Is This Gene Causing Your Autoimmune Problems? (PTPN22)

PTPN22 is a protein that regulates the development and function of T cells, B cells, and other immune system components [R].

PTPN22 can boost the immune system, suppress inflammation, and fight viral and bacterial infections. Often, boosting the immune system and combating inflammation are contradictory, which makes PTPN22 very interesting and complex [R].

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].

However, most studies agree about the downstream consequences of PTPN22 variations.

PTPN22 helps prevent excessive inflammation and fight infections. Risk variants of this gene can contribute to various autoimmune disorders, but scientists are still bickering about the exact mechanism.

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].

The PTPN22 risk variant (rs2476601-A) contributes to autoimmunity by:
 – Being less capable of fighting infections
 – Increasing T cell, Th1 and Th17 activity
 – Suppressing regulatory T cells (Tregs)
 – Activating B cells and self-attacking B cells

The Power of Tregs

Regulatory T cells or Tregs produce interleukin IL-10, both of which inhibit inflammation and uncontrolled immune response [R].

They suppress the over-activated Th1, Th2, and Th17 cells and their cytokines, thus preventing your immune cells from attacking your tissue [R, R, R, R].

Hashimoto’s

According to a study conducted on almost 40,000 people, two PTPN22 variations—rs2476601 (R620W, C1858T, Arg620Trp) and rs6679677—are crucial genetic contributors to autoimmune-based hypothyroidism [R].

Carriers of minor “A” alleles on one of these variations have a 36% higher odds of hypothyroidism, compared with people who carry major alleles (G and C, respectively).

Hashimoto’s disease is the leading cause of low thyroid hormones in the west [R].

Other Autoimmune Conditions

Besides autoimmune hypothyroidism, the conditions associated with risk variant (rs2476601-A) include but are not limited to [R, 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. Grave’s disease (autoimmune hyperthyroidism)
6. Vitiligo
7. Myasthenia Gravis
8. Drug-induced liver injury 
9. Alopecia Areata
10. Addison's Disease
11. Idiopathic inflammatory myopathies
12. Immune thrombocytopenia
13. Anti-neutrophil cytoplasmic antibody-associated vasculitis

Other PTPN22 variants associated with autoimmune diseases include:

• rs6679677-A 
• rs2488457-G (mostly rheumatoid arthritis and type 1 diabetes)
• rs33996649-C (mostly rheumatoid arthritis and ulcerative colitis)

Autoimmune diseases of the skin, gut, brain and eyes overall showed a less significant association with PTPN22 [R].

In the case of Crohn's disease, the risk allele (rs2476601-A) for other autoimmune conditions actually showed a protective effect (around 16% lower odds) [R].

Risk variants of PTPN22 increase the risk of 14+ autoimmune conditions. It doesn't seem to negatively affect autoimmune conditions related to the skin, gut, eyes or brain as much.

SNP Summary

The two main SNPs—rs2476601 and rs6679677—are almost always inherited together. The “A” risk alleles are somewhat rare, appearing in only about 5% of global population. They are much more common in people of European descent, clocking in at 18% of all people [R, R].

Primary SNPs: 

PTPN22 rs2476601

• “A” allele increases your risk of autoimmune problems
• “G” allele doesn’t increase the risk

PTPN22 rs6679677

• “A” allele increases your risk of autoimmune problems
• “C” allele doesn’t increase the risk

Other important SNPs:

PTPN22 rs2488457

• “G” allele increases your risk of autoimmune problems
• “C” allele lowers your risk of autoimmune problems

The highest-risk genotype (GG) on rs2488457 is much more common in East Asian than in European descendants: 36% vs. 5.5%. At the same time, this variant has a bigger impact on Asian people.

PTPN22 rs33996649

• “T” allele lowers your risk of autoimmune problems
• “C” allele increases your risk of autoimmune problems

The risk allele (C) on rs33996649 is present in 95% of European descendants and almost 100% of other populations, so you shouldn’t worry too much about it.