PTPN22

The PTPN22 gene codes for LYP, an enzyme that suppresses T cell activity when dissociated from the regulatory protein Csk. Variants of PTPN22 may play a role in rheumatoid arthritis, lupus, and other autoimmune conditions by producing LYP with reduced Csk-binding ability, resulting in decreased T cell-mediated release of a regulatory immune messenger. (R, R).

Lifestyle, diet, and supplement modifications may counteract the effects of these variants by increasing production of this immune messenger, stimulating regulatory T cells, and suppressing inflammatory T cells.

The PTPN22 gene provides instructions for making a protein that belongs to the PTP (protein tyrosine phosphatases) family. PTP proteins play a role in regulating a process called signal transduction. In signal transduction, the protein relays signals from outside the cell to the cell nucleus. These signals instruct the cell to grow and divide or to mature and take on specialized functions.

The PTPN22 protein is involved in signaling that helps control the activity of immune system cells called T cells. T cells identify foreign substances and defend the body against infection.

The PTPN22 (or LYP) gene encodes a protein from the PTP (protein tyrosine phosphatases) family. This protein regulates the development and function of T cells, B cells, and other immune system components [R].

More precisely, it controls the antiviral immune response and prevents excessive inflammation that can harm the healthy tissue and trigger autoimmunity [R].

Mutations in the PTPN22 gene can cause defective protein synthesis and uncontrolled immune response; they are associated with a range of autoimmune disorders [R].

T cells are critical components of the immune system. Activation of T cells through their receptors normally promotes regulated immune responses, such as the release of immune system messengers (cytokines) [R, R].

The PTPN22 gene codes for lymphoid tyrosine phosphatase (LYP), an enzyme that suppresses T cell activity when separated from the protein Csk [R, R]. 

Studies have shown that variants of PTPN22 may lower the interactive ability of LYP and Csk, resulting in excessive T cell suppression. This may prevent the T cell-mediated release of interleukin-2 (IL-2) [R, R]. 

IL-2 is a cytokine that promotes the development of regulatory T cells (Tregs). Tregs are involved in suppressing the formation of autoantibodies, or antibodies that recognize the body’s own tissues. In this manner, Tregs may function to prevent lupus,  rheumatoid arthritis, and other autoimmune disorders [R, R].

IL-2 also helps prevent the production of T helper 17 (Th17) immune system cells. Th17 cells release inflammatory cytokines, such as TNF-alpha [R, R]. 

Variants of PTPN22 have been associated with rheumatoid arthritis and lupus. These variants may produce a version of LYP that has low Csk-binding ability, leading to excessively low T cell activity,  autoimmunity, and inflammation [R, R, R, R, R, R, R, R, R, R, R, R, R, R, R].

Conditions associated with risk variants of PTPN22 (rs2476601-A) include but are not limited to [R, R, R, R, R, R]:

1. Rheumatoid arthritis
2. Juvenile idiopathic arthritis (a chronic joint disorder in children)
3. Type 1 diabetes
4. Lupus
5. Vitiligo (autoimmune skin discoloration)
6. Myasthenia Gravis (a type of muscle weakness)
7. Alopecia Areata (autoimmune bald spots)
8. Drug-induced liver injury 
9. Addison's Disease

Luckily, the problematic allele “A” on rs2476601 is present in 2.7% of the world population and 9.4% of the people of European ancestry. It’s nearly nonexistent in African and Asian populations.

Autoimmune diseases of the skin, gut, brain, and eyes showed a less significant association with this gene [R].

In the case of Crohn's disease, the "A" allele actually showed an inverse correlation (around 16% lower odds) [R].

As mentioned, mutations in the PTPN22 gene often lead to an overactive immune response, which may harm healthy tissue. One of the possible outcomes is autoimmune thyroid inflammation (thyroiditis).

Scientists haven’t figured out the exact mechanism by which these variations cause harm. The key may lie in defective PTP (protein tyrosine phosphatase) production, which disables the protein and prevents the removal of self-attacking lymphocytes (T and B cells) [R, R].

Additionally, PTPN22 variants may [R, R, R, R]: 

• Hinder an antimicrobial immune response
• Increase the activity of Th1 and Th17 cells
• Suppress regulatory T cells (Tregs)

As a result, the immune system creates antibodies to different structures in the thyroid gland, thus suppressing its functions and lowering thyroid hormones.

There is an ongoing debate in the scientific literature as to whether the main variant (rs2476601-A) increases or decreases PTPN22 function, and which one is better for autoimmunity. Studies have observed both effects in different conditions [R, R, R].

Mechanisms by Which PTPN22 Causes Inflammation

1) Infections seem to play a large role in the risk from this gene.

It could be that people with the risk variant [R]:

• Are more likely to get infections
• Don't clear infections promptly or effectively 
• Have more inflammation after getting an infection

One study from 2013 mentions an "intriguing possibility" that enhanced susceptibility to disease in people who carry the risk variant could result from defective type 1 interferon responses, which makes people more susceptible to both viral and bacterial infections [R].

By the same token, people with the risk variant had a decreased immune response to the flu vaccine and likely decreased protection from the vaccine [R].

PTPN22 increases the production of interferon-beta following infection; according to one study, this may lead to "T-cell exhaustion" and chronic viral infection [R]. 

2) There's an imbalance in the T cells and T Helper system (Th cells).

Studies have demonstrated a decrease in the anti-inflammatory cytokine IL-10 and an increase in Th1 cells in subjects with autoimmune disease carrying the PTPN22 variant. In engineered human T cells mimicking the variation, there was an increased Th1 response  [R, R, R].

There's evidence that Th17 cells and related cytokines are elevated, and that regulatory T cells (Tregs) are not working as well [R, R, R].

PTPN22 variants also seem to increase activated T cells, including effector and memory T cells, which can cause inflammation and autoimmunity [R, R].

3) There's a malfunction in the B cell/antibody system.

Researchers found a rise in self-attacking B cells in healthy carriers of the PTPN22 risk variant. The variant may directly contribute to the development of autoimmunity through its impact on B cell development [R].