Introduction Langerhans’ cell histiocytosis (LCH) is a proliferative dis- order of cells belonging to the dendritic cell lineage, in which the affected cells have many characteristics of Langerhans’ cells (LC; recently reviewed by Schmitz and Favara 1 ). Clini- cally, the symptoms range from a solitary lytic bone lesion that does not require much treatment to a disseminated ‘leukaemia-like’ disease with multiple organs involved and a high mortality rate, despite aggressive treatment. 2 Despite the advances in understanding the clinical picture, improved treatment protocols and internationally accepted criteria for disease, the pathogenesis of LCH is not known. Recent studies have shown that LCH cells are monoclonal in origin and that cytokines and regulatory molecules, such as CD40, are involved (RM Egeler et al. unpubl. data, 1997). 3 The finding of monoclonality, however, suggests that a genetic mutation, occurring at the single cell level, leads to the dys- regulation of cellular survival and proliferation and thus forms the basis of clonal proliferation in LCH. The nature of this initial mutation and subsequent genetic aberrations are then likely to determine the severity of the disease. Along these lines, in the present paper we present the hypothesis that mutations in the LC adhesion molecule E-cadherin and/or molecules in the attached β-catenin signalling cascade play a central role in proliferative dys- regulation of LCH cells. The dual function of β-catenin, as a cytoplasmic attachment molecule to E-cadherin and as transcriptional regulator, makes mutations in this cascade an important cause of epithelial neoplastic proliferation and dis- semination of affected cells (recently reviewed by Ilyas and Tomlinson 4 and Hirohashi 5 ). By analogy, we hypothesize that the E-cadherin–β-catenin cascade is affected in LCH, causing various phenomena actually found in LCH: (i) adhesive dys- regulation due to absence of E-cadherin on LCH cells in extended lesions; 6,7 (ii) presence of a cytokine ‘storm’ at the site of the lesion(s), including multiple cytokines that stimu- late LC proliferation; 3,8,9 and (iii) dysregulation of apoptosis, as manifested by the presence of high levels of nuclear p53. 10 Background E-cadherin and Langerhans’ cell biology E-cadherin is an important cell adhesion molecule in adher- ent junctions, especially of epithelial cells (reviewed by Take- ichi, 11 Birchmeier 12 and Udey 13 ). It belongs to the cadherin family of Ca 2+ -dependent adhesion molecules, including E-, P-, N- and R-cadherin. These molecules mediate homophilic adhesion, suggesting that each cadherin selectively binds to the identical members of the same family, but not to others. E-cadherin is especially known from its critical involve- ment in the maintenance of epithelial integrity. However, some cell types of haematopoietic origin also express E-cadherin, including LC, 13 osteoclasts, 14 erythroblasts 15 and developing thymocytes. For both LC and thymocytes, E-cadherin is essential for interaction with epithelium. Recently, it has been shown that LC and keratinocytes form adherent junctions, in which E-cadherin is contained. 16 The maturation of LC coincides with their migration from the epithelial environment and homing to the local draining lymph node. To enable this, a down-regulation of E-cadherin Immunology and Cell Biology (1999) 77, 460–467 Special Feature Langerhans’ cell histiocytosis is caused by dysregulation of the E-cadherin–β-catenin cascade: A hypothesis PIETER JM LEENEN 1 AND R MAARTEN EGELER 2 1 Department of Immunology, Erasmus University, Rotterdam, The Netherlands and 2 Alberta Children’s Hospital and Tom Baker Cancer Center, University of Calgary, Calgary, Alberta, Canada Summary Langerhans’ cell histiocytosis (LCH) is a proliferative disease of cells of the dendritic cell lineage, closely resembling activated Langerhans’ cells. The clinical picture of LCH is greatly variable, suggesting a scale of aberrancies at the cellular level. Despite progress in clinical treatment, the aetiology and pathogenesis of this disease remain unknown. In the present paper, we present the hypothesis that dysregulation of the E-cadherin–β- catenin–Wnt cascade, which has both adhesive and transcriptional functions, may be fundamental to the develop- ment of LCH. This hypothesis is founded upon two notions: (i) careful regulation of this cascade is essential in normal Langerhans cell activation; and (ii) abnormalities in the E-cadherin–β-catenin cascade are a major cause of epithelial neoplastic proliferation. On the basis of this hypothesis, we present three alternative scenarios that may describe the initial steps in the pathogenesis of LCH. Key words: β-catenin, cell signalling, E-cadherin, Langerhans’ cell histiocytosis. Correspondence: Dr Pieter Leenen, Department of Immunology, Erasmus University, PO Box 1738, 3000 DR Rotterdam, The Netherlands. Email: <leenen@immu.fgg.eur.nl> Received 21 June 1999; accepted 21 June 1999.