Could This Gene Play A Role In Multiple Sclerosis? (STAT3)

The STAT3 gene codes for one member of a family of proteins called signal transducer and activator of transcription, or just “STAT” for short. STAT proteins are activated by other proteins (such as JAK), which causes them to bind to DNA to turn certain genes “on” or “off” [R].

When it comes to the STAT3 protein specifically, its main role is to control the expression of genes involved in the growth, development, and activation of immune system cells. This process is triggered by “messenger molecules” called cytokines. While STAT3 responds to many different cytokines, the main ones that seem to be involved in multiple sclerosis are IL-6 and IL-23 [R, R, R, R].

The STAT3 gene encodes a protein that either activates or blocks the expression of genes required for the function of immune cells, depending on how the protein is activated.

STAT3 and Immunity Regulation

The immune system protects the body from infections and cancer under normal circumstances, but can also cause allergies and inflammatory/autoimmune disorders when imbalanced! STAT3 responds to cytokines that either activate or block the immune response — in other words, it is one of the mechanisms the body uses to fine-tune the immune system.

On the one hand, STAT3 contributes to the development and function of the cells that:

• Promote inflammation and kill microbes (neutrophils) [R, R]
• Present infectious particles to T-cells (dendritic cells) [R]
• Produce antibodies (B-cells) [R, R, R]
• Fight off infections, but which may cause autoimmune and inflammatory disorders if overactivated (Th17 cells) [R, R, R]
• Quickly respond to repeated infections that the body has already developed immunity against (memory T-cells) [R, R]

STAT3 also activates the immune response by reducing the production of immunosuppressive T-cells (also known as “Tregs”) [R].

On the other hand, STAT3 can also act as an immunosuppressant by:

• Increasing the expression of its own blocker (SOC3) [R, R, R]
• Preventing the development of dendritic cells [R]
• Blocking the production of pro-inflammatory cytokines by white blood cells (neutrophils, macrophages, and dendritic cells) [R, R, R]
• Producing the B-cells (commonly known as “Bregs”) that suppress defense and autoimmunity [R]
• Helping Tregs block Th17 development [R, R]

The STAT3 protein plays a fine-tuning role in the immune system, as it can both stimulate or suppress the immune response under different circumstances.

STAT3 and Multiple Sclerosis

Multiple sclerosis (MS) is a chronic autoimmune disease that progressively damages the insulating cover of the nerves in the brain and spinal cord (myelin). This disrupts the ability of the nerve system to communicate with the rest of the body, resulting in a wide range of symptoms such as vision (impaired, blurred, or double vision), physical (loss of coordination, tremors, spasms, weakness), and mental (impaired memory and cognition, depression) problems [R, R, R].

In most cases (~85%), the condition alternates periods of symptom worsening (called "attacks," "relapses," or "flare-ups") and recovery. This form is called "relapse-remitting multiple sclerosis." In some people, the symptoms never go into remission and progressively worsen ("primary-progressive multiple sclerosis"). After years or decades, the relapse-remitting form can develop into the progressive form [R, R].

Unrestrained brain inflammation caused by T-cells (especially Th1 and Th17) crossing the blood-brain barrier and producing cytokines contributes to multiple sclerosis and other autoimmune neurodegenerative conditions [R, R].

STAT3 specifically promotes the development of Th17 cells in response to the cytokines IL-6 and IL-23. Genetically engineered mice lacking STAT3 don’t produce Th17 cells and their T-cells cannot cross the blood-brain barrier, which protects them from multiple sclerosis [R, R, R, R].

In line with this, the T-cells and white blood cells (monocytes) of people with multiple sclerosis are enriched in activated STAT3 and Th17-derived IL-17, especially during flare-ups [R, R, R]. Similarly, higher levels of activated STAT3 in immature T-cells of people with isolated symptoms may predict their progression into clinically defined multiple sclerosis [R].

However, there is also an upside to STAT3 when it comes to multiple sclerosis. A study in rats found that its activation in the cells that produce myelin (oligodendrocytes) promoted the repair of this insulating cover [R].

STAT3 contributes to multiple sclerosis by promoting the development of Th17 cells and the transport of T-cells across the blood-brain barrier. However, preliminary evidence suggests it may also help repair the myelin cover.

The most widely-studied STAT3 polymorphism is rs744166. Although its mechanism remains unknown, some researchers have suggested that certain alleles may alter the structure of the STAT3 protein, thus changing how it responds to cytokines [R].

Three large studies on over 42,000 Europeans associated the minor allele ‘G’ with an increased incidence of multiple sclerosis [R, R, R]. However, the association was not very strong and another study on over 3,000 Spanish people failed to replicate it [R].

