Langerhans Cell and Dendritic Cell Homeostasis in Human Skin
Matthew Collin MD
Newcastle University – Newcastle upon Tyne, United Kingdom
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Langerhans cell histiocytosis (LCH) is a rare but sometimes fatal disorder of unknown cause. The Langerhans cell (LC) normally inhabits the skin and respiratory system in low numbers and is part of the immune system. Patients with LCH may have abnormal collections of LC in the bone, skin, lungs, brain and other organs which cause deformity, metabolic problems and life-threatening complications.
We are trying to find out why LC accumulate in histiocytosis by studying the normal development of these cells. In the past, it has been assumed that LC came from a bone marrow derived cell that enters the tissues at a steady rate from the bloodstream. However, recent evidence from mice suggests that LC are dividing, self-renewing cells, that may grow continuously in the tissues, independently of the bone marrow. Whether this is also true in humans is not known but it is vital for understanding the cause of LCH: it means that LCH may be directly related to abnormal regulation of LC proliferation in the tissues rather than a problem with cells originating in the bone marrow. This concept might explain why many patients with LCH have single or focal lesions rather than widespread disease.
We are testing the idea that LC normally replicate in the tissues by measuring the proliferation of human LC in skin cultured in vitro. We will then use this to test growth factors and inhibitors that influence the rate of proliferation, allowing us to demonstrate which biochemical pathways are functioning in LC and to identify potential drug targets for LCH.
To prove that the replication of LC is important in vivo in humans we will examine the LC of a number of patients with bone marrow failure (myelodysplasia) or genetically abnormal bone marrow (chronic myelpgenous leukemia). In bone marrow failure, the blood precursor cells are lost and LC will become depleted unless they can replenish themselves. In genetically abnormal bone marrow, the LC will become marked with abnormal genes only if they are continuously replaced by cells from the blood. Although these studies do not involve LCH patients they are ‘experiments of nature’ that will tell us about the way LC are controlled in the body and how loss of control might lead to LCH.