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Langerhans cell

Langerhans cells are a specialized subset of dendritic cells that reside in the stratified squamous epithelium of the skin, mucosa, and other barrier tissues, where they function as antigen-presenting cells and immune sentinels, capturing environmental antigens and initiating both tolerogenic and protective immune responses.^[1] Discovered in 1868 by Paul Langerhans, who initially mistook them for neural elements, these cells constitute approximately 2-4% of all epidermal cells and are uniquely identified by their Birbeck granules—rod-shaped organelles visible under electron microscopy—and expression of markers such as CD1a, langerin (CD207), and major histocompatibility complex class II (MHC-II).^[1]^[2] Originating from embryonic precursors in the yolk sac and fetal liver rather than adult bone marrow monocytes under steady-state conditions, Langerhans cells self-renew in situ throughout life, maintaining a dense network in the epidermis without significant turnover from circulating progenitors.^[1]^[3] Programmed by the epidermal microenvironment, including transforming growth factor-beta (TGF-β), they exhibit a distinct transcriptome that differentiates them from other dendritic cells and macrophages, despite sharing ontogenetic roots with the latter.^[1] In their immature state, Langerhans cells patrol the skin via phagocytosis and endocytosis, sampling self-antigens and harmless commensals to promote peripheral tolerance, often by inducing regulatory T cells (Tregs) through interleukin-10 (IL-10) production and presentation of apoptotic cell debris.^[3]^[2] Upon encountering danger signals, such as pathogens or tissue damage, Langerhans cells mature, upregulate co-stimulatory molecules like CD80 and CD86, and migrate to draining lymph nodes via lymphatic vessels, where they prime naïve T cells to orchestrate adaptive immunity, including delayed-type hypersensitivity and antiviral responses.^[1]^[2] This functional plasticity allows them to shift roles in inflammatory contexts; for instance, in psoriasis models, they produce IL-23 to drive IL-17-mediated inflammation, while in ultraviolet (UV)-induced settings, they contribute to immunosuppression by generating Tregs.^[3] Beyond immunity, Langerhans cells play protective roles, such as capturing HIV-1 via langerin to prevent systemic transmission, and are implicated in skin pathologies including histiocytosis and allergic contact dermatitis when dysregulated.^[1]

Introduction and Morphology

Definition and Characteristics

Langerhans cells (LCs) are specialized immune cells that primarily reside in the epidermis, the outermost layer of the skin, where they constitute approximately 2-3% of the total epidermal cell population and serve as key sentinels for immune surveillance against pathogens and environmental antigens.^[1] Traditionally classified as immature dendritic cells due to their antigen-presenting capabilities, LCs have been reclassified in recent years as tissue-resident macrophages based on their embryonic origin from yolk sac progenitors and their self-renewing properties independent of circulating monocytes.^[4] This reclassification highlights their dual functionality, bridging macrophage-like tissue maintenance and dendritic cell-like immune activation.^[5] A hallmark characteristic of LCs is the presence of unique Birbeck granules, rod-shaped cytoplasmic organelles measuring 200-400 nm in length that exhibit a distinctive "tennis racket" appearance under electron microscopy, featuring a central linear body and a terminal bulbous dilation. These granules are involved in endocytic pathways and are considered pathognomonic for LCs, aiding in their identification in both normal and pathological contexts.^[6] LCs express specific surface receptors that underpin their immune roles, including langerin (CD207), a C-type lectin that facilitates the uptake and internalization of glycosylated antigens into Birbeck granules for processing.^[7] Additionally, they express the CB2 cannabinoid receptor, which modulates immune responses by suppressing pro-inflammatory cytokine production and promoting anti-inflammatory pathways in the skin microenvironment.^[8]

Structure and Identification Markers

Langerhans cells exhibit a distinctive dendritic morphology, featuring elongated cytoplasmic processes that extend between adjacent keratinocytes in the epidermis to facilitate environmental sampling. These cells typically measure 10-15 μm in diameter, with an indented or lobulated nucleus and pale, abundant cytoplasm lacking tonofilaments and desmosomes, which distinguishes them from surrounding keratinocytes.^[9]^[10] A hallmark ultrastructural feature of Langerhans cells is the Birbeck granule, a rod- or tennis-racket-shaped organelle unique to these cells and visible under electron microscopy. These granules form through invagination of the plasma membrane, resulting in superimposed membranes with a central striated core, and they contain langerin (CD207), a C-type lectin that binds pathogens and contributes to granule biogenesis.^[7]^[11] The presence of Birbeck granules, often numbering several per cell, serves as a key diagnostic identifier in histological examinations. Immunohistochemically, Langerhans cells are reliably identified by strong positivity for CD1a, S100 protein, and langerin (CD207), markers that highlight their dendritic cell lineage. In steady-state conditions, they exhibit low or weak expression of macrophage-associated markers such as CD68, aiding differentiation from other histiocytic cells.^[12]^[13] These markers enable precise detection in tissue sections, with langerin offering high specificity due to its association with Birbeck granule formation.

