ETS1

ETS1 encodes ETS proto-oncogene 1 transcription factor. This gene encodes a protein that turns ‘on’ and ‘off’ multiple genes, including those involved in the development of immune cells. It also helps stem cell development, cell death, and formation of tumors.It has been associated with celiac disease and other immune conditions. Variants of ETS1 may play a role in rheumatoid arthritis by increasing B cell activity and the production of autoantibodies (R).

Lifestyle, diet, and supplement modifications may counteract the effects of these variants by reducing B cell activity and decreasing autoantibody production.

Transcription factor. Directly controls the expression of cytokine and chemokine genes in a wide variety of different cellular contexts. May control the differentiation, survival and proliferation of lymphoid cells. May also regulate angiogenesis through regulation of expression of genes controlling endothelial cell migration and invasion.

The ETS1 gene encodes a protein called ETS proto-oncogene 1 transcription factor. This gene is involved in the development of stem cells, and it has been implicated in multiple types of cancer. Just as the other 27 members of the ETS family, ETS1 binds to DNA to turn ‘on’ and ‘off’ the expression of multiple genes [R, R, R].

ETS1 is mainly expressed in the bone marrow and thymus, as well as in immune cells produced by these tissues such as T cells, B cells, NK cells, and NKT cells. ETS1 promotes the development, activity, and survival of the following cell types [R, R, R, R]:

• Th1 [R]
• Th2 [R]
• CD8+ [R]
• Tregs [R]
• NK [R, R]
• NKT [R]

In contrast, it prevents the development of Th17 and B cells [R, R, R].

Researchers’ understanding of ETS1 as a potential driver of autoimmunity is fairly recent. However, it has already been linked to systemic lupus erythematosus (SLE) and rheumatoid arthritis [R, R].

New research suggests that ETS1 is required to prevent autoimmunity in animals and humans. According to one study, mice without ETS1 have significantly higher than normal B and T cell activity. These same mice also produce autoantibodies (antibodies that attack their own tissues) at much higher rates, leading to autoimmune disease [R].

Other research has found that ETS1 expression is actually higher than normal in rheumatoid arthritis, however [R, R].

Researchers believe that inflammatory cytokines TNF-alpha and IL-1 directly cause ETS1 to increase. Thus, high expression of ETS1 in rheumatoid arthritis may be a symptom rather than a cause of destructive inflammation—that is, ETS1 itself doesn’t destroy joint tissues; it is upregulated by the system that does [R].

ETS1 is also involved in the production of different cytokines and chemokines by these and other cell types, as well as in the activation of cytokine-related pathways [R].

Celiac disease is an immune disorder triggered in response to gluten, a protein found in grains such as wheat, barley, and rye. The immune cells recognize gluten as a threat and mount an aggressive inflammatory response that damages the small intestine and causes digestive issues and nutrient deficiencies due to poor absorption [R, R].

More specifically, the activation of CD4+ T cells by gluten causes their development into Th1 cells and the release of inflammatory cytokines such as IFN-γ and IL-21 [R, R, R, R].

Other immune cells such as CD8+ and Th17 cells can also recognize gluten and trigger inflammation in response to this protein [R, R].

The contribution of ETS1 to celiac disease may be due to its role in the development of any of these cell types.

The only ETS1 polymorphism associated with celiac disease is rs11221332. A computer program predicted that the ‘T’ variant may alter the protein production process, and possibly ETS1 levels and activity [R].

In a European study on British, Finnish, Dutch, and Italian populations, the minor allele was one of the variants associated with celiac disease [R].

In contrast, this variant protected against rheumatoid arthritis in a Greek study. Because a more recent Chinese study failed to replicate this result, the authors concluded that ethnic differences may play a key role in this association [R, R].

The ‘T’ variant didn’t increase susceptibility to an autoimmune disease of the liver (primary biliary cirrhosis) in a Chinese study, but carriers had two blood markers of this condition (high total protein and HDL-cholesterol levels) [R].

Illustrating the role of the ETS1 gene in immune function, other polymorphisms have been associated with the following conditions:

• Lupus (rs1128334, rs6590330, rs10893872, and rs7932088) [R, R, R]
• Rheumatoid arthritis (rs73013527) [R]
• Ankylosing spondylitis (rs1128334) [R]
• Primary biliary cirrhosis (rs4937333) [R]
• Psoriasis (rs3802826) [R]