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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.