Origin and Development

Embryonic and Postnatal Origin

Langerhans cells (LCs) originate during early embryonic development from yolk sac-derived erythro-myeloid progenitors (EMPs), which emerge around weeks 4-5 of gestation in humans. These progenitors generate primitive hematopoietic cells independently of hematopoietic stem cells (HSCs), marking the first wave of definitive hematopoiesis in the extra-embryonic yolk sac.^[14]^[15] In mouse models, which provide insights applicable to human ontogeny, yolk sac EMPs traffic to the embryo and differentiate into macrophage precursors, including those fated for LCs, before being partially supplemented by fetal liver monocytes.^[16] This HSC-independent pathway ensures the initial seeding of tissue-resident macrophages, including LCs, without reliance on later bone marrow-derived HSCs.^[17] During fetal development, LC precursors migrate to the epidermis, establishing a dense network by approximately 6-8 weeks of gestation in humans. These early LCs, identified by markers such as CD45 and CD1a, reside initially in the basal layer before populating the suprabasal epidermis, forming a self-renewing population that persists lifelong.^[18] In mice, this seeding occurs around embryonic day 16-17, driven by fetal liver monocyte contributions that supersede initial yolk sac-derived cells, highlighting a biphasic origin where yolk sac progenitors initiate but fetal sources predominate. The establishment of this network relies on local environmental cues in the developing skin, enabling LCs to maintain tissue residency through intrinsic proliferative capacity from the outset.^[16] Postnatally, LC maintenance occurs primarily through local proliferation within the steady-state epidermis, with minimal contribution from circulating monocytes. In humans and mice, neonatal LCs undergo massive expansion shortly after birth—peaking around postnatal days 4-7 in mice—to fully populate the epidermis, after which self-renewal sustains the network without significant bone marrow input.^[19] Studies using fate-mapping and depletion models confirm that adult LC turnover is low, relying on stochastic local divisions rather than monocyte recruitment under homeostatic conditions. This resilience underscores the embryonic origins' lasting impact on LC homeostasis. Lineage commitment to LCs is orchestrated by key transcription factors, notably PU.1 (encoded by Sfpi1) and IRF8, which drive myeloid differentiation toward the dendritic cell fate. PU.1 initiates LC specification by regulating TGF-β-responsive networks, including direct binding to promoters of genes like Runx3 essential for epidermal residency. IRF8 complements this by promoting DC commitment while suppressing alternative myeloid paths, ensuring progenitors from yolk sac or fetal liver adopt the LC phenotype during seeding.^[20] These factors' coordinated action establishes the transcriptional programs for LC identity and self-renewal early in development.30337-5)

Maturation and Homeostasis

Langerhans cells (LCs) undergo maturation through differentiation of precursor cells within the skin, transitioning into an immature state specialized for antigen surveillance. This process begins with myelo-monocytic precursors that seed the epidermis during development, where they differentiate under the influence of local cytokine signaling. Transforming growth factor-β (TGF-β), produced by keratinocytes and other epidermal cells, plays a pivotal role in this differentiation by promoting the expression of key markers such as Langerin and E-cadherin, which facilitate LC retention and integration into the epidermal layer.^[21] Additionally, bone morphogenetic protein 7 (BMP7) acts upstream of TGF-β to initiate early commitment, ensuring precursors adopt the characteristic LC phenotype including Birbeck granules.^[21] In steady-state conditions, the LC population exhibits long-term homeostasis characterized by a slow turnover rate, with an estimated half-life of approximately 2 months in the epidermis. This maintenance occurs primarily through in situ proliferation rather than continuous replacement from bone marrow-derived precursors, allowing the resident LC network to self-renew and preserve tissue-specific functions. Local environmental cues, including keratinocyte-derived factors, support this proliferative capacity while minimizing excessive expansion, ensuring the LC density remains stable at around 3-4% of epidermal cells.^[22]^[21] During inflammation or injury, such as in response to infection, the homeostatic balance shifts with recruitment of circulating CCR2+ monocytes from the blood, which differentiate into short-lived monocyte-derived LCs to replenish the epidermal population. These recruited cells replace resident LCs temporarily, adapting the network to heightened immune demands without disrupting the overall architecture. This dynamic replenishment highlights the plasticity of LC homeostasis under stress.^[21]^[23] Regulatory mechanisms, including Notch signaling and microenvironmental factors, fine-tune LC maturation and prevent overproliferation to maintain homeostasis. Notch activation, mediated by ligands such as DLL4, enhances differentiation of monocyte precursors into LCs in combination with TGF-β and GM-CSF, promoting Langerin expression and functional maturity. Microenvironmental signals from the epidermis, such as autocrine TGF-β loops, further constrain proliferation, ensuring controlled self-renewal and tolerance to commensal microbes.^[24]^[25]

Anatomy and Distribution

In the Skin

Langerhans cells primarily reside in the suprabasal layers of the epidermis, particularly the stratum spinosum and stratum granulosum, where they constitute 2-4% of all epidermal cells. Their density in human skin typically ranges from 300 to 1000 cells per mm², forming a contiguous network that covers the entire epidermal surface. This positioning allows them to act as sentinel cells within the skin barrier.^[26]^[22] These cells interact closely with surrounding keratinocytes through extended dendrites that form synapse-like contacts, enabling continuous surveillance of the epidermal environment for potential threats. This dendritic extension and retraction facilitate antigen sampling without disrupting the epidermal barrier. In the dermis, Langerhans cells are rare under steady-state conditions, primarily confined to the papillary layer, but their numbers can increase during inflammatory responses as monocyte-derived precursors repopulate affected areas.^[22]^[27] Density variations exist across body regions, with higher concentrations in the head and neck (approximately 490 cells per mm²) compared to other sites, while palms and soles exhibit notably lower densities, around 200 cells per mm² or less, and genitalia around 300 cells per mm². In healthy adult skin, Langerhans cell density remains independent of sex but decreases with age.^[22]^[28]^[29]

