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Why Are Women and Men So Different in Autoimmune Disease?

That last post on vaccine reactions mentioned autotimmune disease several times, and that brings up a question that’s been outstanding for many decades now. If you look at the distribution of most autoimmune syndromes in the population, you find many obvious differences between male and female incidence rates. Guillain-Barré (discussed yesterday) is less common in women (about 35/65 overall) particularly in older patients, but the younger patients (less common overall) tend to be even or even slightly more female. Ankylosing spondylitis is slightly less common in women than men (45/55) and type I diabetes is about 50/50. But multiple sclerosis is about 75/25 towards women, rheumatoid arthritis is around 80/20, lupus and Hashimoto’s are about 90%, and Sjögren’s is even higher than that. I’m unaware of any autoimmune diseases that affect men over women to those degrees, and when you add up the total number of diseases and the total number of patients, it’s clear that women are far more affected.

Why is that? A lot of work has gone into that question over the years, and as this overview at Nature shows, two of the big obvious possibilities have a lot of evidence behind them: differences in hormone levels and the presence of two X chromosomes (and the genes on them). There are definite fluctuations in some of these diseases as hormone levels change (puberty, pregnancy, menopause), although the details are still being argued out. Which hormones are involved, and are the problems due to an excess of some or to a deficit of others? But there are also clear effects from the X chromosome. Indeed, if you engineer mice to have otherwise identical hormone levels but just bring in an extra X chromosome, they show up more frequently with conditions like lupus. The same thing happens in Klinefelter syndrome in humans, where a male ends up with an extra X chromosome.

So it’s not either/or; both of these factors contribute. And an underlying adaptation might be behind both – the immune system adaptations needed during pregnancy. A pregnant woman is devoting her metabolism to carrying a ever-larger and more complex fetus that is immunologically different from her own tissues, so the immune system clearly has a lot of delicate work to do. Evolutionarily, immune attacks on one’s developing progeny is surely a bad choice, but lowering the immune defenses too much for the mother during the same period is not going to work out well, either. You’re linking directly into the driveshaft of selection pressure either way, and as the Nature article makes clear, we are far from understanding the details of the solutions that have been worked out over the eons. Developmental biology and immunology are both notorious jungles of thickly overgrown pathways and interconnected systems, so their intersection is going to be extremely hard to comprehend.

But one theory is that since women in general spend less of their lives in pregnancy in modern times than they did during the vast stretches of evolutionary time, that the various fine-tunings of the immune response that go on during pregnancy (often mediated, it is believed, by placental tissue) are infrequent enough to throw the balance over towards autoimmunity. That makes for a neat story, and it appears that autoimmune diseases have increased in areas with lower fertility, but there’s a lot more to be worked out. The article describes studies that are looking at large repositories of medical data, trying to correlate autoimmune diagnoses with number of pregnancies, how young a person was at first childbirth, comparisons with women who did not have children, and so on. Of course, you can also ask why some autoimmune syndromes don’t respond in this direction as well: what is it about older men that makes them at greater risk for Guillain-Barré, or what is is about older women that protects them?

It would not surprise me if as we learn more about these things that we find that autoantibody status is a really significant variable in human health and disease. Obviously that’s the case with outright autoimmune disease, but I would have to think that there are a great many people who seem phenotypically average until the right (or wrong!) stimulus comes along. They might be more likely to develop rheumatoid arthritis as they age, or are more likely to have side effects like Sjögren’s syndrome in response to particular drugs, or are at greater risk for something like Guillain-Barré in response to an otherwise unremarkable respiratory viral infection. Perhaps (as that link above suggests) they are at greater risk for severe disease symptoms when infected by an ordinary transmissible virus as well. Many people have wondered about these situations and others, but the challenge has been to get enough understanding to do something about any of them in advance. I hope that we’re getting there.

36 comments on “Why Are Women and Men So Different in Autoimmune Disease?”

  1. happy ITP reader says:

    Pulmonary arterial hypertension is about 75/25 F/M – maybe there are alternative potential common underpinnings than autoimmunity to many of these disorders?

    1. Koss says:

      What about the historic F/M split of smoking?

      1. Snupsnus says:

        Are you suggesting smoking might be… protective?

        1. NKW says:

          It actually is known to be protective in Ulcerative Colitis, probably because it is immunosuppressive

  2. Florian says:

    Anecdotally, and somewhat counter to the theory discussed in the article, I can’t help but wonder if my wife’s pregnancies triggered her autoimmune disease.

