The Langerhans cell - the little star of the epidermis
The human epidermis acts as the body’s main barrier to the outside world. Preventing the entrance of noxious substances and reducing water loss from the body to the external environment. The outer most layer of the skin is made up of about 90% keratinocytes. The rest is made up primarily of melanocytes situated on the basal layer of the epidermis producing melanin which to the surrounding keratinocytes. The remaining percentage of cells are predominantly nerve endings such as Meissner’s corpuscles, Merkel’s cells and free nerve endings but spare a thought for the forgotten cell of the epidermis – the Langerhans cell. Small in number they maybe (about 4% of the epidermis) but they perform a major in role within the epidermis.
The Langerhans cell has an interesting history. It was a cell discovered by chance by Paul Langerhans in 1868, who as a medical student in Germany studying anatomy, assumed them to be neural in origin but it wasn’t for another century until further research discovered their true origin as a leucocyte derived cell (part of the immune system in the skin) unique in mammals. The Langerhans cell is a dendritic cell meaning it is an antigen presenting cell – able to latch onto, process and present antigens to T cells on its cell surface. They can be found as star shaped cells within all areas of the epidermis and histologically they contain dark-staining spots known as Birbeck granules. Additionally, they may also be observed in the oral mucosa, gut, urinary tract and lungs. Most numerous in the stratum spinosum, they have upward projections towards and into the stratum corneum.
Like other dendritic cells, LC’s arise in the bone marrow and then travel to the skin (and other areas) to take up their role as part of the body’s immune-surveillance system from about 12 weeks in utero. Two morphological forms have been shown to exist – type 1 (Pyramidal shaped) LC’s and type 2 which are more spherical in shape with fewer distinctive Birbeck granules.
In any area of the epidermis you may find around 500-100mm2 but curiously the soles and palms have a much lower number of LC’s than skin elsewhere – the reason or consequence of this is unknown. Their function is to patrol the epidermis and effectively “sample” the area in search of non-self or antigens such as bacteria, fungi and viral particles. Recently, this process has been observed in studies and the motion of cell extension and retraction as it samples surrounding cells has been labelled “dSEARCH” (dendrite surveillance extension and retraction cycling (1). In addition, Langerhans cells have been seen to exchange antigens between them by cell-to-cell contact, perhaps as a mechanism to allow a greater area to be searched more efficiently.
The LC is able to recognise pathogens through identifying molecular patterns on potential pathogens as it is equipped with receptors (known as toll-like receptors). When a potential antigen discovered the LC will assimilate such material by phagocytosis. Internally, it is processed by lysosomes and then expressed on the cells surface as a receptor complex. These are displayed on either major histocompatibility complexes I or II (MHC I / II) located on the cell surface. Interaction of pathogenic molecules with surface receptors promote release of chemical mediators which then enhance Langerhans cell function further promoting their migration and antigen presentation abilities to the T cells.
In order to present the material to the T cells, the LC must migrate to the lymph and this is facilitated by local cytokine release (from keratinocytes) which occurs following infection or trauma to the local tissues. These include IL-1, TNF-α and other growth factors. On arrival within the lymph node a complex interaction occurs which is able to prime naïve T cells to respond to generate the appropriate response. The presence of MHC type I and II has individual stimulatory effects on CD8+ cytotoxic T cells and CD4+ T helper cells to promote immunity. CD8+ cytotoxic cells subsequently are then primed to recognise the surface antigen and destroy the affected cells within the local area. With ageing, the numbers of Langerhans cells are known to reduce, along with sensitivity. This may explain, in part, why elderly skin is less likely to succumb to allergy, but chronic skin infection is more of a feature.
Langerhans cells, infection and immune-evasion
The description above gives an interesting insight into Langerhans cell function but as we are all well aware this system can fail, and infection may become established. A few studies in warts have been undertaken looking at Langerhans cell function. The persistence of a warts, for example, maybe due to many related processes. Certainly, it has been established that wart virus infected cells have lower numbers of Langerhans cells within them whilst surrounding skin has normal numbers. In addition, further studies have elucidated that HPV persistence in the skin is facilitated by mechanisms which “blind” the Langerhans cell to the presence of the viral infection. The PI3K pathway is a known HPV tactic which is activated during infection reducing LC potency. Any new treatment developments should look at methods which can lift suppression and therefore allow the start of the epidermis to do its job and maintain order within the epidermis.
Udey MC. Langerhans Cells on Guard in the Epidermis: Poised to dSEARCH and …? J Invest Dermatol. 2006;126(4):705-7.
Jakob, T. (2017). "The changing faces of Langerhans cells." Journal of the European Academy of Dermatology and Venereology 31(11): 1773-1773.
Sparber, F. (2014). "Langerhans cells: an update." JDDG: Journal der Deutschen Dermatologischen Gesellschaft 12(12): 1107-1111.