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Langerhans cell histiocytosis (LCH) is a rare systemic disorder characterized by the accumulation of CD1a+/Langerin+ LCH cells and wide‐ranging organ involvement. Langerhans cell histiocytosis was formerly referred to as histiocytosis X, until it was renamed in 1987. Langerhans cell histiocytosis β was named for its morphological similarity to skin Langerhans cells. Studies have shown that LCH cells originate from myeloid dendritic cells rather than skin Langerhans cells. There has been significant debate regarding whether LCH should be defined as an immune disorder or a neoplasm. A breakthrough in understanding the pathogenesis of LCH occurred in 2010 when a gain‐of‐function mutation in BRAF (V600E) was identified in more than half of LCH patient samples. Studies have since reported that 100% of LCH cases show ERK phosphorylation, indicating that LCH is likely to be a clonally expanding myeloid neoplasm. Langerhans cell histiocytosis is now defined as an inflammatory myeloid neoplasm in the revised 2016 Histiocyte Society classification. Randomized trials and novel approaches have led to improved outcomes for pediatric patients, but no well‐defined treatments for adult patients have been developed to date. Although LCH is not fatal in all cases, delayed diagnosis or treatment can result in serious impairment of organ function and decreased quality of life. This study summarizes recent advances in the pathophysiology and treatment of adult LCH, to raise awareness of this “orphan disease”. Recent studies have shown that Langerhans cell histiocytosis (LCH) is a clonally expanding myeloid neoplasm. Although LCH is not always fatal, delayed diagnosis or treatment can result in serious impairment of organ function and decreased quality of life. This study summarizes recent advances in the pathophysiology and treatment of adult LCH, to raise awareness of this “orphan disease”.

A spectrum of diseases formerly known as histiocytosis X and now called Langerhans-cell histiocytosis is characterized by ERK pathway activation (including BRAF V600E mutations) and diverse clinical manifestations involving bone, skin, lung, and pituitary.

Skin-derived dendritic cells (DCs) play a crucial role in the maintenance of immune homeostasis due to their role in antigen trafficking from the skin to the draining lymph nodes (dLNs). To quantify the spatiotemporal regulation of skin-derived DCs in vivo , we generated knock-in mice expressing the photoconvertible fluorescent protein KikGR. By exposing the skin or dLN of these mice to violet light, we were able to label and track the migration and turnover of endogenous skin-derived DCs. Langerhans cells and CD103 + DCs, including Langerin + CD103 + dermal DCs (DDCs), remained in the dLN for 4–4.5 days after migration from the skin, while CD103 − DDCs persisted for only two days. Application of a skin irritant (chemical stress) induced a transient >10-fold increase in CD103 − DDC migration from the skin to the dLN. Tape stripping (mechanical injury) induced a long-lasting four-fold increase in CD103 − DDC migration to the dLN and accelerated the trafficking of exogenous protein antigens by these cells. Both stresses increased the turnover of CD103 − DDCs within the dLN, causing these cells to die within one day of arrival. Therefore, CD103 − DDCs act as sentinels against skin invasion that respond with increased cellular migration and antigen trafficking from the skin to the dLNs.

Pulmonary Langerhans Cell Histiocytosis (PLCH) is a relatively uncommon lung disease that generally, but not invariably, occurs in cigarette smokers. The pathologic hallmark of PLCH is the accumulation of Langerhans and other inflammatory cells in small airways, resulting in the formation of nodular inflammatory lesions. While the overwhelming majority of patients are smokers, mechanisms by which smoking induces this disease are not known, but likely involve a combination of events resulting in enhanced recruitment and activation of Langerhans cells in small airways. Bronchiolar inflammation may be accompanied by variable lung interstitial and vascular involvement. While cellular inflammation is prominent in early disease, more advanced stages are characterized by cystic lung destruction, cicatricial scarring of airways, and pulmonary vascular remodeling. Pulmonary function is frequently abnormal at presentation. Imaging of the chest with high resolution chest CT scanning may show characteristic nodular and cystic abnormalities. Lung biopsy is necessary for a definitive diagnosis, although may not be required in instances were imaging findings are highly characteristic. There is no general consensus regarding the role of immunosuppressive therapy in smokers with PLCH. All smokers must be counseled on the importance of smoking cessation, which may result in regression of disease and obviate the need for systemic immunosuppressive therapy. The prognosis for most patients is relatively good, particularly if longitudinal lung function testing shows stability. Complications like pneumothoraces and secondary pulmonary hypertension may shorten life expectancy. Patients with progressive disease may require lung transplantation.

