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Langerhans cell
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{{Short description|Macrophage cell of the skin}} {{distinguish|text=the cells of the [[islets of Langerhans]] in the pancreas, or [[Langhans giant cell]]}} {{Infobox cell | Name = Langerhans cell | Image = Dendritic cells.jpg | Caption = Section of skin showing large numbers of Langerhans cells in the [[Epidermis (skin)|epidermis]]. (''[[M. ulcerans]]'' infection, S100 [[immunoperoxidase|immunoperoxidase stain]].) | Image2 = | Caption2 = | System = [[Immune system]] | Precursor = | Function = [[Dendritic cell]] | Pronunciation = | Location = [[Skin]] and [[mucosa]] | Acronym = }} [[File:The representation of Langerhans cells in the Cell Ontology.jpg|thumb|300px|The representation of Langerhans cells in the Cell Ontology. A portion of the Cell Ontology is shown with ovals corresponding to cell types defined in the ontology and arrows corresponding to relations between those cell types. Langerhans cell is represented by a yellow oval; blue arrows correspond to is_a relations, and orange arrows correspond to develops_from relations. Only a subset of Langerhans cell parent types are included in the figure.<ref name="pmid19243617">{{cite journal |doi=10.1186/1471-2105-10-70 |title=An improved ontological representation of dendritic cells as a paradigm for all cell types |year=2009 |last1=Masci |first1=Anna |last2=Arighi |first2=Cecilia N |last3=Diehl |first3=Alexander D |last4=Lieberman |first4=Anne E |last5=Mungall |first5=Chris |last6=Scheuermann |first6=Richard H |last7=Smith |first7=Barry |last8=Cowell |first8=Lindsay G |journal=BMC Bioinformatics |volume=10 |pages=70 |pmid=19243617 |pmc=2662812 |doi-access=free }}</ref>]] A '''Langerhans cell''' ('''LC''') is a tissue-resident [[macrophage]] of the skin<ref>{{cite journal | url=https://pubmed.ncbi.nlm.nih.gov/28720426/ | title=Langerhans Cells – The Macrophage in Dendritic Cell Clothing | year=2017 | pmid=28720426 | last1=Doebel | first1=T. | last2=Voisin | first2=B. | last3=Nagao | first3=K. | journal=Trends in Immunology | volume=38 | issue=11 | pages=817–828 | doi=10.1016/j.it.2017.06.008 }}</ref> once thought to be a resident [[dendritic cell]].<ref>{{cite web | url=https://meshb.nlm.nih.gov/record/ui?ui=D007801 | title=MeSH Browser }}</ref> These cells contain organelles called [[Birbeck granules]]. They are present in all layers of the [[epidermis]] and are most prominent in the [[stratum spinosum]].<ref name="Wheaters">{{cite book |title=Wheater's Functional Histology |edition=4th |last1=Young |first1=Barbara |last2=Heath |first2=John W. |year=2000 |publisher=Churchill Livingstone |isbn=0-443-05612-9 |page=162}}</ref> They also occur in the [[papillary dermis]], particularly around blood vessels,<ref name=Wheaters /> as well as in the [[oral mucosa|mucosa of the mouth]], [[foreskin]], and [[vaginal epithelium]].<ref name=pmid7558138 /> They can be found in other tissues, such as [[lymph node]]s, particularly in association with the condition [[Langerhans cell histiocytosis]] (LCH). ==Function== In [[skin]] [[infection]]s, the local Langerhans cells take up and process [[microbe|microbial]] [[antigen]]s to become fully functional [[antigen-presenting cell]]s.