In Other Tissues

Langerhans cells are present in various mucosal epithelia beyond the skin, including the oral mucosa, vaginal and foreskin epithelium, and bronchial mucosa, where they serve as sentinels adapted to the unique barrier functions of these sites. In the oral mucosa, their density ranges from 160 to 550 cells per mm², comparable to epidermal levels, but they exhibit enhanced stimulatory capacity for T-cell activation, reflecting adaptations to the moist, microbe-rich environment that facilitate rapid antigen sampling and immune initiation.^[30] Similarly, in the vaginal epithelium, Langerhans cells respond to hormonal influences, such as increased numbers under contraceptive use, enabling tailored immune surveillance against pathogens entering via mucosal breaches.^[6] Bronchial mucosal Langerhans cells, often co-expressing CD103, integrate into the respiratory barrier to intercept airborne antigens while maintaining tolerance to commensals.^[6] A subset of Langerhans cells migrates from peripheral tissues to lymph nodes, where they appear as veiled cells within the paracortex, specializing in antigen presentation to T cells. These veiled cells, derived from maturing Langerhans cells, lose some epithelial markers but retain high MHC-II expression and Birbeck granules, positioning them to bridge innate and adaptive immunity in lymphoid environments.^[31] This migration underscores their role in coordinating systemic responses without permanent residency in nodes.^[6] Langerhans cells also populate other extracutaneous sites at lower densities, often recruited during inflammation rather than constituting a stable population. In the liver, langerin-expressing dendritic cells akin to Langerhans cells contribute to hepatic immune surveillance, though their numbers are sparse compared to mucosal sites.^[6] During thymic development, precursors related to Langerhans cells aid in T-cell education, but mature forms are not resident postnatally. In the gingiva, as part of the oral mucosa, they increase up to fivefold in response to bacterial plaque during early gingivitis, highlighting their dynamic recruitment to inflamed barriers.^[30] Tissue-specific adaptations include upregulation of integrins such as αEβ7 (CD103), which promotes retention of Langerhans cells within mucosal epithelia by binding E-cadherin on epithelial cells, ensuring stable positioning for ongoing pathogen monitoring.^[32] This integrin expression is particularly prominent in airway and intestinal mucosal subsets, contrasting with epidermal Langerhans cells and enhancing tissue-specific immune homeostasis.^[33]

Physiological Functions

Antigen Capture and Processing

Langerhans cells (LCs) perform constant immune surveillance in the epidermis by extending and retracting dendritic processes between keratinocytes, a behavior known as dendritic surveillance extension and retraction, which allows them to sample the local microenvironment for potential antigens.^[27] These processes facilitate the uptake of soluble and particulate antigens through macropinocytosis, a non-specific fluid-phase endocytosis mechanism that enables LCs to internalize extracellular material efficiently.^[34] This active sampling is essential for monitoring skin homeostasis and detecting invading pathogens without disrupting the epithelial barrier.^[35] A key mechanism for targeted antigen capture in LCs involves the C-type lectin receptor langerin (CD207), which binds mannose- and fucose-containing glycans on pathogens such as fungi and viruses, directing them into receptor-mediated endocytosis.^[36] Upon binding, langerin induces the formation of Birbeck granules, unique rod-shaped organelles that serve as specialized compartments for compartmentalized antigen uptake and initial processing, isolating captured material from other endocytic pathways.^[37] These granules facilitate the internalization of pathogens like HIV and Mycobacterium, enhancing LCs' role in early defense against microbial threats.^[11] Following capture, antigens undergo intracellular processing primarily in lysosomal compartments enriched with major histocompatibility complex class II (MHC II) molecules, known as MHC class II-enriched compartments (MIIC).^[38] In these acidic, lysosome-like structures, antigens are degraded by proteases into peptides, which are then loaded onto MHC II molecules after the removal of the invariant chain by HLA-DM.^[39] This process equips LCs for subsequent antigen presentation, with MIIC serving as a hub for peptide-MHC II complex assembly.^[40] LCs also capture self-antigens during routine surveillance to induce peripheral tolerance, preventing autoimmune responses by presenting these antigens in a manner that promotes regulatory T cell development or anergy in self-reactive T cells. Additionally, LCs interact directly with epidermal tissue-resident memory T cells to fine-tune responses and promote tolerance to commensal microbes.^[41] Non-activated LCs maintain immune homeostasis in the skin by locally presenting self-antigens to resident regulatory T cells in the epidermis.^[42] This tolerogenic function underscores their dual role in balancing immunity and self-tolerance.^[43]

