IL-23: The Master Regulator Behind Plaque Psoriasis

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Imagine if your immune system was a symphony orchestra lead by a conductor. The conductor’s job is to direct the groups of instruments to play together in order to create a harmonious piece of music that keeps your body healthy and balanced. People who have plaque psoriasis have immune systems whose orchestra is a little off.

 

In the body of a person who suffers from plaque psoriasis, some sections of the orchestra play faster than others, which leads to an overactivation of the immune system. This manifests as inflammation (such as redness, swelling) and excessive production of cells that appear on the skin’s surface as silvery-white plaques and flakes on the elbows, knees, scalp, and lumbar area. Anyone who suffers from plaque psoriasis understands the shame and anxiety it can evoke, which can affect everything from self-esteem to interpersonal relationships to job performance. This strong psychological impact is why new scientific findings about better pathways for treatment are so significant.

 

The History of Biologics

Historically, scientists believed that plaque psoriasis was a disorder of the skin cells, which resulted in many skin-focused treatments. However, over the last forty years scientists have begun to better understand the true source of plaque psoriasis, an overactive immune system.  More specifically, studies showed that plaque psoriasis is caused by overactive T-cells—lymphocytes produced by the thymus gland and are actively involved in our immune responses. In psoriasis, these overactive cells can lead to elevated levels of tumor necrosis factor, which is secreted via the inflammatory process. Cytokines are a category of signaling proteins that move around the body and attach to various cells and then stimulate those cells to behave in different ways, which in turn regulate immune responses in the body. With a better understanding of the underlying cause of plaque psoriasis, scientists identified several pathways as possible targets to treat the disease on a molecular level.

 

Approximately 20 years ago, researchers began treating the condition with a new class of drugs called biologics that directly targeted the immune response. The first generation of these drugs were TNF-alpha agents that targeted the tumor necrosis factor to limit the immune response. However, the discovery of additional immune pathways associated with plaque psoriasis allowed for updated biologics that were more targeted in blocking the immune response. In particular, IL-17 and IL-23 antagonists proved to be highly effective, resulting in dramatic improvements in ∼80–90% of psoriasis patients.

 

With the discovery of IL-23 as the “master regulator” of T17 cells, several antagonists against the p19 subunit of IL-23 were investigated for the treatment of psoriasis. In 2000, around the time where some of the biologics were just starting to be used, scientists at the DNAX Research Institute in Palo Alto, California were looking to develop a more targeted biologic medication to treat immune disorders like plaque psoriasis. Dr. Birgit Oppman and Dr. Robert Kastelein and their team initially observed the IL-23 molecule as a novel sequence in a computational screen. They hypothesized that IL-23, a cytokine produced predominately by inflammatory myeloid cells, was another key conductor that was causing the immune system to get out of sync. They didn’t understand, however, how IL-23 attached to these cells.

 

Dr. Iannis Adamopoulos, an Associate Professor at the Univeristy of California at Davis, who also worked with Dr Kastelein after the discovery of IL-23 has worked extensively on the role of IL-23 in the pathogenesis of plaque psoriasis. Through his work, Dr. Adamopoulos has demonstrated that IL-23 interacts with many cell types in different tissues, including the skin, joints, and bones, and causes abnormal immune responses that produce diseases like plaque psoriasis.

 

This understanding was critical because it allowed for the development of more targeted biologics that could block IL-23 and therefore restore harmony to the overactive immune system orchestra. ILUMYA is one recently developed IL-23 blocking drug for the management of moderate-to-severe plaque psoriasis. Unlike some other psoriasis treatments that need to be administered weekly or monthly, ILUMYA patients receive their shot every twelve weeks after two starter doses. This means a long lasting effect, with six out of ten patients achieving clearer skin after only two doses (at 12 weeks).

 

The Future of IL-23

Recently Dr. Adamopoulos collaborated with Dr. Savvides, a structural biologist at the VIB Insitute, Ghent in Belgium to further solve the structure of the IL-23 and IL-23 receptor complex. Both are required for IL-23 signaling. This discovery allowed them to point to the specific molecular interactions that can inhibit skin inflammation in an animal model of psoriasis which is similar to the skin pathology observed in plaque psoriasis.

 

Dr. Adamopoulos hopes that future research into how the puzzle pieces of each receptor fit together will lead scientists to an even better understanding of how to treat plaque psoriasis.

 

“We can only make speculations at the moment,” he says. “I don’t think there’s just one pathway that is active in this disease, but rather many pathways.”

 

Dr. Adamopoulos is optimistic that with a better understanding of these pathways, scientists will be able to predict better signaling and interactions that were previously not appreciated. This understanding, he says, will contribute to even more direct and effective therapies for plaque psoriasis and other immune diseases.

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