Betrayed by the Defense: Autoimmunity and its triggers

Autoimmunity is a condition in which the body’s immune system mistakes its own healthy tissues as foreign and attacks them. Your body is a fortress where your immune cells, the soldiers of your body are on duty 24/7, checking in for intruders, the pathogens. Your soldiers, after heavy surveillance, identify the intruders, use their weapons (antibodies) to kill the intruders and protect the fortress. But in some cases, it is seen that the soldiers turn against their fortress. They can no longer differentiate between enemies and allies, start killing their allies. How can the soldiers betray their fort? What are the factors that force them to kill the healthy body cells? What weapons do they use? Who supplies them with these weapons?

What is autoimmunity?

The immune system recognizes and differentiates between the body’s own cells (self) and foreign intruders (non-self-cells), targeting pathogens while protecting self-cells. This tendency makes our immune system reliable, but occasionally this important barrier is breached and the immune system fails to distinguish between allies and enemies. That’s when it relentlessly starts killing the body’s own cells (self-cells) and wreaks a havoc, this condition is called Autoimmunity which can lead to widespread damage and chronic inflammation.

How cells are taught to differentiate self and non-self-cells?

Before the actual battle, the soldiers go through rigorous training and screening tests. Only the soldiers who pass these exams are allowed to enter the battlefield.

While the cells are in their early developmental phases, T cell in the thymus and B cell in the Bone Marrow, they are tested against self-antigens, i.e., the different receptors that are present on self-cells. If these cells generate an immune response against self-antigens, they are eliminated from the body. However, if they pass the test and generate no response, they are allowed to stay and are good to go into the blood stream for surveillance. This process of selection is called Immune tolerance, where a tolerance is developed in immune cells for self-cells, i.e., not to elicit and immune response for a self-antigen.

Removal of autoreactive immune cells before they enter circulation is Central tolerance, but some cells are smart enough to escape central tolerance and enter circulation. Here Peripheral tolerance comes into play. It controls these cells by inactivating them by using a special type of T-cells called Regulatory T cell (Treg cells) and prevents the autoreactive cells from attacking the body. Immune cells designed to kill pathogens short-circuit during autoimmunity, and they begin to destroy self-cells.

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Table: Classification of autoimmune disease and their mechanism of action. Adapted from (Marrack et al., 2001)        

Why do your cells betray you?

Understanding the reasons behind this betrayal involves looking at how the immune system works, what triggers its confusion, and why these self-attacks occur. The malfunctions may arise due to faulty genes, bad environment and even chronic infections.

Genetics

Your genes serve as the blueprint for training your immune system soldiers, but if the blueprint is faulty, they receive the wrong training and screening. Instead of learning to protect their body, they graduate with the idea that even friendly cells are enemies. With this flawed training, the misguided soldiers can turn against your body and attack the cells they were meant to defend.

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Genes, like HLA (Human leukocyte antigen) are the significant players who decide the fate of the immune system, contributing to which antigens will be recognized by it. Mutations in major genes like AIR3 (Autoimmune regulator – Wikipedia) or FOXP3 that control the central tolerance and Treg cell function respectively, can result in autoimmunity. Moreover, parents can pass down autoimmune diseases from one generation to the next, making them congenital.

Mistaken Identity (Molecular Mimicry)

An intruder may come disguised as an ally that might confuse your soldiers and they end up using their weapons against self-cells. Occasionally, your immune system encounters a foreign pathogen (any virus or bacteria) whose proteins resemble to those found on your cells. When the body generates antibodies (weapons) against foreign proteins, these antibodies can bind to self-proteins and destroy healthy body cells. This process is termed as Molecular mimicry through which pathogens and chemical agents can induce autoimmunity.  

Toxins and Chemicals

While your immune soldiers are on their surveillance rounds, harmful toxins—like mercury or certain chemicals—sneak in and tamper with the soldiers’ equipment. These toxins confuse the soldiers, making them see their fortress walls as hostile leading to friendly fire, causing the soldiers to attack their city, triggering autoimmune reactions. For instance, some medications like Hydralazine or Procainamide can trick the soldiers into attacking, creating conditions similar to lupus. Studies prove that even smoking can trigger autoimmunity.

Chronic Inflammation

If the fortress is under constant threat, either from infections, injuries, or irritants, the soldiers are always on high alert. Over time, this constant state of readiness overstimulates the soldiers, making them overly aggressive. They start attacking anything that looks even slightly suspicious, including their own city walls. The longer this battle mode continues, the more likely the soldiers are to turn on their own, mistaking friend for foe. This is how chronic inflammation can push the immune system into attacking the body’s own cells.