    1. Amanda says:

      it’s pretty well known that women often exhibit autoimmune disease suppression during pregnancy and often exhibit flairs or even autoimmune onset postpartum; last I remember reading it was thought that the sudden loss of immune dampening that happens during pregnancy was thought to be a triggering event postpartum.

      1. michael a. kiener says:

        My late wife presented symptoms of SLE in her early twenties. One of the most interesting was that she flared when our three children were conceived. By the third one, we coined the flare as a morning after…. event!
        I have often wondered why SLE is very much a flare/remission cycle illness. To me it would suggest a part of an immune cycle is interfered with and then corrected. Also why are there so many nitrogen rich compounds associated with SLE, especially canavanine, that induce, usually reversible SLE symptoms. Could this be a clue to an SLE mechanism?

    2. JonathanN says:

      I had a partner who developed MS immediately after giving birth.

      1. JDK says:

        My wife was diagnosed with MS about 6 months after giving birth but she was exhibiting transient MS symptoms since her teens. Prior to getting pregnant, her doctor sent her for evoked potential tests (didn’t explain why) but these came back equivocal. World distribution of MS is high in countries with significant British/Northern European populations, maybe some common dual X mutation?

        1. eyesoars says:

          I gather that it’s also regional: where people spend their teen years is reflected directly in incidence: the farther north, the greater the (lifelong) incidence.

  3. Henry says:

    Here is an article looking at a X chromosome located amplifier of the immune system:
    https://pubmed.ncbi.nlm.nih.gov/29374079/
    Interesting that they found that this factor doesn’t always get inactivated.

  4. David says:

    Myasthenia gravis has a peculiar distribution: under age 50, females are affected more than males; over age 50 the pattern is reversed and males are affected more often than females.

  5. In Vivo Veritas says:

    Derek, you forgot Scleroderma (aka Systemic Sclerosis). ~30 persons per million population per year & ~125,000 active cases in the United States. By far the most fatal of all the rheumatologic diseases, and ~80% of patients are female. It may be an oversimplification, but the thought is that the same immune flexibility that allows the germination and development of a parasite sharing only 1/2 the DNA of the host (AKA, a da baby), predisposes females to other, less tolerable immune insults or more susceptible to immune avoidance of pathogenic “self” cells.

    1. regdoug says:

      Considering that you include “veritas” in your name, you may want to use the word “parasite” more accurately, since it describes a relationship between different species, not a relationship between a female and da baby

      1. In Vivo Veritas says:

        Regdoug, you must be fun at parties. That’s what’s called a joke. 😉

  6. steve says:

    In general women have more robust immune systems; this has been known since the 1940’s and is true throughout the animal kingdom all the way to sea urchins and involving both the innate and adaptive immune systems. Susceptibility to autoimmune disease is simply the flip side of that.

    1. yfp says:

      Once upon a time , I was studying lupus and had direct experience in mice. When injected with BSA-DNP ( antigen), female mice produced on average 10 times more anti DNP antibodies than male mice.

  7. Alia says:

    Hope you don’t mind my correction but it’s Klinefelter syndrome, not Kleinfelter.

    1. Derek Lowe says:

      Not at all – fixed!

      1. Wallace Grommet says:

        It’s the difference between Calvin and a little night music

  8. Siddharth Dasgupta says:

    Interesting sex differences.. my sister-in-law and the lady next to our house – both have Hashimoto’s.
    Also preponderance of women in my wife’s family with arthritis! And thinking widely in our social circle also – mainly women come to mind!

  9. cynical1 says:

    In people under 50, ALS is much more common in men (about 70/30). It evens out over age 50 almost as if those hormones are somewhat protective.

  10. Aidan Chappuis says:

    Do we know if any of this has to do with an extra X simply leading to more possible antibody/receptor shapes? Sorry if this is a stupid question

    1. Derek Lowe says:

      Not quite sure what you’re getting at, but having an extra X chromosome would provide duplicate genes for everything on it, for sure. That said, most of these get silenced – but not all of them. And apparently that pattern of silencing, and the differences in it between different people, may well be part of the answer here.

      1. Vader says:

        Is there any known association of autoimmune diseases in women with the degree of skewed X-inactivation?

        1. sgcox says:

          Good question – but it will require really substantial and very expensive study.
          The link kindly provided above by Harry
          https://pubmed.ncbi.nlm.nih.gov/29374079/
          is a very interesting paper and indicates it can be done but single cell proteomics on a proper large patient numbers with proper controls ??