<ref name="Monnot">{{cite journal | vauthors = Monnot GC, Wegrecki M, Cheng TY, Chen YL, Sallee BN, Chakravarthy R, Karantza IM, Tin SY, Khaleel AE, Monga I, Uwakwe LN, Tillman A, Cheng B, Youssef S, Ng SW, Shahine A, Garcia-Vilas JA, Uhlemann AC, Bordone LA, Han A, Rohde CH, Ogg G, Moody DB, Rossjohn J, de Jong A| title = Staphylococcal phosphatidylglycerol antigens activate human T cells via CD1a | journal = Nature Immunology | volume = 24 | issue = 1 | pages = 110–122 | date = January 2023 | pmid = 35265979 | doi = 10.1038/s41590-022-01375-z| s2cid = 255039948 | pmc = 10389259 }}</ref> Generally, tissue-resident macrophages are involved in immune homeostasis and the uptake of [[Apoptosis|apoptotic bodies]]. However, Langerhans cells can also take on a [[dendritic cell]]-like phenotype and migrate to [[lymph node]]s to interact with [[naive T-cell]]s.{{Medical citation needed|date=June 2021}} [[Matrix metalloproteinase]] is important and necessary for langerhans cell when it passes [[stratum basale]].<ref>{{Cite journal |last=Ratzinger |first=Gudrun |last2=Stoitzner |first2=Patrizia |last3=Ebner |first3=Susanne |last4=Lutz |first4=Manfred B. |last5=Layton |first5=Guy T. |last6=Rainer |first6=Christian |last7=Senior |first7=Robert M. |last8=Shipley |first8=J. Michael |last9=Fritsch |first9=Peter |last10=Schuler |first10=Gerold |last11=Romani |first11=Nikolaus |date=2002-05-01 |title=Matrix metalloproteinases 9 and 2 are necessary for the migration of Langerhans cells and dermal dendritic cells from human and murine skin |url=https://pubmed.ncbi.nlm.nih.gov/11970978/ |journal=Journal of Immunology |volume=168 |issue=9 |pages=4361–4371 |doi=10.4049/jimmunol.168.9.4361 |issn=0022-1767 |pmid=11970978}}</ref> Langerhans cells derive from primitive erythro-myeloid progenitors that arise in the yolk sac outside the [[embryo]] in the first trimester of pregnancy, and under normal circumstances persist throughout life, being replenished by local [[Cell proliferation|proliferation]] as necessary. If the skin becomes severely inflamed, perhaps because of infection, blood monocytes are recruited to the affected region and [[Cellular differentiation|differentiate]] into replacement LCs.<ref>{{cite journal |doi=10.1097/MOH.0000000000000202 |title=Langerhans cell origin and regulation |year=2016 |last1=Collin|first1=Matthew|last2=Milne|first2=Paul |journal=Current Opinion in Hematology |volume=23 |issue=1 |pages=28–35 |pmc=4685746 |pmid=26554892}}</ref> [[Langerin]] is a protein found in Langerhans cells,<ref name="pmid14610287">{{cite journal |doi=10.1385/IR:28:2:93 |title=Langerin/CD207 Sheds Light on Formation of Birbeck Granules and Their Possible Function in Langerhans Cells |year=2003 |last1=Valladeau |first1=Jenny |last2=Dezutter-Dambuyant |first2=Colette |last3=Saeland |first3=Sem |journal=Immunologic Research |volume=28 |issue=2 |pages=93–107 |pmid=14610287|s2cid=37296843 }}</ref> and [[dendritic cells]].<ref name="pmid18086861">{{cite journal |doi=10.1084/jem.20071724 |title=The dermis contains langerin+ dendritic cells that develop and function independently of epidermal Langerhans cells |year=2007 |last1=Poulin |first1=Lionel Franz |last2=Henri |first2=Sandrine |last3=de Bovis |first3=Béatrice |last4=Devilard |first4=Elisabeth |last5=Kissenpfennig |first5=Adrien |last6=Malissen |first6=Bernard |journal=Journal of Experimental Medicine |volume=204 |issue=13 |pages=3119–31 |pmid=18086861 |pmc=2150992 |url=http://pure.qub.ac.uk/portal/files/18113605/JEM1_2008.pdf |access-date=2018-11-04 |archive-url=https://web.archive.org/web/20180719214424/https://pure.qub.ac.uk/portal/files/18113605/JEM1_2008.pdf |archive-date=2018-07-19 |url-status=dead }}</ref> '''LCs''' contain a large amount of [[cannabinoid receptor type 2]] (CB2), that by activation by [[SR-144,528|agonists]], attenuate both the recruitment of [[eosinophil]]s and ear [[Allergy|swelling]] in chronic [[contact dermatitis]] induced by repeated challenge.