Are autoimmune diseases gender biased?

Around 80% of people with autoimmune diseases are women, due to a strong hormonal influence. In particular, the effects of estrogen make women more vulnerable to developing these conditions. While men have higher levels of testosterone, which tends to suppress excessive immune reactions, estrogen provides a more active immune vigilance in women. Researchers believe that this heightened immune vigilance plays a major role in the gender bias seen in autoimmune conditions.

Furthermore, estrogen is like a strict commander who forces immune soldiers to stay alert and vigilant. This results in enhanced immune responses, making the soldiers more aggressive in their defense. In essence, women’s immune systems are more likely to become hyperactive, leading the immune soldiers to mistake self-tissues for invaders. As a result, women are more prone to developing autoimmune diseases, with the hormonal shifts of menstruation, pregnancy, and menopause playing key roles in triggering or worsening symptoms.

Conclusion

The immune system’s main job is to protect the body from harmful things like bacteria or viruses. However, in autoimmunity, the immune system makes a mistake. Instead of defending the body, it attacks it accidentally. Several circumstances, including genetics, environmental triggers, hormonal fluctuations, and prolonged inflammation, can cause this betrayal. Our immune soldiers need precise training and distinct signals to differentiate between allies and enemies. However, this system malfunctions due to environmental triggers, molecular mimicry, altered self-antigens, and hormonal imbalances. Generally, women are more likely than men to acquire autoimmune diseases. It is largely due to the role of estrogen that makes their immune system hyperactive.

When it comes to your immune system, there is a thin line between self-destructive and self-protective. Many triggers can propel your immune soldiers towards a civil war. Researchers are rigorously studying autoimmunity to better understand the pathways that drive cells towards dysfunction. Understanding these pathways will help researchers to develop therapies which will eventually assist the immune system in restoring its focus and doing its job of protecting the body.

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References

1.http://omicsonline.org/autoimmune-disorders-an-overview-of-molecular-and-cellular-basis-in-todays-perspective-2155-9899.S10-003.pdf – Autoimmune Disorders: An Overview of Molecular and Cellular Basis in Today’s Perspective

2.https://www.niaid.nih.gov/research/immunetolerance#:~:text=Tolerance%20is%20the%20prevention%20of,or%20food%20allergy%20may%20occur

3. https://www.hopkinsmedicine.org/health/wellness-and-prevention/autoimmune-disease-why-is-my-immune-system-attacking-itself

4. https://www.webmd.com/a-to-z-guides/autoimmune-diseases

5.http://www.kau.edu.sa/Files/0001735/Files/20287_LECTURE_7_AUTOIMMUNITY_AND_AUTOIMMUNE_DISEASE_Part1.pdf – AUTOIMMUNITY & AUTOIMMUNE DISEASE LEARNING OBJECTIVES

6. https://my.clevelandclinic.org/health/diseases/21624-autoimmune-diseases

FAQs

What is Autoimmunity?

In autoimmunity, the body’s immune cells confuse and attack its tissues. They can’t tell the difference between the body’s own cells and foreign invaders like bacteria or viruses. Because of this confusion, the immune cells attack healthy body cells mistakenly. This causes damage and ongoing inflammation (swelling) in the body.

2. Elaborate Immune Tolerance. Describe its various types.

The immune system can block a response to its proteins. This is called immune tolerance. There are two kinds of it: peripheral and central. In central tolerance, the body removes faulty immune cells that attack its cells while they are still growing. This happens in the thymus and bone marrow. Peripheral tolerance manages immune cells that slip through central tolerance and move into the bloodstream.

3. What are the factors that lead to autoimmunity?

Autoimmunity might result from a person’s genetics, breached immune tolerance, molecular mimicry, toxins, and chemicals and prolonged inflammation due to chronic infections.

4. What are autoimmune diseases? Mention their types.

Diseases happen when the immune system stops working properly. In these cases, immune cells make a mistake, thinking the body’s own healthy cells are harmful. They attack and damage these healthy cells. Autoimmune diseases can affect the whole body or just one organ.

5. Why are women more prone to autoimmune diseases than men?

Women are, in fact, more likely to develop autoimmune diseases. This tendency arises largely due to the presence of higher levels of estrogen, a hormone that significantly impacts the immune system. Specifically, estrogen can lead to an overactive immune response. Conversely, men have higher levels of testosterone, which serves to calm the immune system. As a result, in women, the immune system can become excessively active. Consequently, this overactivity causes their immune cells to mistakenly attack their own tissues, believing they are harmful invaders.