Migration and Immune Activation

Upon activation by pathogen-associated molecular patterns recognized through Toll-like receptors (TLRs), Langerhans cells (LCs) upregulate the chemokine receptor CCR7, which is essential for their directed migration from the epidermis to the draining lymph nodes via lymphatic vessels.^[44] This process is triggered by inflammatory cytokines such as IL-1β and TNF-α, which initiate the detachment of LCs from keratinocytes and their movement through the dermal lymphatics, typically taking 24-48 hours to reach peak accumulation in the lymph nodes.^[45] The migration occurs in a two-step manner: an initial CXCR4-dependent phase from the epidermis to the dermis, followed by CCR7-mediated entry into the lymphatics guided by CCL19 and CCL21 chemokines.^[45] During this transit, LCs undergo maturation, characterized by the downregulation of adhesive molecules like E-cadherin, which reduces their retention in the epidermis, and the upregulation of costimulatory molecules such as CD80 and CD86, enhancing their capacity to interact with T cells.^[46] This phenotypic shift, driven by signaling pathways including those activated by TLR ligands, transforms LCs from immature antigen-sampling cells into potent activators of adaptive immunity, with increased expression of MHC class II molecules loaded with processed peptides.^[47] In the draining lymph nodes, mature LCs present peptide-MHC II complexes to naive CD4+ T cells, providing signal 1 (TCR engagement) and signal 2 (costimulation via CD80/CD86 binding to CD28), thereby priming antigen-specific T cell responses.^[48] LCs further promote a Th1-biased response through secretion of IL-12, a cytokine that drives differentiation of CD4+ T cells into IFN-γ-producing effectors, crucial for combating intracellular pathogens.^[49] To maintain immune homeostasis, LCs also contribute to feedback mechanisms by promoting tolerance through presentation of self-antigens or harmless environmental antigens, preventing effector T cell responses. This tolerogenic function involves the expression of TGF-β and other suppressive factors, enabling LCs to balance activation and resolution in steady-state conditions.^[43]

Clinical Relevance

Langerhans Cell Histiocytosis

Langerhans cell histiocytosis (LCH) is a rare neoplastic disorder characterized by the clonal proliferation of Langerhans-like cells, which are dendritic cells expressing CD1a and langerin (CD207), leading to granulomatous lesions in single or multiple organ systems.^[50] It primarily affects children under 15 years, with an incidence of up to 8.9 cases per million per year, though it can occur in adults at a lower rate of about 0.07 to 2 cases per million.^[50] The disease arises from the accumulation of these abnormal cells, often accompanied by inflammatory components such as eosinophils, lymphocytes, and multinucleated giant cells, resulting in tissue damage that varies by site of involvement, including bone, skin, lungs, liver, spleen, and the central nervous system.^[51] The pathogenesis of LCH involves somatic mutations in the MAPK/ERK signaling pathway, with the BRAF V600E mutation present in approximately 50-60% of cases, causing constitutive activation of this pathway and promoting uncontrolled cell survival, proliferation, and resistance to apoptosis.^[51] This mutation, a gain-of-function alteration in exon 15 of the BRAF gene, originates in hematopoietic stem or progenitor cells, leading to clonal expansion detectable in monocytes and dendritic cell precursors.^[51] In BRAF-wild-type cases, alternative MAPK pathway alterations, such as MAP2K1 mutations in about 20-30% or mutations in KRAS, NRAS, or ARAF, drive similar oncogenic signaling.^[51] These genetic changes transform normal myeloid precursors into neoplastic Langerhans-like cells, which retain some phenotypic features of mature Langerhans cells but exhibit dysregulated function and inflammatory recruitment.^[50] Clinically, LCH is classified by the Histiocyte Society into single-system disease (unifocal or multifocal) and multisystem disease, with risk stratification based on organ involvement (low-risk: skin, bone, lymph nodes; high-risk: liver, spleen, bone marrow).^[50] Unifocal LCH, often termed eosinophilic granuloma, typically presents as a solitary lytic bone lesion causing pain, swelling, or pathological fracture, while multifocal single-system disease involves multiple bones or sites like the pituitary.^[50] Multisystem LCH includes disseminated forms such as Letterer-Siwe disease, which affects infants with widespread involvement leading to hepatosplenomegaly, anemia, thrombocytopenia, and failure to thrive; skin manifestations commonly appear as scaly, erythematous papules or plaques resembling seborrheic dermatitis, particularly in the scalp, diaper area, and intertriginous regions.^[50] Other symptoms depend on organ affected, such as pulmonary infiltrates causing dyspnea in smokers or diabetes insipidus from hypothalamic-pituitary involvement.^[50] Diagnosis requires histopathological confirmation via biopsy, revealing characteristic Birbeck granules (tennis racket-shaped inclusions) on electron microscopy and immunohistochemical positivity for CD1a, langerin, and S100, distinguishing LCH from reactive or other histiocytic disorders.^[50] Molecular testing for BRAF V600E or other MAPK mutations via PCR or next-generation sequencing is recommended to guide therapy.^[51] Imaging, including skeletal surveys, CT, MRI, or PET-CT, assesses disease extent.^[50] Treatment is tailored to extent and risk: unifocal lesions may be managed with curettage, intralesional steroids, or low-dose radiation; multifocal or multisystem low-risk disease often responds to chemotherapy with vinblastine and prednisone for 6-12 months.^[50] High-risk multisystem LCH requires intensified regimens including cytarabine or cladribine, with salvage options like hematopoietic stem cell transplantation in refractory cases.^[50] For BRAF V600E-mutated LCH, targeted therapies such as vemurafenib or dabrafenib (often combined with MEK inhibitors like trametinib) have shown high response rates, achieving disease control in 70-90% of treated patients, particularly in relapsed or refractory settings.^[52] As of 2025, ongoing phase II trials with type II RAF inhibitors like tovorafenib have demonstrated high response rates (up to 100% in some cohorts) in relapsed or refractory LCH, particularly in pediatric patients.^[53]