<ref>{{Cite journal |last=Oka |first=Saori |date=2006 |title=Involvement of the Cannabinoid CB2 Receptor and Its Endogenous Ligand 2-Arachidonoylglycerol in Oxazolone-Induced Contact Dermatitis in Mice |url=https://journals.aai.org/jimmunol/article/177/12/8796/74027/Involvement-of-the-Cannabinoid-CB2-Receptor-and |access-date=2023-03-26 |journal=Journal of Immunology |volume=177 |issue=12 |pages=8796–9505 |doi=10.4049/jimmunol.177.12.8796 |pmid=17142782 |s2cid=11946479 |doi-access=free }}</ref> ==Clinical significance== ===Langerhans cell histiocytosis=== In the [[rare disease]] [[Langerhans cell histiocytosis]] (LCH), an excess of cells similar to these cells are produced. However LCH cells stain positive to [[CD14]] which is a monocyte marker and shows a different, hematopoietic origin for the disorder.<ref>{{cite web|url=http://medicine.yale.edu/urology/programs/info.aspx?id=CDR600550|title=NCI Summary View > Urology - Yale School of Medicine|website=medicine.yale.edu|access-date=19 April 2018|archive-url=https://web.archive.org/web/20190617091828/https://medicine.yale.edu/urology/programs/info.aspx?id=CDR600550|archive-date=17 June 2019|url-status=dead}}</ref> LCH can cause damage to [[skin]], [[bone]] and other organs.{{citation needed|date=June 2023}} ===HIV=== Langerhans cells may be initial cellular targets in the sexual transmission of HIV,<ref>{{cite journal |doi=10.1016/j.jdermsci.2005.08.009 |title=The role of Langerhans cells in the sexual transmission of HIV |year=2005 |last1=Kawamura |first1=Tatsuyoshi |last2=Kurtz |first2=Stephen E. |last3=Blauvelt |first3=Andrew |last4=Shimada |first4=Shinji |journal=Journal of Dermatological Science |volume=40 |issue=3 |pages=147–55 |pmid=16226431}}</ref> and may be a target, reservoir, and vector of dissemination.<ref>{{cite journal |last1=Dezutter-Dambuyant |first1=C |last2=Charbonnier |first2=AS |last3=Schmitt |first3=D |title=Cellules dendritiques épithéliales et infection par HIV-1 in vivo et in vitro |trans-title=Epithelial dendritic cells and HIV-1 infection in vivo and in vitro |language=fr |journal=Pathologie Biologie |volume=43 |issue=10 |pages=882–8 |date=December 1995 |pmid=8786894}}</ref> Langerhans cells have been observed in foreskin, vaginal, and oral mucosa of humans; the lower concentrations in oral mucosa suggest that it is not a likely source of [[HIV]] infection relative to foreskin and vaginal mucosa.<ref name="pmid7558138">{{cite journal |pmid=7558138 |year=1995 |last1=Hussain |first1=LA |last2=Lehner |first2=T |title=Comparative investigation of Langerhans' cells and potential receptors for HIV in oral, genitourinary and rectal epithelia |volume=85 |issue=3 |pages=475–84 |pmc=1383923 |journal=Immunology}}</ref> === Human papillomavirus === High-risk [[human papillomavirus]]es (HPV) are sexually transmitted viruses causally associated with several cancers including cervical, vaginal, anal, and head and neck cancers that cause significant morbidity and mortality worldwide.<ref>{{Cite journal|title = Human papillomavirus is a necessary cause of invasive cervical cancer worldwide|journal = The Journal of Pathology|date = 1999-09-01|issn = 0022-3417|pmid = 10451482|pages = 12–19|volume = 189|issue = 1|doi = 10.1002/(SICI)1096-9896(199909)189:1<12::AID-PATH431>3.0.CO;2-F |first1 = J. M.|last1 = Walboomers|first2 = M. V.|last2 = Jacobs|first3 = M. M.|last3 = Manos|first4 = F. X.|last4 = Bosch|first5 = J. A.|last5 = Kummer|first6 = K. V.|last6 = Shah|first7 = P. J.|last7 = Snijders|first8 = J.|last8 = Peto|first9 = C. J.