Article previously published in the Cutaneous Lymphoma Foundation's Forum Summer 2011 newsletter.
Most people with cutaneous T-cell lymphoma or CTCL have itching but few have been successful in finding relief from this symptom. Why aren’t there good drugs available to relieve itch?
The reason is that remarkably little was known or investigated about the basic mechanisms that underlie itch until the past several years. The medical community may not have recognized the widespread nature and importance of the problem and the fascination that comes along with understanding itch. That is now changing rapidly. A brief overview of the past, present and future is presented here.
The sensation of itch begins when keratinocytes, a type of skin cell, and sensory nerves in the skin are stimulated and communicate with each other. The result is that a signal is transmitted along these nerves to what is essentially a way station just outside the spinal cord. At this way station, called the dorsal root ganglion, a signal is passed to another set of nerves that run from the spinal cord to the brain. The brain interprets the signal as the sensation of itch and tells you to scratch.
What stimulates the keratinocytes or nerves in the skin or spinal cord and what exactly is being stimulated on them? This is where there has been substantial progress in the past few years. Physicians and patients alike were long frustrated by the limited relief brought by anti-histamines. When histamine is injected into the skin, the sensation of itch ensues and a hive develops. But most itches are not associated with hives. Thus, something other than histamine must be causing itch. It was only in 2008 that researchers found that there were two pathways in the skin that led to itch. One pathway depended on histamine while the other was independent of histamine. At the same time, our research group was studying the pods of a tropical plant known to cause intense itching but not hives. We identified a protein from the plant that was responsible for the itch. We went on to show that there was an equivalent protein in people. The human protein is called cathepsin S. Cathepsin S is a protease, meaning that it cuts other proteins. Cathepsin S was known to be involved in inflammation. Since proteases are good targets for drug development (all of the drugs for HIV are against viral proteases) and inflammation is important, drugs that target cathepsin S are under development. Maybe these will be useful for itch.
But where does cathepsin S come from?
T-cells, which are the tumor cell in CTCL, produce cytokines, similar to hormones. Certain cytokines induce keratinocytes to make cathepsin S. Keratinocytes also make several other proteases including ones called kallikreins. And what do these proteases have to do with itch? Well, they act on something called a receptor that is present on both keratinocytes and nerves. The particular receptor is called protease-activated receptor 2, or PAR2, and several years ago it was found that PAR2 is important in mediating itch. T-cells can also make a molecule called interleukin-31 or IL-31. IL-31 binds to its own receptor on keratinocytes and sensory nerves and appears to be important in atopic dermatitis, or eczema. The role of IL-31 in CTCL needs to be investigated.
The above is a snapshot of just some of the work happening in itch in the skin. Already there are drugs in development that target proteases and drugs that target IL-31. And what about the spinal cord? Exciting research in the past few years has uncovered a molecule and receptor in the spinal cord that are important to itch. The molecule is a small protein called gastrin-releasing peptide or GRP and its receptor is called the gastrin-releasing peptide receptor or GRPR. And where did GRP come from? It was first identified in the skin of frogs and called bombesin, but that’s a story for another day.
Ethan A. Lerner, MD/PhD is an Associate Professor of Dermatology at Harvard Medical School. His research group at Massachusetts General Hospital in Boston is devoted to understanding the basic mechanisms of itch. He is grateful to the National Institutes of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) for support.
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