These scaly red patches are the hallmarks of a common condition called psoriasis. It's a disease involving immune cells. This was discovered by chance when in the late 1970s scientists noticed that the immunosuppressive drugs cyclosporine could improve the condition.
The skin has three primary tissue segments. The epidermis is composed mainly of specialized cells called keratinocytes. These originate from a single layer of basal keratinocytes, which divide continuously and give rise to cells that migrate towards the skin's surface. During this process, they progressively differentiate into corneocytes, which form a protective barrier.
Below the epidermis is the dermis. Here cells called fibroblasts secrete fibers that form a dense extracellular matrix. This layer also contains hair follicles, sweat glands, sebaceous glands, and blood capillaries as well as lymphatic vessels. These are a primary conduit for immune cells such as macrophages, dendritic cells, and T-cells.
Dendritic cells can capture foreign antigen and present it to T-cells. T-cells are immune effector cells, they can broadly be divided into cytotoxic T-cells, which directly kill infected cells, and T-helper cells that play a vital role in orchestrating overall immune responses.
In many ways, the immune pathways that become activated in psoriasis are amplifications of the immune activity of the healthy skin. However, the trigger for this inflammatory disease is unknown. Current models propose that dendritic cells sense stressed keratinocytes and invading microorganisms and start to respond by producing signaling molecules known as cytokines. These activated T-cells and other immune cells, which in turn produce their cytokines. Those signals stimulate keratinocytes to proliferate and to secrete further mediators and create a vicious cycle of inflammatory responses. Overall, this results in an accumulation of immune cells and the formation of a thickened inflamed epidermis.
Several biologic drugs have been developed to target inflammatory mediators in psoriasis. The most widely used agents for severe psoriasis dampened down cytokine TNF alpha. But that treatment doesn't work for everyone. Up to a third of patients ultimately do not respond.
However, in the past decade insights into T-cell biology have uncovered some promising new drug targets. Traditionally T-helper cells have been classified into two subsets:
- T-helper-one cells, which are pro-inflammatory;
- T-helper-two cells, which are anti-inflammatory.
However, the picture has become much more complicated with the identification of many other subsets. Which subset a T-helper cell will belong to depends on the cytokines it encounters when it first interacts with a dendritic cell. Each subset can then be told apart because they secrete characteristic cytokines. In the context of psoriasis and inflammation, T-helper-17 cells have attracted particular attention. They're part of a group known as type-17 cells because they produce the cytokine IL-17. This cytokine can promote chronic inflammation and tissue destruction.
In psoriasis, dendritic cells produce two important cytokines IL-12 and IL-23. IL-12 induces the differentiation of T-helper-one cells, which produce the cytokines interferon gamma and TNF alpha. IL-23 in turn induces T-helper -17 cells, which make IL-17 and other pro-inflammatory cytokines.
Scientists are now developing some biologic drugs that are targeted at IL-17 and other elements of the IL-17 signaling cascade. Interesting targets include IL-23 - a shared subunit of both IL-12 and IL-23, the different isoforms of IL-17 and the IL-17 receptor as well as a protein that's required for the production of IL-17. As IL-17 functions mainly locally in the skin and mucosal tissues, such agents may have fewer side-effects than current drugs, which act systemically and they might be effective in patients, who don't respond to therapies that target TNF alpha. The first of these agents have already been approved for psoriasis, and others have shown promising results in clinical trials. Many of these are also in development for other inflammatory diseases including rheumatoid arthritis, asthma, and colitis, making the IL-17 cascade one of the hottest targets for inflammatory diseases.