|last9 = Meijer| s2cid=1522249 }}</ref><ref>{{Cite journal|title = Worldwide burden of cervical cancer in 2008|journal = Annals of Oncology|date = 2011-12-01|issn = 1569-8041|pmid = 21471563|pages = 2675–2686|volume = 22|issue = 12|doi = 10.1093/annonc/mdr015|first1 = M.|last1 = Arbyn|first2 = X.|last2 = Castellsagué|first3 = S.|last3 = de Sanjosé|first4 = L.|last4 = Bruni|first5 = M.|last5 = Saraiya|first6 = F.|last6 = Bray|first7 = J.|last7 = Ferlay|doi-access = free}}</ref><ref>{{Cite journal|title = Human papillomaviruses and cancer|journal = Radiotherapy and Oncology|date = 2013-09-01|issn = 1879-0887|pmid = 23830197|pages = 397–402|volume = 108|issue = 3|doi = 10.1016/j.radonc.2013.06.004|first1 = Juliane|last1 = Haedicke|first2 = Thomas|last2 = Iftner|doi-access = free}}</ref><ref>{{Cite journal|title = Human papillomavirus infection in head and neck cancer: The role of the secretory leukocyte protease inhibitor|journal = Oncology Reports|date = 2013-05-01|issn = 1021-335X|pmc = 3658815|pmid = 23467841|pages = 1962–1968|volume = 29|issue = 5|doi = 10.3892/or.2013.2327|first1 = MARKUS|last1 = HOFFMANN|first2 = ELGAR S.|last2 = QUABIUS|first3 = SILKE|last3 = TRIBIUS|first4 = LENA|last4 = HEBEBRAND|first5 = TIBOR|last5 = GÖRÖGH|first6 = GORDANA|last6 = HALEC|first7 = TOMAS|last7 = KAHN|first8 = JÜRGEN|last8 = HEDDERICH|first9 = CHRISTOPH|last9 = RÖCKEN}}</ref> Over half of all [[cervical cancer]] cases are associated with HPV16, the most common of the cancer-causing high-risk genotypes.<ref>{{Cite journal|title = Prevalence of human papillomavirus in cervical cancer: a worldwide perspective. International biological study on cervical cancer (IBSCC) Study Group|journal = Journal of the National Cancer Institute|date = 1995-06-07|issn = 0027-8874|pmid = 7791229|pages = 796–802|volume = 87|issue = 11|first1 = F. X.|last1 = Bosch|first2 = M. M.|last2 = Manos|first3 = N.|last3 = Muñoz|first4 = M.|last4 = Sherman|first5 = A. M.|last5 = Jansen|first6 = J.|last6 = Peto|first7 = M. H.|last7 = Schiffman|first8 = V.|last8 = Moreno|first9 = R.|last9 = Kurman|doi=10.1093/jnci/87.11.796}}</ref> During its natural life cycle, HPV16 infects the basal cells of the epithelium and interacts with Langerhans cells within the epithelial layer,<ref>{{Cite journal|title = HPV: from infection to cancer|journal = Biochemical Society Transactions|date = 2007-12-01|issn = 0300-5127|pmid = 18031245|pages = 1456–1460|volume = 35|issue = Pt 6|doi = 10.1042/BST0351456|first1 = M. A.|last1 = Stanley|first2 = M. R.|last2 = Pett|first3 = N.|last3 = Coleman}}</ref> which are responsible for initiating immune responses against epithelial invading pathogens.<ref>{{Cite journal|title = Origin, homeostasis and function of Langerhans cells and other langerin-expressing dendritic cells|journal = Nature Reviews. Immunology|date = 2008-12-01|issn = 1474-1741|pmid = 19029989|pages = 935–947|volume = 8|issue = 12|doi = 10.1038/nri2455|first1 = Miriam|last1 = Merad|first2 = Florent|last2 = Ginhoux|first3 = Matthew|last3 = Collin|s2cid = 22286432}}</ref> However, HPV does not activate Langerhans cells ''in vitro'', and this may represent a key mechanism by which HPV evades immune detection ''in vivo''.<ref>{{Cite journal|title = Human papillomavirus virus-like particles do not activate Langerhans cells: a possible immune escape mechanism used by human papillomaviruses|journal = Journal of Immunology|date = 2002-09-15|issn = 0022-1767|pmid = 12218143|pages = 3242–3249|volume = 169|issue = 6|first1 = Steven C.|last1 = Fausch|first2 = Diane M.|last2 = Da Silva|first3 = Michael P.