Genetic defect leads to excess NF-kappaB activation in autoimmune conditions

NF-kB is the master regulator – the primary means by which inflammation is ‘adjusted’ – turned on and off. Many, many different molecules interact with NF-kB – some stimulating it (increasing inflammation) and others inhibiting it (decreasing inflammation.) The balance between these positive and negative forces determines the extent of inflammation at any given time.

However, the system is not ‘static.’ Various products of inflammation can stimulate further inflammation – or they may inhibit further inflammation. When the products of inflammation inhibit further inflammation, that is a negative feedback loop. Without these negative feedback loops, or with dysfunctional or poorly functioning negative feedback loops, it is difficult to stop inflammation once it gets started.

TNFAIP3 is a key player in some of these negative feedback loops. it’s important. Without properly functioning TNFAIP3, NF-kB might remain set in the “more inflammation” position.

In the study referenced below, researchers found a mutation at the genetic site controlling TNFAIP3. That genetic mutation is associated with Crohn’s disease, rheumatoid arthritis, systemic lupus erythematosus, psoriasis, type 1 diabetes and other inflammation related disease conditions.

This indicates the importance of  TNFAIP3.

It also indicates the importance of NF-kB as the master switch.

It also suggests yet another possible reason why those with one inflammation related condition are more likely to have others as well.

The ubiquitin-editing enzyme A20 (TNFAIP3) is a central regulator of immunopathology.


Nuclear factor kappaB (NF-kB) plays an important role in immunity, and excess NF-kB activity has been associated with many autoimmune and inflammatory diseases. Multiple mechanisms normally ensure the proper termination of NF-kB activation.

TNFAIP3 is a key player in the negative feedback regulation of NF-kB signaling in response to multiple stimuli.

Recent studies have shown a clear association between mutations in TNFAIP3 and conditions such as Crohn’s, rheumatoid arthritis, lupus, psoriasis and diabetes. These findings suggest its importance in inflammation its possible modification as a means to prevent or treat these human pathologies.

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