Role in Infectious Diseases

Langerhans cells (LCs) play a critical role in immune surveillance at skin and mucosal barriers, where they detect and respond to invading pathogens such as bacteria and fungi. Positioned in the epidermis and mucosal epithelia, LCs capture microbial antigens through pattern recognition receptors, including langerin, initiating Th17-mediated responses that promote neutrophil recruitment and clearance of extracellular pathogens like Staphylococcus aureus and Candida albicans.^[54]^[55] However, breaches in the epithelial barrier, such as those caused by trauma or inflammation, expose LCs to direct infection, potentially compromising their function and allowing pathogen dissemination.^[56] In human immunodeficiency virus (HIV) infection, LCs serve as primary targets during mucosal transmission, particularly at sites like the vaginal epithelium and foreskin inner mucosa. These cells efficiently internalize HIV virions via endocytosis, often involving langerin-mediated uptake, although langerin typically degrades the virus in Birbeck granules, acting as a natural barrier to productive infection.^[57]^[58] Despite this, a subset of LCs nonproductively transports intact HIV particles to draining lymph nodes, where they form infectious synapses and transmit the virus to CD4+ T cells, facilitating systemic spread.^[59] In chronic HIV infection, LCs exhibit depletion and dysfunction, with reduced numbers and impaired antigen-presenting capacity observed in infected individuals, contributing to persistent viral replication and immune exhaustion.^[60] Human papillomavirus (HPV) exploits LCs to evade immunity, particularly in high-risk infections leading to warts and cervical lesions. The viral oncoproteins E6 and E7 suppress LC activation by downregulating chemokine production (e.g., CCL20) in keratinocytes, reducing LC recruitment and maturation, and decreasing expression of MHC-II and co-stimulatory molecules.^[61] This inhibition creates an immunosuppressive microenvironment, limiting cytotoxic T-cell responses and promoting viral persistence, which heightens the risk of progression to cervical intraepithelial neoplasia and cancer.^[62] Clearance of HPV correlates with restored LC function and numbers, underscoring their essential role in resolving infection.^[63] During dengue fever, epidermal LCs are among the first cells infected following mosquito inoculation, enabling early viral replication in the skin. Infected LCs undergo activation and migrate to draining lymph nodes, transporting dengue virus (DENV) and promoting its dissemination to systemic sites via lymphatic and hematogenous routes.^[64] This migration amplifies viremia, contributing to the severe manifestations of the disease, while also initiating adaptive immune responses that may limit subsequent infections.^[65]

Impact of Aging

With advancing age, the density of Langerhans cells in human skin decreases, with reductions of up to 50-70% observed in elderly individuals compared to younger adults.^[66] However, age-related declines in the recruitment of circulating precursors, such as CD14+ monocytes, contribute to diminished renewal and maintenance of the Langerhans cell network.^[67] This age-related reduction is part of broader immunosenescence affecting skin-resident immune cells, where Langerhans cells exhibit altered responses to homeostatic signals.^[68] Functionally, aging impairs Langerhans cell migration to draining lymph nodes, leading to reduced mobilization from the epidermis under inflammatory conditions.^[69] Antigen presentation capacity also weakens, as aged Langerhans cells show diminished ability to stimulate T cell proliferation, correlating with increased expression of senescence markers such as p16^INK4a^.^[70] These markers indicate cellular senescence, where Langerhans cells enter a state of permanent growth arrest while retaining metabolic activity that promotes a pro-inflammatory environment.^[71] Such functional declines heighten susceptibility to skin infections in the elderly, as fewer effective Langerhans cells compromise early antigen surveillance and immune priming.^[72] Delayed wound healing arises from impaired coordination between Langerhans cells and keratinocytes, exacerbating chronic inflammation in aged skin.^[73] Additionally, the reduced immunosurveillance elevates risk for non-melanoma skin cancers, including basal cell and squamous cell carcinomas, by allowing unchecked proliferation of UV-damaged cells.^[74] Mechanistically, oxidative stress accumulates in aged skin, damaging Langerhans cell membranes and DNA, thereby accelerating senescence and functional impairment.^[75] An altered cytokine milieu, characterized by decreased transforming growth factor-β (TGF-β) levels, further disrupts Langerhans cell homeostasis and migration, as TGF-β normally supports their differentiation and retention in the epidermis.^[76] Emerging evidence suggests that vitamin D and its analogs play a role in modulating Langerhans cell function in aging skin, promoting immune tolerance through suppression of pro-inflammatory pathways.^[77]

Historical Development

Discovery

Langerhans cells were first identified in 1868 by Paul Langerhans, a 21-year-old medical student studying in Berlin, Germany.^[78] While working in the laboratory of Rudolf Virchow, Langerhans examined samples of human skin using gold chloride staining techniques pioneered by Julius Cohnheim, which highlighted previously obscure structures in the epidermis.^[22] This method allowed him to visualize a network of clear, dendritic cells with branching processes interspersed among keratinocytes, which he initially interpreted as sensory nerve endings or intraepidermal receptors for neural signals rather than immune cells.^[79] In his seminal publication, Langerhans detailed these observations in a paper titled "Ueber die Nerven der menschlichen Haut" ("On the Nerves of the Human Skin"), which served as the basis for his doctoral dissertation and appeared in Virchows Archiv für pathologische Anatomie und Physiologie und für klinische Medizin (volume 44, pages 325–337).^[78] His descriptions included precise illustrations of the cells' morphology, depicting their pale cytoplasm and elongated processes, which distinguished them from melanocytes and other epidermal elements.^[79] This work marked the initial recognition of these "clear cells," though their true immunological function remained unrecognized for over a century.^[22]

