The Genetics of the Sexes: Chromosomes, Autoimmune Diseases and Gender-Specific Differences

In this blog post, we look at the existence of women and men in the smallest detail – namely within genetics. This is because the sex of the embryo is already decided at fertilisation:

‘At the exact moment when the egg cell with its female X chromosomes meets the male XY sperm,
the child’s sex is decided.’

Regitz-Zagrosek & Schmid-Altringer, 2021, p. 16

The sexual organs develop under the influence of the genes. Hormone production starts in the seventh week of pregnancy. The hormones control the different development of both sexes and the genes on the chromosomes control the production of female and male sex hormones. (Regitz-Zagrosek & Schmid-Altringer, 2021, p. 16 – 18) This means that the course for the biological differences between women and men is already set at the very beginning of our conception. [1]

In this post, we want to explain what chromosomes actually are, what effects they have on men and women and what all this has to do with autoimmune diseases. So let’s start finding answers together and gain awareness of our most basic building block – our genetic information!

What are Chromosomes?

Chromosomes are the carriers of genetic information that contain instructions for the production of proteins [2]. They can also be seen as a human building block set in which the differences between the sexes are anchored and coded [2]. The coding of sexual characteristics has consequences for

• Hormones
• Metabolism
• Regulatory mechanism of the cells
• Growth and development of cells

Genetic differences are one reason for diseases that are primarily female-specific or male-specific [2].

What is the Difference between the Chromosome Pairs XX and XY?

Women have two X chromosomes (XX). Due to the double X chromosome, they have a lot of information twice, most of which is deactivated. However, around 15 % remains active and is very useful. The second X chromosome can be seen as a back-up that steps in to compensate for genetic defects in the first X chromosome. [2]

Meanwhile, males have an X chromosome and a Y chromosome (XY). The male Y chromosome is significantly smaller than the X chromosome and therefore carries less genetic information. The information on the Y chromosome is responsible for sexual function and sexual development. In addition, male individuals missing the compensation function (back-up) due to the missing second X chromosome.[2]

Women have another strong advantage over men due to their double X chromosome – women have a stronger immune system than men [2]. This results in the following positive effects:

• Infections are better defended against
• Antibodies are produced more quickly after vaccinations
• Immune response lasts longer than in men

Of course, as always, there are two sides to the coin. The XX chromosome in women also harbours a very serious disadvantage. Women suffer significantly more frequently from autoimmune diseases than men. These include thyroid diseases, multiple sclerosis and rheumatic diseases. [2]

Meanwhile, men have a higher risk of cancer, which is of course due to various influencing factors. However, one probable cause is the sex chromosomes. [2], [3]

Connection between our Genetic Information and the Development of Autoimmune Diseases

To understand the connection between genetic information and the development of autoimmune diseases, we first need to refresh our basic knowledge of our immune system. We need to understand how autoimmune diseases develop. To protect our body from pathogens, our body generates a natural defence system by producing specialised white blood cells and proteins (antibodies). These components circulate through our blood in the body and as soon as they recognise foreign substances or pathogens, they eliminate them. In autoimmune diseases, the immune system attacks its own body. It forms autoantibodies against our body’s own proteins, cells and tissue. The reason for this is a malfunction of the system due to genetic predispositions and environmental factors. The type of autoantibodies determine the severity and type of autoimmune disease. The female XX chromosomes are strongly associated with susceptibility to autoimmunity. A major factor in autoimmune risk appears to be the number of X chromosomes – regardless of gender or hormone status in humans. This ultimately means that the female immune system often overreacts in its immune response. [1]

How often are Women really affected by Autoimmune Diseases?

Women are disproportionately affected by autoimmune diseases. 80% of the patients affected are female. There are various reasons for this [2]. If we look at the distribution of autoimmune diseases between men and women, it becomes clear once again that women are affected more often than men [4]:

• Four out of five patients with autoimmune diseases are female
• In systemic lupus erythematosus (SLE), for example, the ratio of female to male patients is 9:1
• In Sjögren’s syndrome, the ratio of female to male patients is 19:1
• Hashimoto’s thyroiditis occurs 5 times more frequently in women than in men

Autoimmune diseases are among the ten most common causes of death in women under the age of 65. Alarmingly, the number of cases is increasing worldwide every year. Understanding the development and risk factors of autoimmune diseases is becoming increasingly important in view of the rising number of cases. [4]

Why are Women now more frequently affected by Autoimmune Diseases?

Scientists have discovered a possible reason that is partly responsible for the higher prevalence of autoimmune diseases in women. The cause is thought to be a molecule called Xist. Xist is a molecule that is produced by an X chromosome in every female cell. The gene for Xist is present on all X chromosomes. But Xist is only produced if the X chromosome belongs to an XX pair. This means that the male X chromosome does not produce Xist. It can produce antibodies against a woman’s own tissue. [5]

And how exactly does this work?

Xist helps to regulate the protein production of the X chromosomes. Without Xist, women would produce a lethal amount of protein because they have two X chromosomes. Xist coats an X chromosome and renders it (almost) inactive. In science, this process is called X chromosome inactivation. [5]

This X chromosome inactivation itself can already lead to autoimmune diseases. The physical attachment of Xist to one of the X chromosomes causes strange combinations of molecular complexes and proteins. These molecular complexes and proteins bind to Xist and to our DNA, which clings to some of the proteins. These new complexes can also trigger a strong immune response. [5]

How does the Discovery of the Xist Molecule advance the Treatment of Autoimmune Diseases?

Xist-RNP complexes are another and new reason to explain the higher prevalence of autoimmune diseases in women. Science has proven that patients with autoimmune diseases showed significant autoantibodies against several components of the XIST-RNP. [4], [5]
The wide variety of autoimmune diseases and their overlapping features has limited the development of effective therapies and sensitive diagnoses for each autoimmune disease [4].
The discovery of Xist and its associated proteins in autoimmune patients with new antigen groups increases the potential for improved disease detection and monitoring, as autoantibodies can often be detected before or early after disease outbreak [4].
It is precisely such developments that show us that the work of EQUAL CARE is essential. That awareness of the physiological differences between men and women is growing, but science is still in the early stages of understanding female physiology in some areas. Steps are being taken in the right direction, but there is still a long way to go.

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Takeaway Points:

• The sex of an embryo is already determined at fertilisation.
• Chromosomes carry genetic information and control the development of sexual organs and hormone production.
• Women have two X chromosomes (XX), men one X and one Y chromosome (XY), which leads to different genetic and immunological characteristics.
• Women have a stronger immune system, but are more susceptible to autoimmune diseases due to their double X chromosomes.
• Autoimmune diseases predominantly affect women and their causes are linked to genetic factors such as the Xist molecule.
• The discovery of Xist and its associated proteins offers new approaches for the treatment and monitoring of autoimmune diseases.

For more Information

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