|last3 = Rudolf|first4 = W. Martin|last4 = Kast|doi=10.4049/jimmunol.169.6.3242|doi-access = free}}</ref><ref>{{Cite journal|title = Differential uptake and cross-presentation of human papillomavirus virus-like particles by dendritic cells and Langerhans cells|journal = Cancer Research|date = 2003-07-01|issn = 0008-5472|pmid = 12839929|pages = 3478–3482|volume = 63|issue = 13|first1 = Steven C.|last1 = Fausch|first2 = Diane M.|last2 = Da Silva|first3 = W. Martin|last3 = Kast}}</ref><ref>{{Cite journal|title = Human papillomavirus can escape immune recognition through Langerhans cell phosphoinositide 3-kinase activation|journal = Journal of Immunology|date = 2005-06-01|issn = 0022-1767|pmid = 15905561|pages = 7172–7178|volume = 174|issue = 11|first1 = Steven C.|last1 = Fausch|first2 = Laura M.|last2 = Fahey|first3 = Diane M.|last3 = Da Silva|first4 = W. Martin|last4 = Kast|doi=10.4049/jimmunol.174.11.7172|doi-access = free}}</ref><ref>{{Cite journal|title = A major role for the minor capsid protein of human papillomavirus type 16 in immune escape|journal = Journal of Immunology|date = 2009-11-15|issn = 1550-6606|pmid = 19864613|pages = 6151–6156|volume = 183|issue = 10|doi = 10.4049/jimmunol.0902145|first1 = Laura M.|last1 = Fahey|first2 = Adam B.|last2 = Raff|first3 = Diane M.|last3 = Da Silva|first4 = W. Martin|last4 = Kast|pmc = 2947488|doi-access = free}}</ref> Specifically, HPV16 entry into Langerhans cells via the [[annexin A2]]/[[S100A10]] heterotetramer results in suppressive signaling and lack of Langerhans cell-mediated immune responses.<ref>{{Cite journal|title = Inhibition of Langerhans cell maturation by human papillomavirus type 16: a novel role for the annexin A2 heterotetramer in immune suppression|journal = Journal of Immunology|date = 2014-05-15|issn = 1550-6606|pmc = 4019435|pmid = 24719459|pages = 4748–4757|volume = 192|issue = 10|doi = 10.4049/jimmunol.1303190|first1 = Andrew W.|last1 = Woodham|first2 = Adam B.|last2 = Raff|first3 = Laura M.|last3 = Raff|first4 = Diane M.|last4 = Da Silva|first5 = Lisa|last5 = Yan|first6 = Joseph G.|last6 = Skeate|first7 = Michael K.|last7 = Wong|first8 = Yvonne G.|last8 = Lin|first9 = W. Martin|last9 = Kast}}</ref> This Langerhans cell-targeted immune escape mechanism seems to be conserved among different HPV genotypes enabling these viruses to remain undetected in the absence of other inflammatory events.<ref>{{Cite journal|title = Suppression of Langerhans cell activation is conserved amongst human papillomavirus α and β genotypes, but not a μ genotype|journal = Virology|date = 2014-03-01|issn = 1096-0341|pmc = 3987942|pmid = 24606705|pages = 279–286|volume = 452–453|doi = 10.1016/j.virol.2014.01.031|first1 = Diane M.|last1 = Da Silva|first2 = Carly A.|last2 = Movius|first3 = Adam B.|last3 = Raff|first4 = Heike E.|last4 = Brand|first5 = Joseph G.|last5 = Skeate|first6 = Michael K.|last6 = Wong|first7 = W. Martin|last7 = Kast}}</ref> T cells exposed to these inactivated Langerhans cells are not anergic, and can be activated against HPV upon receiving the appropriate stimuli at a later time point.<ref>{{Cite journal|last1=Woodham|first1=Andrew W.|last2=Yan|first2=Lisa|last3=Skeate|first3=Joseph G.|last4=van der Veen|first4=Daniel|last5=Brand|first5=Heike H.|last6=Wong|first6=Michael K.|last7=Da Silva|first7=Diane M.|last8=Kast|first8=W. Martin|date=December 2016|title=T cell ignorance is bliss: T cells are not tolerized by Langerhans cells presenting human papillomavirus antigens in the absence of costimulation|journal=Papillomavirus Research (Amsterdam, Netherlands)|volume=2|pages=21–30|doi=10.1016/j.pvr.2016.01.002|issn=2405-8521|pmc=4862606|pmid=27182559}}</ref> It was demonstrated that Langerhans cells in HPV-induced cervical lesions were spherical, lacked dendrites, and secreted the suppressive cytokine IL-10 ''in vivo''.