SummaryIt has been suggested that epidermal Langerhans cells (LC) bearing immunoglobulin E (IgE) may be involved in the genesis of atopic disease. The identity of the IgE receptor(s) on LC remained unclear, although it represents a crucial point in understanding cellular events linked to the binding of allergens to LC via IgE. In this report, we demonstrate that epidermal LC express the high affinity receptor for the Fc fragment of IgE (FceRI) which has, so far, only been described on mast cells and basophils. Epidermal LC react with antibodies specific for the u subunit of the tetrameric (oL,~,23') FceRI. Specific transcripts for Fc~RIo~ and FceRI3~ were detected in LC and correspond to those of human basophils and of the human basophil cell line KU812. Furthermore, human basophils, KU812 cells, and LC express the putative B subunit. Thus human LC express the complete structure of FceRI. This finding opens new perspectives in the putative functional role of this structure on antigen-presenting cells.T he demonstration of IgE molecules on epidermal Langerhans cells (LC) 1 in patients with atopic dermatitis has implied that these cells should perform a major function in the pathophysiology of atopic disease (1, 2). Although initially, only receptors for the Fc fragment of IgG were identified on epidermal LC (3, 4), the low affinity receptor for IgE FceRII/CD23 (5) and the human IgE binding protein (eBP) (6) have now also been found on these cells in lesional, as well as in normal skin. However, attempts to completely block IgE binding on LC by a variety of anti-FceRII/CD23, antieBP, and/or anti-Fc3,R reagents remained unsuccessful, suggesting the presence of a third IgE-binding structure actually responsible for a part of the IgE-binding capacity of LC. We report here, that normal human LC also express the high a~nity receptor for IgE, Fcelkl, demonstrating that the presence of this structure is not restricted to mast cells and basophils. Our results also document the presence of the putative/~ chain on both human basophils and LC.

Atopic dermatitis (AD) is a paradigmatic inflammatory chronic skin disease. As for other chronic skin diseases, (i) the spectrum of the clinical phenotype and severity as well as (ii) the genetic background and (iii) the underlying mechanisms strongly suggest a high degree of pathophysiological heterogeneity yet leading to a similar clinical pattern, that is, the eczematous skin lesion, but showing distinct progression patterns. This review suggests to exploit the recent knowledge about AD for a novel approach proposing a tentative first molecular taxonomy of this disease based on the genotype and endophenotype. The consequences in terms of personalized prevention and management are delineated.As an evolution of the biomedical research and our genetic and pathophysiological understanding of complex diseases, we are currently experiencing a new trend in the classification of diseases moving from the purely phenotypic definition to a molecular taxonomy. It is expected that in future medicine, every disease will be characterized by three main groups of information: (i) the genotype, including epigenotypic information, (ii) the endophenotype (1) that comprises all available biomarkers (BMs), and (iii) the clinical phenotype (Fig. 1). Among all chronic inflammatory diseases, atopic dermatitis (AD) represents a paradigmatic condition because of its genetic and pathophysiological complexity (2) and finally the result thereof: the wide spectrum of clinical phenotype (3). This wide spectrum includes at one end the very minor forms such as atopic stigmata or simply dry skin with minimal itching and the erythrodermic and most severe form of AD at the other end. Due to the recent progress in the research of genetic, immunologic, and environmental factors (the so-called exposome) leading to AD, we are just starting to understand the complexity of the mechanisms underlying the variety in the clinical phenotype and to make first attempts to link the genotype and endophenotype to distinct clinical forms and courses of this disease such as the atopic march. After exposing a brief update of the clinical phenotype and pathophysiological aspects, this review introduces the concept of molecular taxonomy for AD and the consequences for its future management in the context of stratified or personalized medicine.

Atopic dermatitis (AD) is a chronic inflammatory skin disease with increasing incidence and socio-economical relevance. The diagnosis is made on clinical grounds and different diagnostic criteria sets have been established. The majority of all AD cases is associated with a sensitization to environmental allergens and increased serum IgE (so-called extrinsic AD), but about 10--30% of all cases suffer from the so-called intrinsic AD, which obviously lacks any link to the classical atopic diathesis. The genetic background of AD has been investigated by target gene approach by different groups with mostly contradictory results for each of the genes under study. An imbalance in the spectrum of Th1/Th2 responses, a disturbed prostaglandin metabolism, intrinsic defects in keratinocyte function, delayed eosinophil apoptosis, IgE-mediated facilitated antigen presentation by epidermal dendritic cells, a two phase model of the inflammatory response and staphylococcal superantigen effects are among the currently studied pathogenetical aspects of extrinsic AD, which are reviewed in this paper.

Recently, IgE molecules have been demonstrated on Langerhans cells (LC) frominvolved and, to a much lesser extent, in uninvolved skin of patients with atopic dermatitis, but not on LC from nonatopic individuals (1, 2). This finding indicated that, in atopic dermatitis, LC are induced to either synthesize receptors for IgE and/or to acquire IgE-binding FceR2 split products. As opposed to the selective expression of FcER1 by basophils and mast cells, low affinity Fc-IgE receptors (FceR2/CD23) have been described on numerous cell types including B and T cells, eosinophils, platelets, and monocytes (3, 4). The most recent finding that an anti-FceR2 mAb can inhibit the binding of IgE-coated ox erythrocytes to LC from atopic dermatitis patients (5) supports the contention that the presence of IgE on LC surfaces in this disease results from the binding of IgE to FceR2 . For many of the above cells, FceR2/CD23 expression is not a constitutive event but rather regulated by soluble mediators including human rIL-4 (hrIL-4 ; 6, 7), human rIFN-y (hrIFN -y; 6, 8), and PMA (8).To establish an in vitro model for studying putative T lymphocyte-LC interactions in atopic dermatitis, we asked in this study whether these substances can induce FceR2/CD23 expression on LC isolated from the epidermis of nonatopic individuals and, if so, whether such LC are capable of IgE binding . mAbs against CDla antigen (phycoerythrin [PE]-labeled T6/RDI, IgGI, Coultertronics, Krefeld, FRG; FITC-labeled OKT6, IgGI, Orthopharmaceuticals, Raritan, NJ) were used for LC labeling (9). M-L25 (IgGI ; Institute for Immunology, Munich, FRG) (10) and 3-5 (IgGl ; kindly provided by T. Kishimoto, Institute of Molecular and Cellular Biology, University of Osaka, Japan) (11) are both anti-CD23 mAbs. BIP-1 (IgGI ; Institute of General and Experimental Pathology, University of Vienna, Austria) (12), anti-IgM mAb AF-6 (IgGI ; Immunotech, Marseille, France), and anti-IgG mAb 8a4 (10 hg/ml) (IgGI, Immunotech,

Our data confirm and extend the knowledge of the influence of FLG mutations in AD.