Another polymorphism with an unknown mechanism is rs2293152. Although its major allele ‘C’ was associated with multiple sclerosis in one of the above-mentioned studies [R], this association didn’t reach statistical significance in another one [R].

The ‘G’ allele of rs744166 and the ‘C’ allele of rs2293152 have been linked to multiple sclerosis, but the association was weak in both cases.

You can see your genotype for several STAT3 SNPs in the table below. However, keep in mind that these results are based on association studies suggesting that certain genetic variants are more common in people with multiple sclerosis, and more research will be needed to know what role (if any) these variants play in actually causing this condition. Also, many genetic and environmental factors can influence the risk of multiple sclerosis: therefore, just because you have one of these genotypes does not necessarily mean you are at increased risk of developing it!

Primary SNP: STAT3 rs744166:

• ‘A’ = Less common in people with multiple sclerosis.
• ‘G’ = More common in people with multiple sclerosis.

Population Frequency:

• Both homozygous genotypes are roughly similar in frequency. 44% of the world population has ‘AG’.
• In European descendants, the frequency of the ‘GG’ genotype is reduced to 19%.

Other Important SNPs:

STAT3 rs2293152:

• ‘C’ =  More common in people with multiple sclerosis.
• ‘G’ = Less common in people with multiple sclerosis.

Population Frequency:

• 85% of the world population has at least one ‘C’ allele.
• Only 1% of African descendants have ‘GG’.

If you think you may be experiencing symptoms of multiple sclerosis, make sure to talk to your doctor so that he or she can properly diagnose this condition and prescribe a treatment. Although there is no cure for multiple sclerosis, treatments may help speed recovery after an attack, slow down the progression of the disease, and manage the symptoms.

Multiple sclerosis attacks are normally managed with corticosteroids such as oral prednisone and intravenous methylprednisolone to reduce nerve inflammation. Corticosteroids target several pro-inflammatory mediators, including STAT3 [R].

In people with severe symptoms that don’t respond to corticosteroids, plasma exchange (plasmapheresis) can lower inflammation by removing the antibodies responsible for the autoimmune attack. This procedure consists of separating the liquid part of the blood (plasma) from the cells and replacing it with healthy plasma, or substitutes such as salt solution or albumin.

Disease progression and relapse frequency can be reduced with multiple drugs in people with relapsing-remitting multiple sclerosis:

• Beta interferon: this cytokine is injected under the skin or into the muscles and reduces the frequency and severity of relapses by altering the inflammatory response and reducing the number of T-cells that cross the blood-brain barrier [R]. Its specific effects on STAT3 remain unclear, with different studies reporting that it activates [R] or blocks [R] this protein.
• Glatiramer acetate: injected under the skin, this medication helps reduce the autoimmune attack to the myelin cover of brain cells. It is thought to prevent immature T-cells from developing into inflammatory Th1 and Th17 cells by blocking STAT3 and other components of the immune system [R].
• Fingolimod: this once-daily oral medication with immunosuppressive effects was the first drug approved for multiple sclerosis. A study in rats suggested that fingolimod needs a functional STAT3 protein to exert its protective effects [R].
• Dimethyl fumarate: this is a twice-daily oral medication that reduces relapses. Although these studies investigated its potential use for other conditions, the drug reduced STAT3 activity in cells [R, R].
• Teriflunomide: this once-daily oral medication prevents relapses and has been shown to reduce the activation of STAT3 and other related proteins [R].
• Siponimod: this once-daily oral medication reduces both relapses and disease progression.
• Ocrelizumab is an injectable antibody that targets B-cells. In addition to being used in case of relapse-remitting multiple sclerosis, ocrelizumab is the only drug approved for primary-progressive forms of the disease.
• Natalizumab is another injectable antibody that targets a protein required by T-cells to cross the blood-brain barrier (alpha-4 integrin). Some people experience disease worsening after natalizumab discontinuation, which is in part caused by increased STAT3 activation in immature T-cells [R].
• Alemtuzumab is another injectable antibody that reduces relapses by binding to a protein on the surface of mature immune cells (CD52) and targeting them for destruction. Generally, it’s only recommended in people who don’t respond to other treatments.
• Mitoxantrone: this immunosuppressant is only prescribed in rare, severe cases because it’s associated with heart damage and the development of several cancer types.

Finally, other multiple sclerosis symptoms are commonly managed with the following therapies:

• Physical therapy to improve mobility and leg weakness
• Muscle relaxants, such as baclofen and tizanidine, to reduce muscle stiffness or spasms
• Anti-fatigue medication, such as amantadine, modafinil, and methylphenidate
• Antidepressants, such as SSRIs
• Medication to increase walking speed, such as dalfampridine

Medications for other symptoms such as pain, sexual dysfunction, insomnia, and bladder or bowel control problems.