Why are autoimmune diseases so much more common in women?

The pattern is hard to ignore

I’m not implying that every autoimmune disease is more common in women. But for many of them, the difference is striking.

Lupus is probably the clearest example. Women are affected far more often than men. The same is true for conditions like rheumatoid arthritis, Sjögren’s disease and several autoimmune thyroid disorders.

So this is not just a small statistical quirk. Something about female biology seems to shift the way the immune system behaves.

Our immune system has to walk a very fine line

Your immune system needs to react quickly when something dangerous shows up, whether that is a virus, a bacterium or anything else that should not be there. But it also has to be just as good at knowing what to leave alone. Your own cells. Your own proteins. Your own tissues.

That ability to leave the body’s own molecules alone is called self-tolerance.

In autoimmune disease, the immune system starts reacting to something that is actually part of the body. What gets attacked depends on the disease.

In rheumatoid arthritis, the joints are heavily affected. In multiple sclerosis, the immune system targets structures in the central nervous system. In lupus, the response can involve several different organs.

Although these are all very different conditions, they share the same basic problem: the immune system has started treating part of the body as if it were the enemy.

Women’s immune systems are not simply "weaker" or "stronger"

On average, women can mount stronger immune responses to some infections and vaccines than men. That can be an advantage. It may mean producing more antibodies or responding more strongly when the body encounters a pathogen.

However a stronger response does not necessarily mean a better one. The immune system has to react strongly enough when there is a real threat, without letting that response turn against the body’s own cells.

Researchers think that some of the same biology that helps women mount stronger immune responses might also make this balance easier to disrupt.

One of the most interesting pieces of the puzzle may actually be the X chromosome.

The X chromosome...

Most women have two X chromosomes, while most men have one X and one Y.

At first, that sounds pretty straightforward. But having two X chromosomes creates a small biological problem: if both were fully active, some genes would end up being expressed twice as much. So very early in development, cells mostly switch one X chromosome off. This is called X-chromosome inactivation.

You would think that solves the problem completely. One X stays active, the other stays quiet... Except the "quiet" X is not completely quiet. Some genes escape this shutdown and remain active on both X chromosomes.

And a number of those genes are involved in how the immune system works! And that is one reason the X chromosome has become such an interesting place to look for answers.

TLR7

TLR7 is a gene found on the X chromosome. It helps immune cells detect single-stranded RNA, which can be an important warning sign during some viral infections.

So, in simple terms, TLR7 is part of the body’s alarm system.

What makes it interesting is that in some female immune cells, TLR7 can escape X-chromosome inactivation.

That means those cells may use TLR7 from both X chromosomes instead of just one.

And that matters because TLR7 is also strongly linked to lupus.

If this pathway becomes too active, it can increase inflammation, activate B cells and boost antibody production. Those are all useful responses when the immune system is fighting a real threat, but they can become a problem if the immune system starts reacting to the body’s own material.

And I know you might be thinking, what is the big deal about having an extra copy of a gene?

Usually, nothing bad happens. But with genes like TLR7, an extra active copy can mean a stronger immune signal than usual.

And when that signal is part of a pathway already linked to autoimmunity, that extra push may start to matter.

And then scientists found something even stranger about the “inactive” X

Remember how one X chromosome is mostly switched off? The body uses a molecule called XIST to help do that.

You can think of XIST almost like a blanket. It spreads across one X chromosome and helps keep most of its genes quiet.

For years, scientists mostly thought of XIST as part of the machinery that keeps that second X switched off.

But then they noticed that XIST attaches to lots of different proteins inside the cell.

And some of those proteins happen to be the same kinds of proteins the immune system can mistakenly attack in autoimmune diseases.

That raised a really interesting question: could the process of shutting down one X chromosome somehow be connected to autoimmunity?

In 2024, researchers explored this idea in mice. They found that XIST-related complexes could help trigger lupus-like immune activity in animals that were already genetically prone to autoimmunity.

They also found antibodies against some XIST-associated proteins in people with autoimmune diseases.

That does not mean XIST causes autoimmune disease in women.

The mouse experiments needed other risk factors too, and human autoimmune disease is much more complicated.

But it gave scientists another clue. The X chromosome we call inactive may not be quite as inactive (or as unimportant) as we once thought.

So where do hormones fit into all of this?

Immune cells can respond to hormones such as oestrogen, progesterone and testosterone, meaning that changes in these hormones can also change the way our immune cells behave.

Oestrogen, for example, can influence B cells, T cells and antibody production.

The effect depends on the hormone level, the type of immune cell involved and the condition itself.

We can actually see how complicated this is during major hormonal changes.

Some autoimmune diseases improve during pregnancy. Others can become worse. Symptoms can also shift after pregnancy or around menopause.

If hormones were the whole story, the pattern would be much easier to explain, but instead they seem to be just one part of a much bigger picture involving our chromosomes, genes and immune system.

It also matters how our genes are used

Having a certain gene does not mean that it is always active in exactly the same way.

Cells can turn genes up, turn them down or keep them almost completely quiet, depending on what the body needs. Scientists call this epigenetic regulation.

This is especially important in the immune system, where cells need to change their behaviour constantly. If that control starts to shift, some immune cells may become more inflammatory or more likely to react to the body’s own tissues.

And this is where everything we have talked about begins to overlap. Hormones can affect the way genes are regulated, while X-chromosome inactivation is itself controlled through epigenetic mechanisms.

So epigenetics may be another part of the reason why the same immune system can behave differently in women and men.

Your microbiome

Men and women both have a microbiome, of course. What scientists are interested in is whether differences in hormones can also shape the microbes living in our gut and whether those microbes can then influence the immune system in slightly different ways.

It seems to be a two-way relationship. Sex hormones can affect the gut microbiome, while gut bacteria can also influence how some hormones are processed in the body.

Researchers are now looking at whether this interaction could be one small part of the reason autoimmune diseases behave differently in women and men.

For now, though, this is still an area of active research rather than a complete explanation.

So, why women?

After looking at all of this, I think the most useful way to understand it is that women’s immune systems seem to work from a slightly different biological starting point.

Women often mount stronger immune responses, which can be incredibly useful when the body is fighting an infection. But that same strength, in some people, it may make it a little easier for the immune system to become misdirected and start reacting to the body itself.

The X chromosome seems to play an important part. Many immune-related genes sit on the X, and because women usually have two of them, some of those genes can stay active on both copies. Hormones can then influence the same immune pathways and change how strongly certain cells respond.

So the answer is probably the way all of these things come together.

And to me, what makes this so fascinating is that the same biology that can help create a strong immune response may also, in some women, make autoimmunity more likely