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Psoriasis and beyond: targeting the IL-17 pathway

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Psoriasis is a chronic inflammatory skin disorder that affects about 2-3% of the population. It is triggered by the immune system, and new insights into the immune processes have thrown up a number of exciting drug targets. This Nature Reviews Drug Discovery animation explores how the immune system goes awry in psoriasis and illustrates how agents that target the cytokine interleukin 17, or other players in the same pathway, are being developed into novel therapies for psoriasis.

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 can improve the condition skin has three major tissue segments the epidermis is composed largely 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 differentiates into cornea sites 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 major 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 key role in orchestrating overall immune responses in many ways the immune pathways that become activated in psoriasis are amplifications of the immune activity of normal skin however the trigger for this inflammatory disease is unknown current models proposed that dendritic

Cells sense stressed keratinocytes and invading microorganisms and start to respond by producing signaling molecules known as cytokines these activate t cells and other immune cells which in turn produce their own 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 1 cells which are pro-inflammatory and t helper 2 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 produced two important cytokines il-12 and il-23 il-12 induces the differentiation of t helper 1 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 a number of 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 il-17 as

Il-17 functions mainly locally in the skin and in mucosal tissues such agents may have fewer side-effects and current drugs which acts systemically and they might be effective in patients who don’t respond to therapies that target tnf alpha the first of these agents has 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 you

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Psoriasis and beyond: targeting the IL-17 pathway By nature video