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[ intro ]
Our immune systems are awesome.
I mean, while we’re sitting on the couch
shoving our faces full of Doritos or whatever,
they’re recognizing pathogens and other
things that don’t belong,
and ousting them from our bodies.
And on top of that,
they remember previous intruders,
and make it harder for them to invade again—
all while leaving our cells and the microbes
that help us alone.
Basically, our immune systems are like really
good bouncers
for the happening clubs that are our bodies.
Except for when they’re not.
Sometimes, a body’s immune system mistakenly
decides
its own tissues are foreign—
what immunologists call autoimmunity.
Currently, there are more than
80 autoimmune conditions defined by doctors.
These include a slew of well-known conditions
like lupus,
rheumatoid arthritis, and multiple sclerosis,
as well as lots of more rare ones.
They tend to be chronic and are often debilitating.
And taken together,
they’re a leading cause of death and disability
worldwide—
it’s estimated that from three to ten percent
of people
have an autoimmune condition at some point.
But if you were to put all of the people with
autoimmune conditions in one room,
you’d notice something.
They’re almost all women.
A whopping 75% of U.S. cases of autoimmunity
are in people who identify as women,
and rates are similar in other countries.
And for some autoimmune conditions,
the disparity is even higher.
Which is not only super unfair,
it’s also a scientific enigma.
This gender bias of autoimmunity is considered
one of the great mysteries of medicine.
And it’s one that researchers are fervently
trying to solve,
because it could reveal new ways of treating
these usually incurable and often devastating
conditions.
Now, we’d be remiss if we didn’t mention
that part of the reason—
perhaps even a lot of the reason—
we don’t fully understand these immunological
betrayals is cultural.
Conditions that predominantly affect women
have been historically understudied,
and studied in sexist ways when researchers
have looked at them.
And, historically,
clinicians as a group just haven’t taken
women as seriously—
an issue that persists today.
But also, early work in the field of immunology
threw scientists off for decades.
At the turn of the twentieth century,
biologist and Nobel laureate Paul Ehrlich
performed a series of experiments in animals
which found the animals didn’t develop antibodies
in response to their own tissues.
Those are the Y-shaped proteins your immune
system uses to recognize
and neutralize things like bacteria, viruses,
and parasites.
And if Ehrlich wasn't seeing them, clearly,
autoimmune conditions couldn't be a thing.
He even coined a term based on his results:
horror autotoxicus—
which literally means the horror of self-toxicity.
But the thing with Nobel prize winners is
that sometimes scientists heed them,
when they’re wrong.
And that’s what researchers say happened
with horror autotoxicus and the immunology
community.
Still, over time,
the evidence became too clear to ignore.
Like, in 1946,
a British immunologist developed a test that
could detect self-targeting
or autoantibodies attached
to the surface of a person’s red blood cells.
Then there was the discovery of rheumatoid
factor—
a type of autoantibody that occurs in rheumatoid
arthritis
and some other autoimmune diseases.
Long story short,
these findings piled up until finally, in
1964,
the global immunology community rang in their
acceptance of autoimmunity
as an actual thing with an international conference.
Research into autoimmunity in the decades
since has come a long way.
But the mystery of why these conditions are
so much more prevalent in women remains.
And, just to be clear,
we do mean women,
not just people with two X chromosomes or
a uterus and ovaries.
It’s true that the bulk of autoimmune research
has been conducted on people whose sex assigned
at birth matches their gender identity.
But it’s also been shown that some autoimmune
conditions are more common
than expected in transgender women.
Often, these conditions are associated with
medical transitioning,
but not always.
And some occur at higher rates in people with
what are sometimes called
differences of sex development or intersex
traits—
where parts of their biology like their chromosomes
or genitals
diverge from the typical definitions of male
and female.
In fact, including transgender people and
people with hormonal, developmental, or chromosomal
variations in immunological research
has been an important part of evaluating the
hypotheses
for the bias in autoimmunity we’re about
to discuss.
You see, researchers have been searching for
the root cause of autoimmunity—
one or two nearly universal or nearly universal
things
that are to blame for the immune system going
rogue.
