A Potential Target to Prevent One Class of Autoimmune Diseases
Autoimmune diseases, in which the immune system malfunctions to attack the patient's own tissues, are a challenge to investigate. The immune system is enormously complex, and making a definitive determination of the specific problems in its regulation that cause autoimmunity has yet to be achieved for most forms of autoimmune disease. Fortunately there has been some progress, such as the identification of age-associated B cells as necessary in the development of autoimmunity, and here the determination that JunB is critical to some autoimmune diseases. In both cases, these mechanisms might be targeted to produce broadly effective therapies. Yet even in absence of any useful targets, if there was a way to safely destroy all immune cells - without the use of damaging chemotherapeutic drugs that cause significant side-effects and mortality - then all autoimmune diseases could be cured. Malfunctions are a matter of state, and that state is stored in the immune cells themselves; if they are all removed, and the immune system allowed to repopulate itself from scratch, then this effectively restores a pristine and correctly functioning state.
Most of the current treatments against auto-immune diseases require to shut down major parts of the immune system, inhibiting desirable immune responses and, leaving the patient vulnerable to potentially life-threatening bacterial and viral infections. Such a drastic solution is required because until now scientists had yet not fully identified a different mechanism in these rogue cells they could use as a selective target - the known genetic material was common between healthy and rogue cells. But researchers have reported a previously undiscovered role for a known molecule - named "JunB" - and its associated gene: JunB seems to be essential for a specific type of white blood cell to turn toxic.
The scientists were investigating T Helper white blood cells, which coordinate the immune system response by secreting a diverse range of communication signals in the shape of molecules called interleukins. JunB operates in 'T Helper 17' cells, a subdivision that specifically promotes the initial immune response against an infection. But sometimes, these T Helper 17 cells turns rogue and become toxic for our guts and joints. "We have a lot of T Helper 17 cells in our guts. They have three major impacts on our body: first to maintain a healthy gut and second to deal with bacterial and fungi infections. The third is their toxicity leading to auto-immune diseases, which is something we want to avoid."
The scientists studied the process in which T-Helper 17 cells become toxic. One of the immune system communication molecules - interleukin 23 - is required to "wake up" T-Helper 17 cells during an infection and make it start fighting the invaders. But interleukin 23 is a double-edged sword: it also responsible for sometimes triggering the same T Helper 17 cell to turn rogue. For T helper 17 cells to hear the wake-up call, they need to display interleukin 23 receptors on their surface, which means the corresponding gene - usually switched off - needs to be activated. Finding a way to stop this interleukin 23 receptor gene from being activated is potentially key to shut down the entire process. And this is where JunB, the focus of this research, comes into play.
JunB is a transcription factor, which means it regulates - switches on and/or off - the activity of a gene or a group of genes in the cell's DNA. Researchers identified JunB by systematically checking transcription factors in the T Helper 17 cell DNA. For this purpose, they would "knock down" - meaning disrupt the gene DNA sequence - the genes for each transcription factor one by one. For each knocked down gene, they checked if the T Helper 17 cell still display its interleukin-23 receptors. When they knocked down JunB, they realized the T Helper 17 cells were no longer displaying interleukin 23 receptors and were unable to turn rogue. Moreover, mice in which T Helper cells lacked JunB were incapable of developing T Helper 17-related auto-immune diseases. An exciting part of this research is that T Helper 17 cells deprived of JunB are still able to accumulate in the gut and likely to cope and fight infections. Therefore, if scientists design a drug able to target JunB specifically, it should prevent T Helper 17 cells from turning rogue without impacting the immune system as a whole.