Langerhans cells
Samplers of the skin environment.
Credit: Art by Nelli Aghekyan. Set in motion by Dr. Emanuele Petretto. Words by Semeli Platsaki. Project Coordinator: Dr. Masia Maksymowicz. Series Director: Dr. Radhika Patnala
#Extraordinarycelltypes #sciart #lifescience
The discovery: What was Paul looking at?
In 1868, an undergraduate medical student named Paul Langerhans used gold chloride to stain skin tissue, as part of a science competition in Berlin (1). The cells he visualized looked, he thought, like neurons and were named after him. It took over 100 years more, and the work of Silberberg et al. in the 1970s (2), to show that Langerhans cells (LCs) form close contacts with lymphocytes, implying a role for LCs in immune function (3, 4).
Orchestrating skin homeostasis
As it turns out, Langerhan cells orchestrate skin homeostasis by regulating tolerance versus immune response (3). If this sounds vague, imagine a world in which each external stimulus generates a severe skin reaction or one where the skin barrier does not sufficiently block pathogen intrusion. A nightmare. As the largest organ of the body and the first line of defence against the external environment, the skin holds the heavy duty of screening for danger signals and deciding whether to activate an immune response or maintain tolerance. Located at the epidermis, and representing only 3% of the skin’s cell population (4), LCs extend dendritic protrusions to the outermost layers of the skin in order to sample the skin environment (5). At the same time, they keep the skin barrier intact through tight interactions with keratinocytes (5–7). Morphologically speaking, two types of LCs have been identified, varying in shape (pyramidal versus spherical) and in the content of their cytoplasm in Birbeck granules (more versus less abundant, respectively) (4, 8). The latter are tennis racket-shaped organelles thought to have a role in pathogen retention and degradation (9).
A functional controversy!
LCs are involved in both the innate and the adaptive immune response (3, 10), with the epidermis environment itself playing an important role in the regulation of the two states. LCs travel from the skin to the draining lymph nodes during homeostasis, with this turnover rate increasing in the case of inflammation (11). In ‘times of peace’, they orchestrate a continuous immune tolerance by selectively activating the skin regulatory T cells. A constant cytokine dialogue between keratinocytes and LCs controls the in situ maturation of the latter, together with their retention in the epidermis (12, 13).
In the case of inflammation, as a first step, cytokine signaling contributes to the activation of LCs, their motility and their ability to sense pathogens (14, 15). When sensing danger, LCs instruct T lymphocytes to mount an efficient immune response. Consistent with their position in the skin they sense invading viruses (such as the human immunodeficiency virus (HIV), herpes simplex virus (HSV) or varicella zoster virus (VZV), among others) (6). Nevertheless, although they express a number of receptors dedicated to pattern recognition (a process through which molecular structures presented on the surface of pathogens are recognised, initiating the cascade of the innate immune response), they are unable to internalize bacteria, suggesting a role in priming antiviral innate immunity (6).
Incognito agents of immunity
LCs have been described as macrophages in disguise (16, 17). Originating from the bone marrow, they migrate to the epidermis to serve in antigen recognition and presentation (4). On one hand, LCs are tissue-resident macrophages (16–18), derived from common macrophage precursors located in the skin epidermis before birth (6). On the other hand, they share similarities with dendritic cells, as they are able to migrate to lymph nodes, have antigen-presenting abilities and interact with naïve T cells (19–21). In fact, LCs and dendritic cells are thought to be developmentally close, deriving from common precursor cells that differentiate according to environmental queues (4, 6). Unlike dendritic cells, directly derived from a myeloid progenitor, signaling at the level of the epidermis can modify the function and development of LCs at the very early stages of their creation (3, 22). Clearly, placing LCs in the spectrum between macrophages and dendritic cells is not an easy feat.
In sickness and in health
As the nature and function of LCs are still under investigation, their exact role in skin pathologies is not completely understood yet. In viral infections, for example, LCs have, paradoxically, been accused of both promoting and fighting viral infection, depending on the virus type. In the case of VZV, LCs promote infection by capturing virus antigens and aiding the transport of infectious virus to the lymph nodes (23–25). There, in turn, infected LCs spread the virus to T cells which then migrate to the skin to infect more keratinocytes, causing new skin lesions (26). In contrast, when HIV has to cross the mucosal barrier, as the first step of infection, LCs capture the virus and internalize it in the Birbeck granules (remember these tennis racket-shaped organelles?). In this case, LCs repress viral transmission (27).
