Genome

Is This The Reason More Females Suffer From Autoimmune Disease?

Posted on 17 September 2021

Our immune systems are usually capable of telling the difference between our own cells and those of another organism. It’s why people receiving organ transplants need to take immune system-supressing drugs, and why blood type matters when receiving a transfusion. Unfortunately, the immune system can sometimes get things wrong, leading it to recognise the body’s own cells as a threat and attack them. Diseases caused by these reactions are collectively known as autoimmune diseases, and include the likes of multiple sclerosis (in which the immune system attacks the protective sheaths around nerve fibres) and rheumatoid arthritis (in which cells lining the joints are attacked).

Normal immune response vs multiple sclerosis.
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We still don’t really understand what sets off most autoimmune diseases. One peculiarity of autoimmunity is that it seems to occur much more often in females than in males. Females are over twice as likely to suffer from multiple sclerosis, 3 times as likely to suffer from rheumatoid arthritis, and about 9 times as likely to suffer from lupus when compared with their male counterparts. Why might this be the case? There are many theories, most relating to differences between the male and female immune systems. We know that the female immune system is more adept at fighting pathogenic infections due to higher numbers and activity of certain immune cells. This heightened activity, while helpful if you’re trying to survive a pandemic, might also make female immune systems more prone to becoming ‘overzealous’ and attacking the body’s own cells. This theory makes sense, but is there a more precise explanation? What makes female immune systems more active, anyway? The answer may lie with the X chromosome, and a fascinating genetic phenomenon called Lyonisation (also known as X chromosome inactivation).

What Is Lyonisation?

As you probably know, females inherit one X chromosome from each parent. However, in any given cell, only one X chromosome is fully functional: during development, one X chromosome in each cell is shut down in a process called Lyonisation, condensing into a structure known as a Barr body. This process is random for each cell: in some cells the mother’s X chromosome will be active, while in others it will be the father’s. The ‘decision’ over which chromosome gets turned off is then conserved through cell division: if a cell has turned off the father’s chromosome, it will divide to produce two cells in which the father’s chromosome is inactive.

Epigenetics - Biochemistry - Medbullets Step 1
Lyonisation means that female tissues are mosaics of cells expressing different X chromosomes.
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What is the point of Lyonisation? Most of the genes on the inactivated X chromosome are silenced (they don’t get expressed and so don’t result in the production of a protein). Were this not the case, some genes would get expressed at twice the level in females as they are in males. Lyonisation ensures that gene expression is equalised between the sexes. Lyonsiation also offers some protection against inherited genetic diseases. Suppose that one of the X chromosomes carries a disease-causing mutation. That mutated gene will not be expressed in every cell which, depending on the nature of the mutation and the proportion of cells affected (it’s not necessarily 50:50), may be enough to spare the individual from the effects of the disease.

X Chromosomes And Autoimmunity: What’s The Link?

We once thought that Lyonisation was a very stable process, meaning that once an X chromosome got inactivated, it would stay inactivated forever. It turns out that’s not quite true: it seems that in some cells, the inactive X chromosome can wake up. In 2016, Montserrat Anguera and her team decided to study X chromosome inactivation in the immune cells of women with lupus.

Human B cells with DNA stained blue and long non-coding RNA stained pink.
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What you’re seeing above are microscope images of the nuclei of two B cells. A fluorescent probe has been used to light up long noncoding RNA in pink – this is a molecule that plays a role in orchestrating X-inactivation. In the cell on the left, the RNA is concentrated around the X chromosome, but on the right it is dispersed, indicating that X-inactivation has partially broken down. In this image, X – inactivation has been prevented by genetic manipulation. However, the researchers observed the same patterns in many of the T and B cells from patients with lupus, suggesting that the X chromosome is being partially reactivated.

Why is this a big deal? Remember how Lyonisation helps equalise gene expression between the sexes? It just so happens that the X chromosome carries many genes related to the immune system, and the researchers found evidence that expression of these genes is higher in the immune cells of people with lupus. In other words, the partial reactivation of the second X chromosome may have led to the overexpression of immune-related genes, leading to hyperactivity of the immune cells.

Intriguingly, some immune cells appeared to have unsilenced their second X chromosome even in healthy people, which might help explain why the female immune system is generally more effective.

So… Mystery Solved?

Not exactly! There’s still a lot more research needed – lupus is just one of over 100 autoimmune diseases, and even if X reactivation is important, it won’t fully explain the sex differences when it comes to the immune system. Hormonal differences, for example, are likely to play an important role. We’re also pitifully ignorant when it comes to what sets off autoimmunity in most cases. Males still get autoimmune diseases, so X reactivation clearly isn’t required to trigger autoimmunity, but it offers a compelling explanation as to why females suffer from these diseases much more frequently.


References

Unusual maintenance of X chromosome inactivation predisposes female lymphocytes for increased expression from the inactive X: https://dx.doi.org/10.1073%2Fpnas.1520113113

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