Yes, environmental factors like diet are a
big part of the equation,
but the thinking is that there has to be something
physiological
that makes some people more likely to develop
autoimmunity
when exposed to those environmental factors.
Find that something,
and you’ll find the best way to manage or
even cure autoimmunity.
And that something, presumably,
tends to differ between men and women, and
therefore,
can explain why women are so much more prone.
This is what led to the earliest and perhaps
most immediately obvious hypothesis:
that autoimmunity has something to do with
sex hormones—
the hormones involved in sexual differentiation
and reproduction.
If that’s true, it could mean autoimmune
conditions could be better treated
by tweaking a person’s hormone levels or
the pathways those hormones interact with.
But researchers don’t always agree on which
sex hormones are most important,
and overall, results are mixed.
Like, some think it’s all about testosterone
or other hormones that generally occur at
higher levels in men.
And There is pretty solid evidence
that testosterone suppresses immune function.
And scientists know for sure that increasing
a person’s testosterone level
reduces the number of B cells in their body—
a type of white blood cell that recognizes
foreign stuff,
and the only type of cell that produces antibodies.
So the idea has been that since testosterone
reduces B cells,
and B cells produce antibodies,
that may be why men generally have weaker
immune responses than women...
...the upside to which could be that a less
aggressive immune system
is also less likely to misplace its attacks.
Like, one 2018 study looked at hormones and
key components of the immune system
in cisgender and transgender volunteers
as well as people with atypical sex chromosomes.
The researchers found that even when accounting
for different combinations of sex chromosomes,
higher testosterone levels were associated
with less interfereon alpha—
an immunological protein suspected to play
a role in autoimmune conditions like rheumatoid
arthritis.
But that’s just one study,
and research connecting hormone levels to
autoimmune conditions is kind of all over
the place.
Other studies have suggested estrogens
or other hormones that tend to be higher in
women matter more.
And some studies have pointed out that even
if hormones modulate these conditions,
they’re probably not what causes them.
So many researchers think there’s something
else at play—
like, perhaps, sex chromosomes.
Those are the chromosomes which help steer
sex development and sex hormone levels.
Males usually have an X and a Y chromosome,
while females usually have two Xs.
But these chromosomes don’t just affect
the differentiation of gonads or levels of
hormones.
For example, the human X chromosome has more
immune system related genes
than any other chromosome.
And it’s possible that autoimmunity somehow
stems from those genes
in a way that isn’t dependent on sex hormones.
That would explain why anyone can develop
autoimmunity,
because everyone has an X chromosome.
And, if X-linked genes are somehow the ultimate
cause of autoimmunity,
it would also make sense that people with
two Xs are more prone to it—
whether or not they’re women.
There is evidence that’s the case, too.
For example, autoimmune conditions are also
more common in men with Klinefelter’s syndrome—
where they have two X chromosomes and a Y
chromosome.
In fact, the proportion of people with Kleinfelter’s
syndrome is 17 times higher
if you just look at men with Sjögren’s
syndrome—
an autoimmune condition which affects salivary
and tear glands—
than if you look at men in the general population.
But why the X chromosome predisposes people
to autoimmune issues is up for debate,
and there are several related-but-separate
hypotheses.
One idea is that the overproduction of certain
proteins somehow triggers autoimmunity—
which would be why having two X chromosomes
increases the odds,
but isn’t required.
And there has been some evidence for this
from mouse models of multiple sclerosis—
a condition where the immune system attacks
the brain and spinal cord.
If confirmed in people,
that could indicate that the key to solving
autoimmunity
is to somehow reduce the abundance of proteins
produced by genes on the X chromosome .
But most X-linked genes aren’t expressed
more in cells with two Xs.
About 85% of the genes from the extra X are
turned off in each cell.
So, some scientists think things related to
X chromosome inactivation
better explain autoimmunity.
There’s evidence that cells exposed to stress
can inadvertently scramble a bit of the inactive
X chromosome,
for example; that causes them to spit out
proteins
that the immune system sees as foreign.
And if that’s why the immune system is engaging
in friendly fire,
then finding a way to prevent the production
of those scrambled bits
or remove them quickly could help.
Autoimmunity could also have something to
do with how the inactivation takes place.
