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The 'why' question of autoimmune disorders

Q: Why do allergies and autoimmune diseases develop? Why does our immune system become so destructive sometimes?

Krishna: It is difficult to answer the 'why' question because the research on this is still going on and takes some time to exactly pinpoint the specific causes.

In autoimmune disorders, the immune system mistakenly identifies the body's own healthy cells, tissues, or organs as foreign invaders and attacks them. This occurs because the immune system's tolerance for "self" – its ability to distinguish between foreign and own – is compromised. The exact reasons for this breakdown in tolerance are complex and not fully understood, but they likely involve a combination of genetic predisposition, environmental factors, and potentially infections.

In autoimmune diseases, specific immune cells, like T cells and B cells, become reactive against the body's own tissues.

T cells: T cells help activate B cells, which produce antibodies. In autoimmune diseases, T cells can be activated to target self-antigens, leading to the production of autoantibodies.

B cells: B cells produce antibodies, and in autoimmune diseases, they produce autoantibodies that attack the body's own tissues.

The immune response against self-tissues leads to inflammation, tissue damage, and various symptoms depending on the affected organs or tissues.

And I came across some of these studies which give us some clues why this happens.

A group of researchers (1), led by scientists at KU Leuven, a university in Belgium, infected mice with Citrobacter rodentium to mimic food poisoning, while at the same time feeding them with ovalbumin (a protein found in egg whites).

After the infection had cleared and the mice were next fed ovalbumin, they developed IBS-like symptoms. It’s thought that the combination of the infection and the ovalbumin led to the mice developing an allergy to that food.

This is like the immune system falsely connecting the bacterium with a certain food!

Distinguishing between self and non-self is a critical ability of the immune system. Some pathogens have evolved proteins that resemble those of their host, a mechanism called molecular mimicry, in an attempt to evade this surveillance system.

However, immune training isn’t perfect, so host cells that recognize self-proteins occasionally slip into the milieu. Their presence doesn’t immediately raise any alarms, but if a pathogen with this same mimicked protein invades the body, it can trigger an immune response against the same sequence on the body’s own cells.

A screen of human-infecting viruses identified extensive examples of viral proteins that resembled human sequences, which could trigger autoimmune diseases (2,3) like multiple sclerosis.

Screening more than 100 human-infecting viruses for mimicry in short, linear peptide sequences, researchers demonstrated that this phenomenon is widespread across the virome. These findings, published in Nature Communications, could help researchers explore novel autoimmune triggers and potential interventions.

If you look at other autoimmune diseases [beyond Multiple Sclerosis], they're really associated with a variety of herpes viruses. So, seeing this trend at a family level was interesting because it might point to one reason why herpes viruses often associate with autoimmunity.

Individuals with a genetic predisposition to autoimmune diseases may be more susceptible to these breakdowns in tolerance.

Environmental toxins, medications, or other factors could also play a role in disrupting immune tolerance.

What is more bothersome is women get affected more. Women have up to a fourfold increase in risk for autoimmune disease compared to men. (5)

Scleroderma affects approximately 300,000 people in the U.S., with about one-third developing systemic disease, which can affect major organs such as the lungs, kidneys or heart. Women are four times more likely than men to be diagnosed with the disease, but until now, the underlying reason for this gender disparity had remained elusive.

In one study, a team of researchers led by Franck Barrat, Ph.D., found that two genetic receptors called TLR7 and TLR8, which are present on the X chromosome, are important drivers for the activation of plasmacytoid dendritic cells (pDCs), fueling chronic fibrosis. pDCs are immune cells found in fibrotic skin but not in healthy skin and have previously been shown to contribute to scleroderma.

In healthy cells, one X chromosome is typically deactivated. However, the study revealed that in patients with scleroderma, this process is disrupted due to the ability of TLR7 and TLR8 to escape X chromosome deactivation in pDCs. The magnitude of this escape was striking.

In healthy individuals, 10 to 15% of cells can evade the deactivation process. But in scleroderma patients, the escape occurred in more than 35% of the pDCs. This was a significant and unexpected difference.

The expression of two copies of the TLR7 and TLR8 in such a large number of cells can very well explain the chronic activation of these immune cells and why this disease is so prevalent in female patients. (4)

Women are more susceptible to autoimmune diseases than men due to a combination of factors, including sex chromosomes, hormones, and the immune system's overall function. The presence of two X chromosomes in females, and the unique way they are handled by the body, plays a significant role. Additionally, sex hormones, particularly estrogen, can influence immune system activity, potentially increasing the risk of autoimmune diseases in women.

Women have two X chromosomes, while men typically have one X and one Y chromosome. While one X chromosome is inactivated in women, some genes on the inactivated X still escape inactivation and are expressed. This expression can lead to a higher number of immune-related genes being produced in women, potentially contributing to a more reactive immune system.

Estrogen and progesterone levels in women can influence immune system function and inflammation. For example, some studies suggest that estrogen can have an immunosuppressive effect, while progesterone may stimulate the immune system. These hormonal fluctuations can contribute to the variability in immune responses seen in women, potentially increasing their risk of developing autoimmune diseases.

The presence of fetal cells in the mother's body after pregnancy (microchimerism) can alter a woman's immune system, potentially leading to autoimmune responses.

The female immune system may have evolved to be more reactive and protective, possibly to protect against infections that could harm a developing fetus. This heightened immune response could, in some cases, lead to the development of autoimmune diseases.

Women generally have higher antibody levels than men, which could be a contributing factor to the higher prevalence of autoimmune diseases in women.

Environmental factors, microbiome differences, and genetic variations can also play a role in the development of autoimmune diseases.

These are the things we understood till now about autoimmune disorders. Still there is a lot to study and know.

If I find more about this health issue, I will definitely share it with you in the future.

Footnotes:

1. https://www.sciencefocus.com/the-human-body/ibs-an-experts-guide-to...

2. https://www.mdpi.com/2076-0817/11/11/1362

3. https://www.nature.com/articles/s41467-024-53658-8

4. Journal of Experimental Medicine (2025).

https://medicalxpress.com/news/2025-03-reveals-scleroderma-affects-...

5. https://pmc.ncbi.nlm.nih.gov/articles/PMC7980266/

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