SH2B3

SH2B3 encodes SH2B adapter protein 3. It keeps inflammation in check by suppressing cytokines such as TNF-alpha, IL-6, and IL-1b. Due to certain genetic variants, SH2B3 may fail to control an overactive immune response, opening the door to autoimmunity.Variants of SH2B3 may play a role in:

• high blood pressure by increasing B2M and inflammatory cytokines. 
• lupus and other autoimmune diseases by increasing Th1 cell activity and autoantibody production.
• allergies by altering the Th1/Th2 balance and increasing eosinophil counts.
• Protecting against celiac disease by suppressing T-cells, inflammatory cytokines, and auto-antibodies.

Lifestyle, diet, and supplement modifications may counteract the effects of these variants by decreasing IL-6 and TNF-alpha, the Th1 and Th2 immune response, and eosinophil counts.

Links T-cell receptor activation signal to phospholipase C-gamma-1, GRB2 and phosphatidylinositol 3-kinase.

The SH2B3 gene codes for SH2B adapter protein 3, also known as the lymphocyte adaptor protein LNK. This protein helps regulate an array of essential pathways, including [R, R]:

• Inflammation and the immune response
• Blood cell formation (hematopoiesis)
• Cell growth and migration

Due to its wide range of functions, SH2B3 has considerable significance for human health. Studies have linked its variants with different autoimmune conditions, heart disease, blood disorders, and more [R, R].

Studies of bone marrow transplants have revealed that SH2B3 regulates blood pressure through its expression in the tissues that grow and build new blood cells [R].

In a study of over 7,000 people, those with lower SH2B3 gene expression had higher levels of a protein called beta-2 microglobulin (β2M or B2M) circulating in their blood. Higher B2M, in turn, is associated with higher blood pressure measurements [R].

SH2B3 also decreases the expression of multiple inflammatory cytokines that have been implicated in high blood pressure [R, R].

More specifically, SH2B3 fine-tunes the production of IL-6, IL-1b, and TNF-alpha [R, R, R].

SH2B3 primarily regulates the function of T cells and has been associated with relative numbers of eosinophils (a type of white blood cell). It may suppress Th1 cell response and prevent autoimmunity by inhibiting the formation of auto-antibodies [R, R, R].

Some evidence suggests this gene may also be involved in fine-tuning the inflammatory response. For example, a rare human case of a genetic SH2B3 loss resulted in severe autoimmune disease, along with other developmental issues. In mice without this protein, scientists have observed over-production of inflammatory cytokines [R, R, R].

Because of these factors, it’s unsurprising that SH2B3 has been associated with lupus [R, R, R].

However, when the Th1 response is suppressed, the Th2 response may increase to compensate. The Th2 response is responsible for allergic inflammation, so this change may increase susceptibility to allergies. This is an example of why it’s so important to keep Th1 and Th2 in balance [R, R].

Celiac disease (CD) is an immune gut disorder in which gluten, a protein found in most grains, damages the small intestine. The immune cells recognize gluten as a threat and trigger an aggressive inflammatory response, usually causing digestive issues and malabsorption [R, R].

Scientists are still investigating the exact role of SH2B3 in CD development. This protein helps balance the immune response by reducing the activity of T-cells, pro-inflammatory cytokines, and various growth factors, which also has an effect on thyroid health [R].

More precisely, SH2B3 may suppress Th-1 cell response, which is crucial for CD development. It may also prevent autoimmunity by inhibiting the formation of auto-antibodies [R].

In thyroid autoimmunity, overactive T cells stimulate the production of different thyroid antibodies. SH2B3 acts to prevent this by keeping pro-inflammatory cytokines — such as TNF-alpha and IL-6 — in check [R, R, R].

Some evidence suggests this gene may also be involved in suppressing or fine-tuning the inflammatory response. For example, a rare human case of a genetic SH2B3 loss resulted in early-onset Hashimoto's disease, along with other developmental issues [R]. In mice without this protein, scientists have observed over-production of inflammatory cytokines [R].

These findings suggest a significant suppressive effect of the SH2B3 protein on cytokines that keeps inflammation in check. Hence, SH2B3 variants associated with thyroid autoimmunity probably reduce the activity of this gene, which then fails to suppress self-attacking antibodies. More research will be needed to clarify the exact mechanisms further.