Evolution of Understanding

In the early 20th century, Langerhans cells were often misidentified as effete melanocytes or wandering phagocytic cells due to their dendritic morphology and intraepidermal location, with limited understanding of their distinct identity beyond superficial resemblances to pigment-producing or scavenging elements.^[80] This ambiguity persisted until 1961, when Michael S. Birbeck and colleagues used electron microscopy to identify unique rod-shaped organelles, later termed Birbeck granules, within the cytoplasm of these cells in human fetal epidermis, providing the first ultrastructural hallmark that distinguished them from other epidermal components.^[81] By the mid-20th century, particularly in the 1970s and 1980s, research linked Langerhans cells to adaptive immunity, reclassifying them as specialized dendritic cells capable of antigen presentation. The 1973 discovery of dendritic cells by Ralph M. Steinman and Zanvil A. Cohn in mouse spleen suspensions influenced this shift, as subsequent studies demonstrated that Langerhans cells shared functional similarities, including potent T-cell stimulation after migration from the epidermis. A key milestone was the identification of CD1a expression on their surface in the early 1980s, confirming their role in presenting lipid antigens to T cells and solidifying their immunological significance. In the late 20th century, the 1990s brought further characterization with the discovery of langerin (CD207), a C-type lectin endocytic receptor specific to Langerhans cells that induces Birbeck granule formation and facilitates pathogen uptake.80160-0) Entering the 2000s, ontogenetic studies reclassified Langerhans cells as tissue-resident macrophages rather than classical dendritic cells, revealing their embryonic origins primarily from fetal liver monocytes with a minor yolk sac contribution, as shown by fate-mapping in mouse models. This paradigm shift, building on work by Florent Ginhoux and colleagues, emphasized their self-renewal and long-term tissue maintenance independent of circulating monocytes.^[82] The 2010s clarified their dual roles in immune tolerance and pathology through genetic and functional analyses, including the identification of recurrent BRAF V600E mutations in approximately 57% of Langerhans cell histiocytosis cases, establishing the disease as a neoplastic proliferation driven by MAPK pathway activation.^[83] Comprehensive reviews highlighted their contributions to peripheral tolerance by promoting regulatory T cells in steady-state skin and exacerbating inflammatory diseases like atopic dermatitis when dysregulated.^[84]

