Psoriasis mechanism of disease: Pathogenesis
Oregon Medical Research Center
In this installment of Discourses in Dermatology, Dr Andrew Blauvelt, a dermatologist from Portland, Oregon and investigator at Oregon Medical Research Center, sits down with Dr Jason Hawkes, a medical dermatologist from Sacramento, California, to discuss the pathogenesis of psoriasis. Over the course of their conversation, they provide an overview of the immunology of psoriasis, explore the relationship between IL-23 and IL-17, highlight the isoforms that dermatologists need to know, and examine the role of TNF in the pathogenesis of psoriasis.
Overview of the immunology of psoriasis
Dr Hawkes begins with a high-level overview and considers the primary signal that drives the clinical features of psoriasis dermatologists see in the clinic. He notes that IL-17, both IL-17A and IL-17F, is the cytokine that drives the hyperproliferative effects in psoriasis, with IL-23 helping sustain those T cells and making high levels of IL-17. He comments that this serves as the predominant role of what drives psoriasis.
Another aspect he considers is the skin once it’s been activated. Once it’s in the hyperproliferative state, it begins making its own signals like IL-17C, IL-19, and CCL20, which go back to the immune system to reactivate dendritic cells and T-cells. This is a feed-forward cycle that begins with the IL-23 and IL-17 axis activating the skin cells and signals coming back that activate the dendritic cells and T cells further, creating a chronic cycle of disease. This serves as the framework by which we can then examine the nuances of psoriasis.
- IL-17 (both A and F) is the cytokine that drives the hyperproliferative effects in psoriasis
- IL-23 helps to sustain T-cells and make high levels of IL-17
The IL-23 and IL-17 axis activates skin cells with signals coming back that activate dendritic cells and T cells, which creates a feed-forward cycle that promotes a chronic cycle of disease
The relationship between IL-23 and IL-17
Dr Hawkes remarks that he views IL-23 as the regulatory signal that helps T cells differentiate into IL-17-producing T cells. Th17 is commonly discussed, but T-17 must also be mentioned since it includes both the CD4+ and CV8+ T cells.
He summarizes the relationship between IL-23 and IL-17 by explaining that IL-23 is upstream of IL-17 and helps T cells differentiate into IL-17 high-producing cells. From IL-17-producing T cells, we see both IL-17A and IL-17F. Dr Hawkes also mentions IL-17C, which is produced by keratinocytes as opposed to IL-17A and F which come from T cells.
- IL-23 is the regulatory signal that helps T cells differentiate into IL-17-producing cells
- IL-17A and IL-17F come from IL-17-producing T cells
IL-17C is produced by keratinocytes
Isoforms that dermatologists need to know
Dr Blauvelt comments on the number of different isoforms included in A though F and asks Dr Hawkes which key IL-17 cytokines are important for dermatologists to know about when it comes to the pathogenesis of psoriasis.
Dr Hawkes explains that there are 6 dimeric cytokines in the IL-17 family, IL-17 A through IL-17 F. These cytokines can pair, so there may be an IL-17 AA homodimer or an AF for example, which is relevant in driving psoriasis. He notes that not much is known about IL-17 B, D, E.
He identifies 3 cytokines that are important for dermatologists to pay attention to. IL-17A and IL-17 F are primarily produced by the T cells. The AA homodimer, the AF heterodimer, and the FF homodimer are the key signals from the T cell compartment.
From the keratinocytes, we see IL-17 C.
He remarks that we don’t yet know the role of the other IL-17 cytokines play in psoriasis, but IL-17 A, F, and C drive the predominant features we see in the immune compartment and in the keratinocyte or epidermal compartment.
- There are 6 dimeric cytokines in the IL-17 family (A-F)
- These cytokines can pair, which is relevant in driving psoriasis
IL-17A, F, and C drive the predominant features of psoriasis
The role of TNF in psoriasis pathogenesis
Dr Blauvelt continues the conversation by introducing tumor necrosis factor (TNF). He believes TNF is made all over as opposed to specifically upstream, midstream, or downstream and asks Dr Hawkes for his input on where TNF fits into the psoriasis pathogenesis picture.
Dr Hawkes agrees and describes TNF as a very potent proinflammatory signal and a cytokine that changes thousands of genes compared to hundreds with IL-17 and IL-23.
This creates a big activating system. There are portions of it upstream; plasmacytoid dendritic cells make high levels of interferon and the myeloid or mature dendritic cells make high levels of TNF, but we also see TNF working much further downstream.
He references research from Dr James Krueger’s laboratory that has shown IL-17 has its own impact on the skin as does TNF being proinflammatory, but together, that synergy creates a much more powerful impact. We see other cytokines as working with those predominant signals with IL-23 and IL-17, and they’re working to potentiate or amplify the proinflammatory effect.
Dr Hawkes notes that many residents have asked how TNF inhibitors work if IL-23 and IL-17 are so central. He replies that the blockade of TNF helps to indirectly reduce levels of IL-17 because it’s an upstream signal like IL-23. By blocking it, it also blocks the potentiating effects and magnifying synergistic effects that IL-17 has on the skin driving hyperproliferation. Because it’s broad acting, it works in different levels.
He also comments on the downside of TNF having that broader impact versus more targeted agents. He describes this as immune collateral damage, but it’s also not a very strong potent inhibitor of that central pathway of IL-17 and IL-23. Those targeted agents have a better way of shutting off the driving signal.
Dr Blauvelt concludes by describing TNF blockers as anti-inflammatory in general, which is why they work for a variety of inflammatory diseases. and IL-17s and IL23s as much more targeted to psoriatic inflammation, which is why we don’t see a lot of the side effects seen with TNF blockers.
- TNF is a potent proinflammatory signal and cytokine that changes thousands of genes, creating a large activation system
- The synergy between IL-17 and TNF creates a powerful impact
- TNF indirectly reduces levels of IL-17, thus blocking magnifying synergistic effects that IL-17 has on driving hyperproliferation
- The broad impact of TNF can be described as immune collateral damage
- IL-17s and IL-23s are much more targeted to psoriatic inflammation versus TNF blockers, which are anti-inflammatory in general