  11. Jordan says:

    This is a timely review Derek — thank you for sharing it.

    Our daughter developed Juvenile Idiopathic Arthritis (JIA) at very young age. Her case was mild, as these things go, but it took several rounds of treatment to make it go away, culminating in weekly methotrexate injections at age 3. It can be very bad, in some kids. We are thankful that, in our daughter’s case, it appears to be gone for good.

    Despite those affected being very young (usually many years before puberty), JIA still affects girls far more than boys — the ratio is something like 5:1. This lends credence to the idea that it is related to gene expression on the X-chromosome, rather than hormones per se.

  12. aairfccha says:

    “But one theory is that since women in general spend less of their lives in pregnancy in modern times than they did during the vast stretches of evolutionary time, that the various fine-tunings of the immune response that go on during pregnancy (often mediated, it is believed, by placental tissue) are infrequent enough to throw the balance over towards autoimmunity.”

    In other words, there might actually be a reason to bring the pregnancy substitutes from “Brave New World” from literature to reality?

  13. bewick says:

    it begs the question should all clinical trials be run on men and women separately ?

  14. ROBERT BROMMAGE says:

    Another autoimmune curiosity is that these diseases can be transient. I am a male who developed both autoimmune hemolytic anemia and systemic sclerosis during my late 50s. Anemia was successfully treated with 2 rounds of prednisone and has not returned. I also had Rituximab infusion without any acute effect. SSc appears in different versions and I have minimal skin involvement. My pulmonary fibrosis never progressed beyond what was observed at the initial diagnosis. I am now 70. One sister has three autoimmune conditions: ongoing thyroid replacement therapy and experienced transient autoimmune hepatitis and two episodes of vasculitis. Our immune systems are certainly complex.

    1. Anonsters says:

      Truth.

      I’m in my late-30s. I got the flu. The flu somehow caused or led to an activation of CMV. Those in contamination led to immune thrombocytopenia (my immune system ate all my platelets—and by “all” I mean I was in the emergency room with an unstoppable nose bleed and 0 platelets reported (which doesn’t mean literally 0 platelets but you get the point)).

      After getting it under control, I had wild platelet number swings that typically started to crater after a week or two, leading to lots of IVIG. After a four-week course of Rituxan, my platelet levels steadily rose and I haven’t had any fluctuations or drops for 2 years now. My hematologist talks about how they can see certain patterns in clinical indicators and treatment outcomes, but there’s no real explanation for any of it. They don’t even know why Rituxan actually works for it in some cases and not others. Nor do they really even understand the Rituxan mechanism (they know it’s anti-CD-20, which takes out most of your B cells except for very early in the hematopoesis process and for plasma B cells, but that’s about all they know).

      1. Anonsters says:

        One addition…

        After getting this all under control, I had the reward of getting to get some dental work finished.

        I told the dental assistant about the delay, and she was like, “You’re kidding! I’ve had four kids, and ITP has been an issue for me every time I get pregnant.”

        Heh.

      2. Cachi says:

        Wow thanks both for sharing your stories. Autoimmune diseases are indeed a very complex topic.

        Also happy to hear that you’re doing better!

  15. debinski says:

    Autoimmune liver diseases are also much more common in women: for autoimmune hepatitis type 1 it’s 4:1, type 2 it’s 10:1 and for primary biliary cholangitis (PBC) the ratio is estimated at 9:1 or greater (22:1 in one study).

  16. GOP says:

    Very interesting thread. Thank you as always Derek.

    My understanding is that a huge part of the issue is oestradiol itself. When I was a first year graduate student (some time ago….) our lab was involved with this. Now, time clouds and all that, but I remember a key experiment being in BW-F1s where male and female mice were castrated and transplanted with peristaltic pumps releasing an estrogen and an androgen, respectively. The estrogen-supplemented, castrated males developed murine lupus to the same degree as intact females, while the androgen-supplemented castrated females were protected.

    It no longer seems to be widely appreciated that lymphocytes from males have E2 receptors and that this modifies their responses – Th and monos/macs in particular.

    An excellent investigator at Cleveland Clinic continues in this field and her work is worth a look (eg PMID: 24477163)

    1. GOP says:

      so.. it turns out that while our lab may have repeated the experiment, the original work was by Roubiniann and Talal PMID: 308087. My apologies!

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