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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—