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Nov 19, 2013

Unexpected Twist in Understanding How Skin Wards Off Infection

  • Researchers at the Australia-based Walter and Eliza Hall Institute, along with investigators at the NIH, have discovered that Langerhans cells, which provide the first line of defense of microbial attacks through the skin, come in two different types. It had long been thought that these cells were all genetically identical and had the same function, according to the scientific team.

    This surprise finding (“Langerhans cells are generated by two distinct PU.1-dependent transcriptional networks”) was just published in the Journal of Experimental Medicine. The researchers believe their discovery could have repercussions for developing and refining therapies for skin infections and skin cancers.

    “Langerhans cells are produced and found in the skin and are quite unique among immune cells because they do not have a definite lifespan; they can last for a lifetime,” said the Institute’s Stephen Nutt, Ph.D. “They are only replaced when necessary, such as when the skin is damaged by a burn or a cut. When that happens, new Langerhans cells have to be produced by the bone marrow. These cells look the same, so it was always thought that they were genetically the same and their function was the same. We have shown that this isn't the case.”

    Although Langerhans cells were discovered nearly 150 years ago, Michael Chopin, Ph.D., also at the Institute, pointed out that there were still a lot of gaps in our knowledge about how they develop and their role in responding to foreign invaders. Dr. Chopin said the research team was initially trying to understand the role of Langerhans cells. “Not everything that makes contact with the skin is harmful, so it is important the immune system doesn't overreact,” he said. “We were trying to find out whether Langerhans cells were there to activate an immune response to invaders, or to suppress the immune system to prevent it from overreacting.”

    “We addressed the function of a group of key DC transcription factors—PU.1, ID2, IRF4, and IRF8—in the establishment of the LC [Langerhans cells] network. We show that although steady-state LC homeostasis depends on PU.1 and ID2, the latter is dispensable for bone marrow–derived LCs,” wrote the scientists. “PU.1 controls LC differentiation by regulating the expression of the critical TGF-β responsive transcription factor RUNX3. PU.1 directly binds to the Runx3 regulatory elements in a TGF-β–dependent manner, whereas ectopic expression of RUNX3 rescued LC differentiation in the absence of PU.1 and promoted LC differentiation from PU.1-sufficient progenitors. These findings highlight the dual molecular network underlying LC differentiation, and show the central role of PU.1 in these processes.”

    “While designing the experiment, we found that the genes that define the Langerhans cells that are produced in the skin were different to those of Langerhans cells that came from bone marrow,” added Dr. Chopin. “In essence we now know that there are two different types of Langerhans cells where we thought there was one. We now need to find out if they behave differently as well.”

    Dr. Nutt said the research could explain why some promising new drugs have not had the desired effect in the clinic. “Some clinical trials of drugs that were designed to help boost Langerhans cells in response to infections have not responded as the researchers expected,” explained Dr. Nutt. “Our finding may help explain why these drugs didn't work outside the laboratory, and our current research may provide guidance in developing therapeutics to treat skin infections or skin cancer.”



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