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Oct 12, 2021 · Two representative cells of each subset are shown in the same row. Scale bar, 10 μm. (K) Transmission electron microscopy (TEM) of LC1 and LC2 ...Missing: diameter | Show results with:diameter<|separator|>
[26]
Human Langerhans Cells with Pro-inflammatory Features Relocate ...
Feb 22, 2018 · Human LCs form a network capable of sensing the entire skin surface (12) and comprise 2–4% of epidermal cells with a surface density of 500–1, ...Missing: mm² | Show results with:mm²
[27]
Redefining the Role of Langerhans Cells As Immune Regulators ...
Jan 5, 2018 · Langerhans cells (LC) are a unique population of tissue-resident macrophages that form a network of cells across the epidermis of the skin.
[28]
Anatomical mapping of epidermal Langerhans cell densities in adults
The regional mean densities (+/- s.e.m.) of epidermal Langerhans cells per mm2 were: head and neck, 489 +/- 27; chest, 466 +/- 22; back, 466 +/- 11; upper ...Missing: 300-1000 | Show results with:300-1000
[29]
Langerhans Cells and Their Role in Oral Mucosal Diseases - NIH
Langerhans cells are "sentinels" of the mucosa, altering the immune system, and are important in oral mucosal diseases, initiating immune responses.
[30]
Relation between langerhans cells, veiled cells, and interdigitating ...
On morphological functional and cytochemical criteria it is likely that the Langerhans cell (LC) in the epidermis, the veiled cell (VC) in the afferent lymph ...
[31]
Pivotal role of CD103 in the development of psoriasiform dermatitis
May 20, 2020 · The integrin αE known as CD103 binds integrin β7 to form the complete heterodimeric integrin molecule αEβ7. CD103 is mainly expressed by ...
[32]
Distinct Murine Mucosal Langerhans Cell Subsets Develop from Pre ...
Aug 18, 2015 · Langerhans cells (LCs) populate the mucosal epithelium, a major entry portal for pathogens, yet their ontogeny remains unclear.
[33]
Macropinocytosis Is the Principal Uptake Mechanism of Antigen ...
... macropinocytosis as the principal uptake mechanism ... presentation of human papillomavirus virus-like particles by dendritic cells and Langerhans cells.
[34]
Real Time Visualization of Macromolecule Uptake by Epidermal ...
As a skin-resident member of the dendritic cell (DC) family, Langerhans cells (LCs) are generally regarded to function as professional antigen presenting cells.
[35]
Langerin, a novel C-type lectin specific to Langerhans cells, is an ...
Langerin, a novel C-type lectin specific to Langerhans cells, is an endocytic receptor that induces the formation of Birbeck granules ... antigen-processing ...
[36]
Birbeck Granules Are Subdomains of Endosomal Recycling ...
Langerin, a novel C-type lectin specific to Langerhans cells, is an endocytic receptor that induces the formation of Birbeck granules. Immunity. 2000;12:71 ...
[37]
Human Resident Langerhans Cells Display a Lysosomal ...
Taken together, these data show that MIIC in Langerhans cells share characteristics with lysosomes. I-chain, which is associated with MHC-II molecules in early ...
[38]
Antigen capture and major histocompatibility class II compartments ...
The MIIC in both types of DC are acidic, contain invariant chain, and express the recently described HLA-DM molecule that can contribute to antigen presentation ...
[39]
Human resident langerhans cells display a lysosomal ... - PubMed
We studied the intracellular distribution of MHC-II molecules and invariant chain (I-chain) in resident Langerhans cells using immunogold labeling.
[40]
Human Epidermal Langerhans Cells Maintain Immune Homeostasis ...
May 25, 2012 · Resting epidermal Langerhan cells (LCs) selectively and specifically induced the activation and proliferation of skin resident regulatory T (Treg) cells.Missing: maturation | Show results with:maturation
[41]
Langerhans cells are precommitted to immune tolerance induction
Here, we tested whether epidermal Langerhans cells (LCs) can support immunogenic responses in vivo in the absence of antigen presentation by other DC subsets.
[42]
Dendritic cell migration in inflammation and immunity - Nature
Jul 23, 2021 · These so-called semimature DCs express CCR7 under steady-state conditions and migrate to lymph nodes for the maintenance of immune tolerance ...
[43]
A two-step model for Langerhans cell migration to skin-draining LN
It has been demonstrated that CCR7 is crucial for DC migration from peripheral tissues to the draining LN at all major surfaces exposed to the external ...
[44]
Disruption of E-cadherin-mediated adhesion induces a functionally ...
These results suggested that the loss of E-cadherin-mediated adhesion might provide a spatial cue for the generation of mature, migratory DCs but without the ...
[45]
Smad2/4 Signaling Pathway Is Critical for Epidermal Langerhans ...
During cell maturation, LCs have increased expression of MHCII and cell membrane costimulatory molecules, such as CD80 and CD86. Prior research has shown ...
[46]
Langerhans Cells Activate Naive Self-Antigen-Specific CD8 T Cells ...
alization of peptide-specific T cell immunity and peripheral tolerance ization of T helper cell type 1 (Th1)-inducing dendritic cells. Absence of CCR2 ...
[47]
IL-12 promotes the accessory cell function of epidermal Langerhans ...
It is well-known that costimulatory molecules together with MHC class II molecules are required for the full activation of T cells by antigen presenting cells, ...
[48]
Langerhans Cells Favor Skin Flora Tolerance through Limited ...
Original Article. Langerhans Cells Favor Skin Flora Tolerance through Limited Presentation of Bacterial Antigens and Induction of Regulatory T Cells.Missing: feedback | Show results with:feedback
[49]
Langerhans Cell Histiocytosis - StatPearls - NCBI Bookshelf - NIH
Langerhans cell histiocytosis (LCH) is a neoplastic disorder that arises from an expansion of early myeloid cells in the bone marrow compartment.Missing: pathogenesis | Show results with:pathogenesis
[50]
Langerhans cell histiocytosis: current advances in molecular ...
Oct 26, 2023 · In this review, we focus on the newest updates regarding the molecular pathogenesis of LCH and novel suggested pathways with treatment potential.
[51]
Efficacy of BRAF‐Inhibitor Therapy in BRAFV600E‐Mutated Adult ...
Oct 12, 2020 · Optimal first‐line treatment for Langerhans cell histiocytosis (LCH) has not been established. This case series evaluates the use of BRAF ...
[52]
Ontogeny and function of epidermal murine Langerhans cells - PMC
Mar 18, 2019 · Langerhans cells (LC) are epidermal resident antigen-presenting cells that share a common ontogeny with macrophages but function as dendritic cells (DC).
[53]
Langerhans Cells Sense Staphylococcus aureus Wall Teichoic Acid ...
