Autoimmune Disease Genetic Risk Factors: CTLA-4 Gene

Autoimmune diseases are caused by your immune system targeting and attacking cells in your body. This can result in a number of different problems:  joint pain (rheumatoid arthritis), scaly, thick skin (psoriasis), hypothyroidism (Hashimoto's), and more. It is often difficult to get a solid diagnosis with autoimmune conditions since the symptoms overlap with other conditions.

This article covers one genetic cause of increased susceptibility to several different autoimmune diseases. It dives into the variants you can check in your genetic raw data, and it gives possible solutions to investigate, based on your variants.

Keep in mind that genetic variants just add to the susceptibility to autoimmune diseases -- there is usually an additional factor that triggers the disease.

CTLA-4 and Autoimmune Diseases:

The CTLA4 gene codes for a protein that is important in the immune system. It acts as a checkpoint that can downregulate your immune system response. CTLA4 is active in regulatory T cells (Tregs), which are the part of the immune system that maintains your tolerance to self-antigens.[ref][ref]

Basically, you want a powerful response from your immune system when you are exposed to a pathogen that causes a disease - pneumonia, West Nile virus, cholera, measles, flu... But you don't want an out of control immune system.

Your body needs to control your immune response when it isn't needed. Checks and balances.  The Treg cells are the checks keeping your immune system from going out of control and attacking your own cells.

As an example, one way in which the body needs to deactivate the immune response is during pregnancy.  Think about it -- a mother's body has an organism with foreign DNA growing in it. There has to be a system in place to keep the mother's body from attacking the fetus. Immune checkpoint molecules (CTLA4 is one of them), keeps the maternal immune system from attacking the fetus.[ref]

Consequently, when researchers decrease the amount of CTLA-4 in mice, it causes autoimmunity.[ref]

Autoimmune conditions associated with CLTA-4  include:

  • Graves' disease (TSH-receptor autoantibodies cause hyperthyroidism)
  • Hashimoto's disease (hypothyroidism)
  • Rheumatoid arthritis[ref]
  • Type 1 diabetes[ref]
  • Lupus[ref]
  • Vitiligo
  • Multiple Sclerosis[ref]
  • Celiac disease[ref]
  • Myasthenia gravis

Keep in mind, though, autoimmune conditions aren't solely caused by decreased CTLA-4. This is just one player in the autoimmune profile.

Checkpoint inhibitors in cancer:

The flip side of this CTLA-4 story is that inhibiting CTLA-4 is now a powerful tool in cancer therapy for certain types of cancers. Taking away the brakes on the immune system - decreasing that checkpoint for downregulating the immune system - allows the body to have a better shot at destroying cancer cells.


Genetic variants in the CTLA4 gene:

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Genetic variants that decrease the function of the CTLA4 can could cause an increased immune system response. These variants increase the risk of many autoimmune diseases.

 


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