When it comes to skin conditions, the landscape is equally divided. Atopic dermatitis is caused by a hypersensitivity of the skin to otherwise non-pathogenic factors. In this case, LCs are speculated to promote skin reactivity, through their involvement in immune response to allergens. Psoriasis, a chronic inflammatory disease of the skin, characterized by the abnormal differentiation and proliferation of keratinocytes, results in skin scaling in the affected zones and is another example in which LCs are suspected to play a role. In recent years, LCs have been shown to be one of the main populations, among other dendritic cells, that produce pro-inflammatory cytokines which, in turn, promote inflammatory signaling that precedes psoriasis (28). Finally, histiocytosis is a rare proliferative neoplastic disease in which some of the functional characteristics of the physiological cell counterpart are maintained (29). In two-thirds of LC histiocytosis cases, mutations in the RAF/MEK/ERK pathway result in the accumulation of activated LCs in lesions (30). All and all, the character and function of LCs are still rather elusive and significant breakthroughs in our understanding of their function are yet to come!
Recognizing and appreciating the labs working in this space
- Akira Takashima Lab, Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
- Patrizia Stoitzner Lab, Head of the Langerhans Cell Research Lab, Department of Dermatology, Venereology & Allergology, Medical University of Innsbruck
- Clare Bennett Lab, School of Life & Medical Sciences, Faculty of Medical Sciences, Cancer Institute, Research Department of Haematology @BennettlabUCL
- Ullrich Lab, Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas. https://www.linkedin.com/in/stephen-ullrich-13a28b11/
- Banchereau Lab, Baylor Institute for Immunology, Research, Baylor Research Institute, Dallas, Texas 75246, USA.
- Nagao Lab, Dermatology Branch, National Cancer Institute (NCI), Bethesda, MD, USA. https://www.niams.nih.gov/labs/nagao-lab
- Haematopoiesis and Immunity Laboratory, Institute of Clinical and Translational Research, Newcastle University, UK. https://research.ncl.ac.uk/hilab/research/ @HI_Lab_NCL
- Marta Polak, Systems Immmunology Group, Clinical and Experimental Sciences, Sir Henry Wellcome Laboratories, Faculty of Medicine, University of Southampton, Southampton, UK.
References
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2. Clayton, Kalum et al. “Langerhans Cells-Programmed by the Epidermis.” Frontiers in immunology vol. 8 1676. 29 Nov. 2017, doi:10.3389/fimmu.2017.01676
3. Silberberg, I et al. “The role of Langerhans cells in allergic contact hypersensitivity. A review of findings in man and guinea pigs.” The Journal of investigative dermatology vol. 66,4 (1976): 210–7. doi:10.1111/1523–1747.ep12482139
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26. Leinweber, Bernd et al. “Histopathologic features of cutaneous herpes virus infections (herpes simplex, herpes varicella/zoster): a broad spectrum of presentations with common pseudolymphomatous aspects.” The American journal of surgical pathology vol. 30,1 (2006): 50–8. doi:10.1097/01.pas.0000176427.99004.d7
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About the author:
DR. SEMELI PLATSAKI
Content Editor The League of Extraordinary Cell Types, Sci-Illustrate Stories
Semeli is a biochemist at heart, holding a degree in Chemistry and a PhD in protein biochemistry. After working as a researcher studying the structure-function relationship of protein in a range of biological contexts, from bacterial metalloproteins to synaptic signaling, Semeli moved on to a role in Scientific communication and project management in the European Virus Archive, a collection of virus and virus-derived resources available to researchers worldwide. Semeli is passionate about the creative mix of art, words and science, one of the best ways to make Science impactful.
About the artist:
NELLY AGHEKYAN
Contributing Artist The League of Extraordinary Cell Types, Sci-Illustrate Stories
Nelli Aghekyan, did a bachelor’s and master’s in Architecture in Armenia, after studying architecture and interior design for 6 years, she concentrated on her drawing skills and continued her path in the illustration world. She works mainly on children’s book illustrations, some of her books are now being published. Currently living in Italy, she works as a full-time freelance artist, collaborating with different companies and clients.
About the animator:
DR. EMANUELE PETRETTO
Animator The League of Extraordinary Cell Types, Sci-Illustrate Stories
Dr. Petretto received his Ph.D. in Biochemistry at the University of Fribourg, Switzerland, focusing on the behavior of matter at nanoscopic scales and the stability of colloidal systems. Using molecular dynamics simulations, he explored the delicate interaction among particles, interfaces, and solvents.
Currently, he is fully pursuing another delicate interaction: the intricate interplay between art and science. Through data visualization, motion design, and games, he wants to show the wonders of the complexity surrounding us.
About the series:
The League of Extraordinary Cell types
The team at Sci-Illustrate and Endosymbiont bring to you an exciting series where we dive deep into the wondrous cell types in our body, that make our hearts tick ❤.
