Disruption of the langerin/CD207 Gene Abolishes Birbeck Granules without a Marked Loss of Langerhans Cell Function

Langerin is a C-type lectin expressed by a subset of dendritic leukocytes, the Langerhans cells (LC). Langerin is a cell surface receptor that induces the formation of an LC-specific organelle, the Birbeck granule (BG). We generated a langerin(-/-) mouse on a C57BL/6 background which did not display any macroscopic aberrant development. In the absence of langerin, LC were detected in normal numbers in the epidermis but the cells lacked BG. LC of langerin(-/-) mice did not present other phenotypic alterations compared to wild-type littermates. Functionally, the langerin(-/-) LC were able to capture antigen, to migrate towards skin draining lymph nodes, and to undergo phenotypic maturation. In addition, langerin(-/-) mice were not impaired in their capacity to process native OVA protein for I-A(b)-restricted presentation to CD4(+) T lymphocytes or for H-2K(b)-restricted cross-presentation to CD8(+) T lymphocytes. langerin(-/-) mice inoculated with mannosylated or skin-tropic microorganisms did not display an altered pathogen susceptibility. Finally, chemical mutagenesis resulted in a similar rate of skin tumor development in langerin(-/-) and wild-type mice. Overall, our data indicate that langerin and BG are dispensable for a number of LC functions. The langerin(-/-) C57BL/6 mouse should be a valuable model for further functional exploration of langerin and the role of BG.

Langerhans cell (LC) proliferation mediates neonatal development, homeostasis, and inflammation-associated expansion of the epidermal LC network.

Most tissues develop from stem cells and precursors that undergo differentiation as their proliferative potential decreases. Mature differentiated cells rarely proliferate and are replaced at the end of their life by new cells derived from precursors. Langerhans cells (LCs) of the epidermis, although of myeloid origin, were shown to renew in tissues independently from the bone marrow, suggesting the existence of a dermal or epidermal progenitor. We investigated the mechanisms involved in LC development and homeostasis. We observed that a single wave of LC precursors was recruited in the epidermis of mice around embryonic day 18 and acquired a dendritic morphology, major histocompatibility complex II, CD11c, and langerin expression immediately after birth. Langerin+ cells then undergo a massive burst of proliferation between postnatal day 2 (P2) and P7, expanding their numbers by 10–20-fold. After the first week of life, we observed low-level proliferation of langerin+ cells within the epidermis. However, in a mouse model of atopic dermatitis (AD), a keratinocyte signal triggered increased epidermal LC proliferation. Similar findings were observed in epidermis from human patients with AD. Therefore, proliferation of differentiated resident cells represents an alternative pathway for development in the newborn, homeostasis, and expansion in adults of selected myeloid cell populations such as LCs. This mechanism may be relevant in locations where leukocyte trafficking is limited.

Insights into Langerhans Cell Function from LC Deficient Mice

Invited Review

Insights into Langerhans cell function from Langerhans cell ablation models

Langerhans cells (LC) are the principal dendritic cell (DC) population in the epidermis of the skin. Owing to their prominent position at the environmental barrier, LC have long been considered to be prototypic sentinel DC. More recently, the precise role of LC in the initiation and control of cutaneous immune responses has become debatable. To elucidate their contribution to immune regulation in the skin, our laboratories have generated genetically modified mice in which LC can be followed in situ by expression of enhanced green fluorescent protein and can be either inducibly or constitutively depleted in vivo. This review highlights the similarities and differences between these mouse models, discusses the discovery and functional significance of Langerin(+) dermal DC, and examines some recent data that help to shed light on LC function.

Extra-osseous involvement of Langerhans' cell histiocytosis in children.

The predominant clinical and radiological features of Langerhans' cell histiocytosis (LCH) in children are due to osseous involvement. Extra-osseous disease is far less common, occurring in association with bone disease or in isolation; nearly all anatomical sites may be affected and in very various combinations. The following article is based on a multicentre review of 31 children with extra-osseous LCH. The objective is to summarise the diverse possibilities of organ involvement. The radiological manifestations using different imaging modalities are rarely pathognomonic on their own. Nevertheless, familiarity with the imaging findings, especially in children with systemic disease, may be essential for early diagnosis.

Development of an ex vivo human skin model for intradermal vaccination : tissue viability and Langerhans cell behaviour

The presence of resident Langerhans cells (LCs) in the epidermis makes the skin an attractive target for DNA vaccination. However, reliable animal models for cutaneous vaccination studies are limited. We demonstrate an ex vivo human skin model for cutaneous DNA vaccination which can potentially bridge the gap between pre-clinical in vivo animal models and clinical studies. Cutaneous transgene expression was utilised to demonstrate epidermal tissue viability in culture. LC response to the culture environment was monitored by immunohistochemistry. Full-thickness and split-thickness skin remained genetically viable in culture for at least 72 h in both phosphate-buffered saline (PBS) and full organ culture medium (OCM). The epidermis of explants cultured in OCM remained morphologically intact throughout the culture duration. LCs in full-thickness skin exhibited a delayed response (reduction in cell number and increase in cell size) to the culture conditions compared with split-thickness skin, whose response was immediate. In conclusion, excised human skin can be cultured for a minimum of 72 h for analysis of gene expression and immune cell activation. However, the use of split-thickness skin for vaccine formulation studies may not be appropriate because of the nature of the activation. Full-thickness skin explants are a more suitable model to assess cutaneous vaccination ex vivo.

