Editing Langerhans cell (section)

=== 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}}