Which X chromosome gets shut off in each cell
is supposed to be random,
so each X gets more or less equal play in
the body.
But that’s not what always happens.
In some people, well over half of the cells
have the same active X—
a phenomenon known as skewed X chromosome
inactivation.
And this kind of skew has been linked to a
variety of autoimmune conditions.
That might be because the genetic driver of
this skew also somehow triggers self-targeting—
even, perhaps, in people with only one X.
So, treating autoimmunity might be a matter
of figuring out what causes skewing and why.
Or, it might be more about the degree of skewing.
Sometimes, inactivation can be really skewed—
like, more than 90% of a person’s tissues
have the same X switched on.
If that happens,
it’s possible that the immune system doesn’t
see the slightly-different versions of proteins
produced by the other X
often enough to recognize them as coming from
the same person.
So when the immune system does
come in contact with those cells with the
other X activated,
it thinks they’re foreign.
If that’s true,
there might be a way to teach the immune system
that those cells aren’t the enemy,
sort of like how some allergy treatments
slowly teach the immune system not to overreact
to allergens.
But, some studies suggest the presence of
one or two X chromosomes
is less important than the presence of a Y.
You know, just to make things messy.
After all, the Y chromosome has its own immune-related
genes.
And the Y chromosome itself is a bit weird
because it has more repetition than other
chromosomes.
One person’s Y might have just two copies
of a specific gene or piece of a gene,
while another has way more.
They’re called multicopy genes.
And v.
But research in this area is still really
new, so scientists aren’t sure what about
them drives that result.
Still, if genes on the Y chromosome have something
to do with autoimmune susceptibility,
that could reveal unexpected treatments—
even for people who don’t have one.
So the secrets to solving autoimmunity could
lie in further study of the Y chromosome.
Or the X chromosome.
Or hormones.
The thing is, after decades of research,
there just doesn’t seem to be a single thing
that connects all cases of autoimmunity.
It’s possible—even likely—
that different conditions arise for different
reasons,
so you simply can’t lump lupus in with,
say, rheumatoid arthritis.
But there might be bigger evolutionary dynamics
at play—
something that does bring together all these
seemingly different explanations.
One of the most recent hypotheses to explain
autoimmunity
is that it all of this ultimately comes down
to pregnancy…
or lack thereof.
The researchers who proposed the idea have
dubbed it
the pregnancy compensation hypothesis.
And basically, it posits that autoimmune conditions
are so prevalent now
because people with uteruses are spending
less of their lives pregnant.
Pregnancy is a remarkable feat for the human
body—
and not just because it means producing a
new human.
It means people have to harbor cells that
are half-foreign for months
without their immune systems ousting them.
That could be what drove differences in how
immune systems function
between people with uteruses and people without—
whether those differences are enacted by sex
chromosome genes, hormone levels, or whatever.
But more importantly,
this might suggest that being pregnant alters
the immune system
in a way that helps rein in over-eager immune
cells.
And the total number of pregnancies per person
has dropped dramatically
in just the last 50 years.
So, it could be that a system that evolved
for handling lots of pregnancies
has gotten thrown out of whack without them.
That would explain why these conditions are
so prevalent now
and seem to be becoming more prevalent over
time.
This is a new idea, so it hasn’t really
been tested yet,
but immunologists seem to agree that it’s
promising.
And if autoimmune conditions are ultimately
tied to pregnancy,
there could be a whole other suite of treatments
to consider.
I mean, not just getting pregnant, but science
is awesome,
so there might be ways to reap the immune
benefits without having kids,
like mimicking the molecular pathways that
occur during pregnancy.
So there you have it, or maybe, there you
don’t have it.
We still don’t fully know why women are
so much more likely
to have autoimmune conditions than men.
But the good news is that the investigation
is well underway.
and the reason we haven't figured it out
is because it's very complicated
Thanks for watching this episode of SciShow!
And thanks to Kyle, Tim, Anna, Karla,
and every other patron and supporter who has
asked us about
autoimmune conditions over the years
as your questions inspired this episode.
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it!
Fasthosts is a web hosting company based in
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Since Fasthosts wants to support all kinds
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Released in 1964,
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[ outro ]