Adult Langerhans cell histiocytosis presenting as metachronous colonic polyps

Langerhans cell histiocytosis (LCH) is a rare disease characterized by proliferation of Langerhans-type cells that express CD1a, Langerin (CD207) and S100 protein. Birbeck granules are a hallmark by ultrastructural examination. LCH presents with a wide clinical spectrum, ranging from solitary lesions of a single site (usually bone or skin) to multiple or disseminated multisystemic lesions, which can lead to severe organ dysfunction. Most cases occur in children. Gastrointestinal tract involvement is rare and has been associated with systemic illness and poor prognosis especially in children under the age of 2 years. Adult gastrointestinal LCH is very rare. We report a case of a previously healthy, nonsmoking 48-year-old male who was referred for routine screening colonoscopy. Two sessile, smooth, firm and yellowish LCH polyps measuring 0.2 cm and 0.3 cm were detected in the sigmoid colon. Fifteen months later a second colonoscopy found two histologically confirmed hyperplastic polyps at the sigmoid colon. No other LCH lesions were seen. A third colonoscopy after 28 months of follow-up found a submucosal 0.5 cm infiltrated and ulcerated LCH polyp in the cecum, close to the ostium of the appendix. The patient had been asymptomatic for all this period. Imaging investigation for systemic or multiorgan disease did not find any sign of extracolonic involvement. On histology all lesions showed typical LCH features and immunohistochemical analysis showed strong and diffuse staining for CD1a and CD207. This case illustrates two distinct clinicopathologic features not previously reported in this particular clinical setting: metachronous colonic involvement and positivity for CD207.

Langerhans cell histiocytosis as differential diagnosis of a mediastinal tumor

We describe the case of a 55-year-old man who presented with parasternal swelling. The chest CT scan showed a large tumor of the chest wall infiltrating the subcutaneous tissue. To assume histologic diagnosis an open biopsy was performed. Between the myofibrils a coarse, white tumor with infiltrative growth was noted. Histopathologic examination revealed expanded atrophic skeletal muscle that was infiltrated by histiocytic cells. Numerous eosinophilic granulocytes and lymphocytes CD20 and CD3 positive could be detected and immunohistochemical staining was also positive for S-100 proteins and CD1a. Histologic findings were characteristic of Langerhans cell histiocytosis (LCH). To the best of our knowledge a LCH originating from the mediastinum in an adult as presented has not been previously described.

[Unusual pulmonary presentation of systemic Langerhans cell histiocytosis]

An 80-year-old nonsmoking man was referred to our hospital with bilateral perihilar pulmonary opacities. He had a history of epilepsy, sclerosing cholangitis, cutaneous lesions previously diagnosed as localised Langerhans cell histiocytosis. Symptoms included dry cough and dyspnea. Chest CT showed bilateral perihilar alveolar consolidation with bronchiectasis. Histological examination of a lung biopsy showed typical features of Langerhans cell granulomatosis. Investigations revealed anterior and posterior hypopituitarism. An important improvement occurred with corticosteroid and vinblastine treatment.

Extraosseous langerhans cell histiocytosis in children

Langerhans cell histiocytosis, a rare disease that occurs mainly in children, may produce a broad range of manifestations, from a single osseous lesion to multiple lesions involving more than one organ or system. The clinical course varies widely in relation to the patient's age. Multisystem disease may demonstrate especially aggressive behavior in very young children, with the outcome depending largely on the stage of disease and the degree of related organ dysfunction at the time of diagnosis. Extraosseous manifestations are less commonly seen than osseous ones and may be more difficult to identify. To accurately detect extraosseous Langerhans cell histiocytosis at an early stage, radiologists must recognize the significance of individual clinical and laboratory findings as well as the relevance of imaging features for the differential diagnosis. The pattern and severity of pulmonary, thymic, hepatobiliary, splenic, gastrointestinal, neurologic, mucocutaneous, soft-tissue (head and neck), and salivary involvement in Langerhans cell histiocytosis generally are well depicted with conventional radiography, ultrasonography, computed tomography, and magnetic resonance imaging. However, the imaging features are not pathognomonic, and a biopsy usually is necessary to establish a definitive diagnosis.

Epstein-Barr virus infection of Langerhans cell precursors as a mechanism of oral epithelial entry, persistence, and reactivation.

Epstein-Barr virus (EBV) is a ubiquitous human herpesvirus associated with many malignant and nonmalignant human diseases. Life-long latent EBV persistence occurs in blood-borne B lymphocytes, while EBV intermittently productively replicates in mucosal epithelia. Although several models have previously been proposed, the mechanism of EBV transition between these two reservoirs of infection has not been determined. In this study, we present the first evidence demonstrating that EBV latently infects a unique subset of blood-borne mononuclear cells that are direct precursors to Langerhans cells and that EBV both latently and productively infects oral epithelium-resident cells that are likely Langerhans cells. These data form the basis of a proposed new model of EBV transition from blood to oral epithelium in which EBV-infected Langerhans cell precursors serve to transport EBV to the oral epithelium as they migrate and differentiate into oral Langerhans cells. This new model contributes fresh insight into the natural history of EBV infection and the pathogenesis of EBV-associated epithelial disease.