May 14, 2019 · Langerhans cells (LCs) are key sentinel cells in the skin epidermis and are implicated in S. aureus-induced skin inflammation. LCs are equipped ...
[54]
Skin Immune Landscape: Inside and Outside the Organism - PMC
The skin forms a complex and dynamic ecosystem colonized by about 10 12 microorganisms including bacteria, fungi, and viruses known as skin microbiota.Missing: surveillance | Show results with:surveillance
[55]
Langerin is a natural barrier to HIV-1 transmission by Langerhans cells
Mar 4, 2007 · Langerin is a natural barrier to HIV-1 transmission by Langerhans cells. Lot de Witte,; Alexey Nabatov,; Marjorie Pion,; Donna Fluitsma ...
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Setting the stage – HIV host invasion - PMC - PubMed Central
In the human vagina, intraepithelial CD4+ T cells and CD1a+ Langerhans cells are the first cells infected by HIV-1.Figure 1. Hiv Invasion Sites · Hiv Entry Through The Female... · Hiv Infection Of...
[57]
Vaginal Langerhans Cells Nonproductively Transporting HIV-1 ... - NIH
Langerin is a natural barrier to HIV-1 transmission by Langerhans cells. Nat. Med. 13:367–371 [DOI] [PubMed] [Google Scholar]; 5. Flamand L., et al. 1998 ...
[58]
Dendritic cell infection, depletion and dysfunction in HIV ... - NIH
Infection, depletion and impaired function of DC occur in early HIV infection. HIV seropositive patients who were asymptomatic and those with symptoms of ...Missing: chronic | Show results with:chronic
[59]
Modulation of antigen presenting cell functions during chronic HPV ...
Aug 18, 2017 · High-risk human papillomaviruses (HR-HPV) infect basal keratinocytes, where in some individuals they evade host immune responses and persist.
[60]
Evasion of Host Immune Defenses by Human Papillomavirus - PMC
In addition to repression of proinflammatory gene expression, the HPV oncoproteins E6 and E7 also upregulate expression of immunosuppressive genes in host cells ...
[61]
The association of cervicovaginal Langerhans cells with clearance ...
Suppression of LCs activities facilitated an immunosuppressive microenvironment that is permissive for HPV persistence (51–53), which was documented by reduced ...
[62]
Immune responses to dengue virus in the skin - PMC - NIH
Aug 22, 2018 · After skin infection, DENV must achieve systemic infection in order to complete its transmission cycle by infecting new mosquito hosts [14].
[63]
The Dynamic Relationship between Dengue Virus and the Human ...
May 4, 2024 · This review will summarize the functional role of human skin, the cutaneous innate immune response to DENV, the contribution of the arthropod vector,
[64]
Langerhans cell density in normal human oral mucosa and skin ...
No significant effect of age on mucosal or skin LC density was found, whilst a history of smoking was associated with an increase in LC density in lateral ...Missing: impact | Show results with:impact
[65]
Aging affects epidermal Langerhans cell development and function ...
Nov 24, 2012 · Aged LCs exhibited a reduced ability to stimulate T cell proliferation. However, aged LCs migration toward skin draining lymph nodes was not ...
[66]
Age-Related Alterations in Macrophage Distribution and Function ...
Our work provides insights into how poorly healing aged wounds are phenotypically defined by the presence of macrophages with reduced proliferative capacity.
[67]
CCR7 Governs Skin Dendritic Cell Migration under Inflammatory ...
Our data identify CCR7 as a key regulator that governs trafficking of skin DC under both inflammatory and steady-state conditions.
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Cellular senescence: a key therapeutic target in aging and diseases
Aug 1, 2022 · Cellular senescence is a hallmark of aging defined by stable exit from the cell cycle in response to cellular damage and stress.
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Immune Senescence and Inflammaging Mini-Review | Bio-Rad
Langerhans cells, the specialized skin antigen presenting cells, markedly diminish in number with age, which could contribute to increased skin infections seen ...
[70]
Cellular senescence and wound healing in aged and diabetic skin
Feb 18, 2024 · p16-Positive melanocytes represent a significant population of senescent cells in the lesions associated with aged and photodamaged skin and ...<|separator|>
[71]
Wound Care in an Aging Population: Special Considerations
Apr 1, 2004 · The decrease in melanocytes (loss of 10%- 20% per decade) and in Langerhans' cells increases the risk of skin cancer and infection. The ...
[72]
Focus on the Contribution of Oxidative Stress in Skin Aging - PMC
This review proposes an update on the role of oxidative stress in the appearance of the clinical manifestation of skin agingMissing: immunomodulators | Show results with:immunomodulators
[73]
Mechanism of action and therapeutic effects of oxidative stress ... - NIH
Another signaling pathway in which MMP is involved in skin aging is the transforming growth factor beta (TGF-β)/Smad pathway, which is impaired upon the ...
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https://www.pharmacytimes.com/view/2004-04-7840
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Paul Langerhans - PMC - NIH
The precision of his observation and description of the cells seems incredible when his drawings of 1868, made with the use of a primitive light microscope, are ...
[76]
The Role of Langerhans' Cells in Immunity | JAMA Dermatology
In 1868, Paul Langerhans, a medical student in Berlin, described a network of cells in human epidermis in an article entitled On Nerves of the Human Skin.
[77]
The historical milestones in the understanding of leukocyte biology ...
May 31, 2011 · For many years thereafter, Langerhans cells were thought to be related to melanocytes ... early 20th century, links between the different cells ...
[78]
An Electron Microscope Study of Basal Melanocytes and High-Level ...
Full Length Report. An Electron Microscope Study of Basal Melanocytes and High-Level Clear Cells (Langerhans Cells) in Vitiligo* ; Michael S · Birbeck MA ; Aodán S ...
[79]
Adult Langerhans cells derive predominantly from embryonic fetal ...
Langerhans cells (LCs) are the dendritic cells (DCs) of the epidermis, forming one of the first hematopoietic lines of defense against skin pathogens. In ...
[80]
Recurrent BRAF mutations in Langerhans cell histiocytosis - PMC
High prevalence, recurrent BRAF mutations in LCH indicate that it is a neoplastic disease that may respond to RAF pathway inhibitors. Introduction. Langerhans ...
[81]
Uncovering the Mysteries of Langerhans Cells, Inflammatory ... - NIH
Jul 30, 2018 · Langerhans cells are unique cells residing in the upper layer of the epidermis and are now regarded as part of the macrophage family due to its ...