Lupus Study Identifies Potential SLE Cure Through AHR Activation

The autoimmune condition lupus – formally termed systemic lupus erythematosus (SLE) – is difficult to manage and burdensome for those living with it.

Its unpredictable episodes of pain, inflammation and fatigue are a "cruel mystery" with no known cause. Affecting 1.5 million people in the United States, the disease can irreparably damage almost any organ, including the kidneys, brain and heart.

Helper T cells and lupus imbalance

Helper T cells, a type of immune cell, are known to be excessively active in people with SLE. Researchers may now have pinpointed an important underlying cause. A thorough investigation by scientists at Northwestern University and Brigham and Women's Hospital examined the process in detail and uncovered an imbalance that might be driving other symptoms.

"Up until this point, all therapy for lupus is a blunt instrument. It's broad immunosuppression," explains immunologist Jaehyuk Choi from Northwestern University.

"By identifying a cause for this disease, we have found a potential cure that will not have the side effects of current therapies."

The study was carried out by dozens of researchers, led by Northwestern biochemical scientist Calvin Law and Brigham and Women's Hospital immunologists Vanessa Sue Wacleche and Ye Cao. Their results indicate that the immune systems of people with lupus are fundamentally out of balance.

Blood tests from 19 people with SLE and 19 participants without an autoimmune condition revealed important differences in the expression of various helper T-cell types.

These vital immune cells prompt the creation of other immune cells that make antibodies – proteins which normally attach to foreign substances and pathogens, marking and neutralising them.

To grasp why the varying T-cell expression matters, picture a tug-of-war. The knot at its centre represents a T cell that can adopt two distinct forms. Pulled in one direction, the cell is expressed in a particular way and becomes one kind of helper T cell. Pulled the other way, it is expressed in the opposite manner.

AHR activation and type I interferon

In people without an autoimmune condition, powerful forces activate the aryl hydrocarbon receptor (AHR), pulling the T cell decisively towards one side.

This receptor is considered "critical in the regulation of innate and adaptive immunity", and has been linked to several autoimmune conditions, including multiple sclerosis, inflammatory bowel disease and SLE.

For people with SLE, however, AHR on T cells is not activated sufficiently. A competing force, driven by a signalling molecule known as type I interferon, appears to pull the T cell away from its usual expression and role.

This produces an excess of immune cells that encourage autoantibodies. These attack the body's own cells and prompt further type I interferon production, forming a positive feedback loop.

When the team added AHR-activating molecules back into blood samples from people with lupus, the immune cells returned to balance.

"We found that if we either activate the AHR pathway with small molecule activators or limit the pathologically excessive interferon in the blood, we can reduce the number of these disease-causing cells," says Choi.

"If these effects are durable, this may be a potential cure."

A treatment based on these results remains a long way from being shown to be safe and effective for SLE. Yet, given the limited options currently available to patients, the findings offer a promising beginning.

"We think that the opportunity here is to not broadly suppress the immune system for patients with autoimmune disease," Choi explains, "but reprogram the cells that are actually causing the disease."

The study was published in Nature.