Progress in understanding the rare disease Langerhans cell histiocytosis has stimulated immersive meetings occurring annually over a 30-year period that bring together clinicians, scientists and patients in a unique collaboration.

Tissue-specific Langerhans cells and microglia develop in situ before birth. Colonna and colleagues identify IL-34 produced by keratinocytes and neurons as the relevant ligand of CSF1R necessary for their generation. The differentiation of bone marrow–derived progenitor cells into monocytes, tissue macrophages and some dendritic cell (DC) subtypes requires the growth factor CSF1 and its receptor, CSF1R. Langerhans cells (LCs) and microglia develop from embryonic myeloid precursor cells that populate the epidermis and central nervous system (CNS) before birth. Notably, LCs and microglia are present in CSF1-deficient mice but absent from CSF1R-deficient mice. Here we investigated whether an alternative CSF1R ligand, interleukin 34 (IL-34), is responsible for this discrepancy. Through the use of IL-34-deficient ( Il34 LacZ/LacZ ) reporter mice, we found that keratinocytes and neurons were the main sources of IL-34. Il34 LacZ/LacZ mice selectively lacked LCs and microglia and responded poorly to skin antigens and viral infection of the CNS. Thus, IL-34 specifically directs the differentiation of myeloid cells in the skin epidermis and CNS.

Human TRIM5α restricts HIV-1 infection of Langerhans cells through Langerin-dependent autophagy pathway. C-type lectin receptor-mediated anti-HIV activity Teunis Geijtenbeek and colleagues find a role for human E3-ubiquitin ligase tri-partite-containing motif 5α (TRIM5α) in restricting HIV-1 infection in Langerhans cells, a subset of dendritic cells present at the mucosal barrier. They show that capture of HIV-1 by the C-type lectin receptor Langerin serves to route the virus to a TRIM5α- and Langerin-dependent autophagy pathway. This mechanism of TRIM5α-mediated restriction differs from the proteasome-dependent mechanism by which rhesus TRIM5α is thought to restrict HIV-1, and seems to be a Langerhans-cell-specific restriction mechanism operating at the mucosal barrier. Langerhans cells are important in the defence against HIV-1 infection during sexual transmission, and this work highlights the potential of interventions involving C-type lectin receptors and autophagy-targeting strategies to promote cell-mediated resistance to HIV-1. The most prevalent route of HIV-1 infection is across mucosal tissues after sexual contact. Langerhans cells (LCs) belong to the subset of dendritic cells (DCs) that line the mucosal epithelia of vagina and foreskin and have the ability to sense and induce immunity to invading pathogens 1 . Anatomical and functional characteristics make LCs one of the primary targets of HIV-1 infection 2 . Notably, LCs form a protective barrier against HIV-1 infection and transmission 3 , 4 , 5 . LCs restrict HIV-1 infection through the capture of HIV-1 by the C-type lectin receptor Langerin and subsequent internalization into Birbeck granules 5 . However, the underlying molecular mechanism of HIV-1 restriction in LCs remains unknown. Here we show that human E3-ubiquitin ligase tri-partite-containing motif 5α (TRIM5α) potently restricts HIV-1 infection of LCs but not of subepithelial DC-SIGN + DCs. HIV-1 restriction by TRIM5α was thus far considered to be reserved to non-human primate TRIM5α orthologues 6 , 7 , 8 , 9 , but our data strongly suggest that human TRIM5α is a cell-specific restriction factor dependent on C-type lectin receptor function. Our findings highlight the importance of HIV-1 binding to Langerin for the routeing of HIV-1 into the human TRIM5α-mediated restriction pathway. TRIM5α mediates the assembly of an autophagy-activating scaffold to Langerin, which targets HIV-1 for autophagic degradation and prevents infection of LCs. By contrast, HIV-1 binding to DC-SIGN + DCs leads to disassociation of TRIM5α from DC-SIGN, which abrogates TRIM5α restriction. Thus, our data strongly suggest that restriction by human TRIM5α is controlled by C-type-lectin-receptor-dependent uptake of HIV-1, dictating protection or infection of human DC subsets. Therapeutic interventions that incorporate C-type lectin receptors and autophagy-targeting strategies could thus provide cell-mediated resistance to HIV-1 in humans.

