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 just one genetic cause of increased susceptibility to several different autoimmune diseases. 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 that keep your immune system from going out of control and attacking your own cells.

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]

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, that 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 CLTA4 gene:

Genetic variants that decrease the function of the CTLA4 can could cause an increased immune system response.

Check your genetic data for rs231775 49A/G (23andMe v4, v5; AncestryDNA):

  • A/A: normal risk of autoimmune conditions
  • A/G: increased risk of autoimmune conditions, decrease CTLA4 expression; increased risk of Grave’s [ref]; increased risk of Hashimoto’s; increased risk of myasthenia gravis;
  • G/G: increased risk of autoimmune conditions, decrease CTLA4 expression; increased risk of Grave’s [ref]; increased risk of Hashimoto’s [ref]; increased risk of myasthenia gravis [ref]; decreased mortality risk in sepsis patients[ref]; increased risk of type 1 diabetes[ref]

 

Check your genetic data for rs3087243 60C/T (23andMe v4, v5; AncestryDNA):

  • A/A: normal risk of autoimmune conditions
  • A/G: increased risk of autoimmune conditions, decrease CTLA4 expression; increased risk of Grave’s [ref]; increased risk of myasthenia gravis [ref]; slightly increased risk of type 1 diabetes, celiac
  • G/G: increased risk of autoimmune conditions, decrease CTLA4 expression; increased risk of Grave’s [ref]; increased risk of myasthenia gravis [ref]; slightly increased risk of type 1 diabetes[ref][ref]; reduced tumor growth in breast cancer[ref]; celiac [ref]

One study showed that a combination of carrying each of the above risk alleles increased the risk of autoimmune disease almost 5-fold. [ref]


Lifehacks:

If you have an autoimmune condition, your doctor can best guide you in the new immune suppression medications on the market today.

Diet:

The autoimmune paleo diet has been effective for many people with autoimmune diseases. A clinical trial of the autoimmune paleo diet showed good results for women with Hashimoto’s thyroiditis. [ref]

Dr. Terry Wahl’s also has a dietary protocol that has been shown to be effective in multiple sclerosis patients.[ref]

Both of those diets focus on fresh vegetables and fruits, high-quality meats and proteins, and avoid gluten, dairy, and eggs.

Vitamin D:

Active vitamin D levels (1,25 (OH)2D3) can increase the expression of CTLA-4. [ref] This may be part of the connection between low vitamin D and an increased risk for many autoimmune conditions.

What can you do to raise your vitamin D levels?  First, you should check to see if your levels are low. Your doctor may be willing to run this for you or you can order your own test-  UltaLab Tests – 1,25(OH)D test (insurance won’t pay if you order your own). Sun exposure on as much skin as possible, but not so long as to get sunburned or skin damage. [ref] If you go the vitamin D supplement route, a lot of the cheap vitamin D supplements contain soybean oil. Personally, I like the idea of coconut oil-based vitamin D supplements instead.

DHA:

DHA is an omega-3 fatty acid found in fish oil.  One study shows that DHA upregulated CTLA-4. [ref] If you are low in DHA, consider adding more fish to your diet or taking a fish oil supplement.

cAMP:

Studies show that substances that upregulate cyclic adenosine monophosphate (cAMP) cause an upregulation of CTLA-4.  Cholera toxin is one substance that is used in studies, but not something that I would recommend as a ‘lifehack’ :-)[ref]

cAMP is important in regulating blood sugar, glycogen, and using fat for fuel. Forskolin is a supplement derived from the Indian Coleus plant. It also is used in research to increase cAMP and increase CTLA-4.[ref]

Curcumin and resveratrol are two more natural supplements that have been shown to upregulate cAMP. [ref]

Raising cAMP does more, though, than just upregulate CTLA4. It is a second-messenger within cells that is important for a bunch of different biological responses. Thus, it may or may not be an effective way to decrease symptoms in an autoimmune condition.

 

More to read:

 

References:

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—. “Association of Single Nucleotide Polymorphisms in Cytotoxic T-Lymphocyte Antigen 4 and Susceptibility to Autoimmune Type 1 Diabetes in Tunisians.” Clinical and Vaccine Immunology: CVI, vol. 17, no. 9, Sept. 2010, pp. 1473–77. PubMed, doi:10.1128/CVI.00099-10.
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