes in the entire genome.
Some of these genes have been found
to sneak around Xist’s suppression.
Excessive expression of X-linked genes is often seen in people
with lupus who have XX chromosomes, but not XY.
Extra X-linked genes may be even more of an issue if they’re
running amok in the very cells that turn against you -- immune cells.
A 2020 paper reported that female mice with a lupus-like disease
had reduced Xist signals in a subset of immune cells,
and that these cells had too many copies of genes
from the X chromosome being expressed.
Some of these upregulated genes had been implicated
in autoimmunity before, although exactly how this might lead to
autoimmune disorders still needs further investigation.
That makes faulty X inactivation an important line of inquiry
for scientists looking into autoimmune disorders.
But one research group has made a provocative suggestion:
the cause isn’t faulty X inactivation, but the very process itself.
As reported in a 2024 paper, they made a male mouse model
that could express Xist, even though it would
normally only be found in females.
These mouse models also mimicked the symptoms of lupus,
although it had to be induced by the researchers.
And when they did so, the severity of the disease
was much worse in the male mice with Xist.
They also showed that many autoimmune patients
have antibodies for Xist and its friends.
The explanation they proposed is basically this:
Xist is a huge molecule with lots of identical sites
for antibodies to potentially recognize.
When cells die, they explode and release Xist into the bloodstream,
where they’d have ample opportunity to be spotted
by the immune system and for antibodies to bind.
The authors reasoned that, under the right conditions, all of this
self-stickiness would lead to a cascade of immune autoreactivity.
And that doesn’t mean Xist causes autoimmune disease all by itself.
Individuals with XY chromosomes, who don’t make Xist,
still sometimes get autoimmune diseases.
Furthermore, twin studies show that for some autoimmune disorders,
like lupus, as few as 40% of identical twins will both develop
the disease, meaning that genetics can’t be the only factor.
Environmental triggers like components of your diet,
an imbalance of gut microbes, and infections probably
also come into play along with genes.
However, the 2024 study is still a big step forward in understanding
an important aspect of how autoimmune diseases work.
This research has implications for diagnostics too.
If patients have antibodies to Xist, that’d be pretty easy to screen for.
Even better if they have those antibodies before showing
symptoms of disease – if so, that’s a great recipe for early detection.
There’s still a lot of work to do, but after hundreds of years
of these diseases going understudied, it’s exciting
that we’re finally exploring these potential explanations.
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