Aryl Hydrocarbon Receptors and Lupus

A receptor called the Aryl Hydrocarbon Receptor has been revealed as a key factor for lupus. Is it going to be a target for treatment?

Lupus is an autoimmune disease, which means that the body’s Immune system attacks itself. When it is working properly, the immune system fights infection, heals damage, and protects the body. It is a complicated system with many moving parts, and you can read more about it, here. Normally, the immune system corrects itself and avoids attacking its own cells. In lupus, this regulation is not working properly, and aryl hydrocarbon receptors are part of this. 

What is AHR? 

The immune system has many ways that it regulates itself, and receptors are one of them. Receptors ‘receive’ other molecules. Some of these are molecules that the cells of our body need to function, others are messengers that our cells use to communicate with each other. The aryl hydrocarbon receptor (AHR) is a little different – it detects what is happening in the body and makes sure that the body responds.  

Aryl hydrocarbon receptors are tolerogenic – it enables the immune system to not react to everything that it encounters. AHR ‘receives’ a wide range of molecules, linking up to many different kinds of allergens, chemicals in the environment, and essentially anything that might end up in the body from the outside world.  

Depending on the molecule, AHR changes shape and signals the cells to produce certain molecules. These immune system molecules signal the body to react in different ways. In a sense, AHR acts as a sort of “detector” for toxins coming in from the environment or produced by infections.  

You can read about a different immune system signalling protein, B-Cell activating factor here.  

What does AHR do? 

AHR helps the immune system react correctly to invaders from the outside world, like bacteria and pollutants, dead cells in the body, and other changes in blood chemistry like metabolized medications or drugs. It is found in and on cells throughout the body, particularly in immune system-related cells, and mainly detects anything that actually can get into the cell itself. It then moves to the nucleus of the cell and triggers the production of molecules that control the immune system, among other things. 

AHR is a regulatory molecule – it tunes the immune system into the correct response. In some cases, it turns up the immune response. Other times, it turns down the immune system response. It effects many different cells, including CD4 T-Cells, which are cells in the immune system that specialize in fighting diseases that use the body’s own cells. Specifically, CD4 T-Cells, which are a type of white blood cell that attacks viruses and tumors, and in a healthy immune system, they are able to avoid harming non-infected cells. When they are not working properly, or are overreacting due to general inflammation, they can start to attack healthy cells as well.  

Previous research has noted that many different immune system molecules and factors affect the production, ‘quality control’ and reactivity of T-cells. This includes ‘leaky gut’ syndrome, which introduces particles into the bloodstream that are not supposed to be there. While the particles themselves usually aren’t directly damaging the body, they rile up the immune system and leading to inflammation. You can read more about them here.  

Though ‘leaky gut’ syndrome interacts with aryl hydrocarbon receptors, this doesn’t appear to be hugely correlated with lupus according to Frontiers in Immunology. (Interestingly, it does interact with UV light! You can read more about UV light, light sensitivity, and lupus, here.)  

When the Aryl hydrocarbon receptor in particular is not working properly, or is blocked from working by excessive levels of interferon, the immune system starts reacting to pollutants in the environment that it isn’t supposed to. When this happens, allergies, inflammation, and organ damage can come as a result. The body also becomes less able to focus on and properly deal with actual threats like viruses and bacteria.  

For these reasons, AHR is potentially a key factor in how lupus works as a chronic autoimmune disorder.  

What’s the Research on AHR? 

Most studies indicate that aryl hydrocarbon receptor, when activated, reduces autoimmune symptoms by reducing inflammation in the body. AHR receptor activators were being investigated as a known inflammation inhibitor, but researchers thought that the medications were too potent and could cause harm. However, medical technology has progressed to a point where we can make more targeted and lower-impact therapies, and we understand how AHR works much better.  

In a 2024 study, researchers wanted to see if they could restore the function of AHR in people with lupus. In theory, this is possible – when they added medication to blood samples of people with lupus, it did seem to limit the T cells in the sample. It has also been tested in mouse models, but the effects seem to be very different for mice versus humans. 

There have also been clinical trials looking at AHR and cancer. There, blocking aryl hydrocarbon receptors using a drug called BAY 2416964 was being investigated as a way to reduce the inflammation ‘noise’ and allow the immune system to better attack the cancer tumors. This ‘noise’ is why we don’t want the body to react to everything it comes across – there are other ways for the body to deal with environmental pollutants. If there isn’t as much noise, the immune system, in theory, will make fewer ‘mistakes’ targeting healthy cells. In this case, the researchers were hoping that targeting AHR would make the immune response more powerful, instead of suppressing it, because they wanted the immune system to attack and destroy the cancerous cells.  

While promising initially, the clinical trial didn’t lead to consistent benefits for people with cancer. This is likely also going to be the case for people with lupus. The formula of the drug will need to be tweaked, potentially. Due to the complexity of the immune system, it will likely need to be taken in combination with other therapies. You can read more about medications used for lupus here. So not a ‘magic bullet’ for lupus, and not available for a while. You can read more about how clinical trials work here.  

A Lupus Warrior’s Takeaway 

AHR is an interesting and vital part of the immune system and a potential target for treating lupus. However, it is not the only immune system molecule known to be involved with lupus, it has many different effects on the immune system (depending on what it comes into contact with,) and it has many other roles in the body that are still not fully understood. While therapies and medications that target specific immune system molecules are potential game changers for people with lupus, they are also not a one-size-fits-all deal. Still, it’s another potential option for people with lupus on the horizon, and that’s reason enough to be optimistic for the future.