Background The relationship between various external agents such as pollen, food, and infectious agents and human sensitivity exists and is variable depending upon individual’s health conditions. For example, we believe that the pathogenetic potential of the Merkel cell polyomavirus (MCPyV), the resident virus in skin, is variable and depends from the degree of individual’s reactivity. MCPyV as well as Epstein-Barr virus, which are normally connected with humans under the form of subclinical infection, are thought to be involved at various degrees in several neoplastic and inflammatory diseases. In this review, we cover two types of Langerhans cell neoplasms, the Langerhans cell sarcoma (LCS) and Langerhans cell histiocytosis (LCH), represented as either neoplastic or inflammatory diseases caused by MCPyV. Methods We meta-analyzed both our previous analyses, composed of quantitative PCR for MCPyV-DNA, proteomics, immunohistochemistry which construct IL-17 endocrine model and interleukin-1 (IL-1) activation loop model, and other groups’ data. Results We have shown that there were subgroups associated with the MCPyV as a causal agent in these two different neoplasms. Comparatively, LCS, distinct from the LCH, is a neoplastic lesion (or sarcoma) without presence of inflammatory granuloma frequently observed in the elderly. LCH is a proliferative disease of Langerhans-like abnormal cells which carry mutations of genes involved in the RAS / MAPK signaling pathway. We found that MCPyV may be involved in the development of LCH. Conclusion We hypothesized that a subgroup of LCS developed according the same mechanism involved in Merkel cell carcinoma pathogenesis. We proposed LCH developed from an inflammatory process that was sustained due to gene mutations. We hypothesized that MCPyV infection triggered an IL-1 activation loop that lies beneath the pathogenesis of LCH and propose a new triple-factor model.

Key Points In contrast to most dendritic-cell populations, Langerhans cells repopulate locally throughout life in the steady state, independently of any input from the blood circulation. In contrast to quiescent skin, in major inflammatory skin injuries (such as exposure to ultraviolet B radiation) Langerhans cells are replaced by circulating monocytes. Langerhans cells repopulate locally after a lethal dose of radiation and remain of host origin following congenic bone-marrow transplantation. By contrast, following allogeneic bone-marrow transplantation, cutaneous graft-versus-host disease occurs and leads to the elimination of recipient Langerhans cells and their replacement with donor-derived cells. Langerhans cells are absent in mice that lack the macrophage colony-stimulating factor (M-CSF) receptor but remain unaffected in mice that lack the receptor for FMS-like-tyrosine-kinase 3 ligand (FLT3). Langerin is not uniquely expressed by Langerhans cells in the skin, but is also expressed by dendritic cells in stratified epithelial surfaces and by a subset of dendritic cells that is present in most connective tissues, including the dermis, lung, kidney and liver. Langerin + dendritic cells can be distinguished from Langerhans cells based on the expression of the integrin CD103 and the low expression of CD11b. Our understanding of the origin, phenotype and function of epidermal Langerhans cells and langerin-expressing dendritic cells has expanded in recent years, details of which, as well as the challenges that remain, are discussed in this Review. Langerhans cells (LCs) are a specialized subset of dendritic cells (DCs) that populate the epidermal layer of the skin. Langerin is a lectin that serves as a valuable marker for LCs in mice and humans. In recent years, new mouse models have led to the identification of other langerin + DC subsets that are not present in the epidermis, including a subset of DCs that is found in most non-lymphoid tissues. In this Review we describe new developments in the understanding of the biology of LCs and other langerin + DCs and discuss the challenges that remain in identifying the role of different DC subsets in tissue immunity.

On the outermost edge of the body a dense network of dendritic cells (DCs), the so-called Langerhans cells (LCs), represents the first immune barrier. The establishment and maintenance of this epidermal network is dependent on the cytokine transforming growth factor-β1 (TGF-β1) expressed by keratinocytes (KC) and LCs. We recently identified a crucial downstream effector of TGF-β1, the receptor tyrosine kinase Axl. Axl belongs to the TAM receptor family, which also includes Tyro3 and Mer, and is activated through the vitamin K-dependent ligands Gas6 and Protein S. We have now established that TGF-β1 dependent human LC generation from CD34 progenitor cells can be enhanced by Axl over-expression. Additionally, we supplemented vitamin K into serum-free human LC generation cultures in order to activate the endogenous ligands Gas6 and Protein S. Vitamin K exhibited supportive effects on LC differentiation and LC-associated gene expression. The vitamin K antagonist warfarin on the other hand, hindered efficient LC differentiation. Blocking antibodies against Axl abrogated the positive effect of vitamin K on LC differentiation. Lastly, vitamin K downregulated the immune activation marker CD86 during LC differentiation and blocked the upregulation of CD86 during LC activation , in an Axl independent manner. Taken together, we provide evidence for the supportive role of vitamin K in regulating skin immunity.