<ref>{{Cite journal|title = Local immunosuppression induced by high viral load of human papillomavirus: characterization of cellular phenotypes producing interleukin-10 in cervical neoplastic lesions|journal = Immunology|date = 2015-09-01|issn = 1365-2567|pmc = 4552506|pmid = 26059395|pages = 113–121|volume = 146|issue = 1|doi = 10.1111/imm.12487|first1 = Thiago Theodoro Martins|last1 = Prata|first2 = Camila Mareti|last2 = Bonin|first3 = Alda Maria Teixeira|last3 = Ferreira|first4 = Cacilda Tezelli Junqueira|last4 = Padovani|first5 = Carlos Eurico Dos Santos|last5 = Fernandes|first6 = Ana Paula|last6 = Machado|first7 = Inês Aparecida|last7 = Tozetti}}</ref> The authors further demonstrated that the number of [[Interleukin 10|IL-10]] secreting immunosuppressive Langerhans cells, and the amount of IL-10 produced in lesions, corresponded with the severity of histopathology and HPV viral load, providing evidence of an active immunosuppressive mechanism employed by HPV that targets Langerhans cells ''in vivo''.{{citation needed|date=June 2023}} === Dengue fever === Langerhans cells are also the initial target of the virus that causes [[dengue fever]] during its development.<ref>Martina BE, Koraka P, Osterhaus AD (October 2009). "Dengue virus pathogenesis: an integrated view". ''Clinical Microbiology Reviews''. '''22''' (4): 564–81. [[Doi (identifier)|doi]]:10.1128/CMR.00035-09. [[PMC (identifier)|PMC]] 2772360. [[PMID (identifier)|PMID]] 19822889.</ref> === Declining function during ageing === During ageing the capacity of Langerhans cells to migrate declines.<ref>{{Cite journal|title = Lower levels of interleukin-1β gene expression are associated with impaired Langerhans' cell migration in aged human skin |journal = Immunology|volume = 153|issue = 1|pages = 60–70|pmc = 5721243|pmid = 28777886|doi = 10.1111/imm.12810|display-authors=etal|first = S|last = Pilkington|year=2018}}</ref> This compromises immunity and exposes the skin to infectious diseases and cancer.{{citation needed|date=June 2023}} ==History== Langerhans cells are named after [[Paul Langerhans]], a [[Germany|German]] [[physician]] and [[anatomist]], who discovered the cells at the age of 21 while he was a [[medical student]].<ref>{{cite journal |doi=10.1007/BF01959006 |title=Ueber die Nerven der menschlichen Haut |trans-title=On the nerves of the human skin |language=de |year=1868 |last1=Langerhans |first1=Paul |journal=Archiv für pathologische Anatomie und Physiologie und für klinische Medicin |volume=44 |issue=2–3 |pages=325–37|s2cid=6282875 |url=https://zenodo.org/record/2319860 }}</ref> Because of their [[dendrite]]-like appearance, he mistakenly identified the cells as part of the [[nervous system]].<ref name="omim-lch">{{OMIM|604856|Langerhans cell histiocytosis}}</ref> ==See also== * [[Langhans giant cell]] * [[List of distinct cell types in the adult human body]] ==References== {{reflist|30em}} ==External links== * {{eMedicine|derm|216|Langerhans Cell Histiocytosis}} * {{webarchive |url=https://web.archive.org/web/20040127135809/http://www.trinity.edu/rblyston/MicroA/Lectures/L34-html/img018.jpg |date=January 27, 2004 |title=Illustration at trinity.edu }} *{{cite journal |first1=Scott C. |last1=Brun |first2=Peter A. D. |last2=Rubin |year=1997 |title=25 year old kickboxer with progressive proptosis |journal=Digital Journal of Ophthalmology |volume=3 |issue=26 |url=http://www.djo.harvard.edu/site.php?url=/physicians/gr/356}} * {{MeshName|Langerhans+Cells}} {{Blood}} [[Category:Mononuclear phagocytes]] [[Category:Skin anatomy]] [[Category:Epithelial cells]]
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