Coloring Agents/adverse effects , Conjunctivitis, Allergic/chemically induced , Cosmetics/adverse effects , Dermatitis, Allergic Contact/etiology , Edema/chemically induced , Phenylenediamines/adverse effects , Adolescent , Eyelashes , Facial Dermatoses/chemically induced , Female , Humans , Middle Aged
BACKGROUND: Mutations in the gene encoding filaggrin (FLG), an epidermal structural protein, are the strongest risk factor identified for the development of atopic dermatitis (AD). Up to 50% of patients with moderate-to-severe AD in European populations have FLG-null alleles compared with a general population frequency of 7% to 10%. OBJECTIVE: This study aimed to investigate the relationship between FLG-null mutations and epidermal antigen-presenting cell (APC) maturation in subjects with and without AD. Additionally, we investigated whether the cis isomer of urocanic acid (UCA), a filaggrin breakdown product, exerts immunomodulatory effects on dendritic cells. METHODS: Epidermal APCs from nonlesional skin were assessed by using flow cytometry (n = 27) and confocal microscopy (n = 16). Monocyte-derived dendritic cells from healthy volunteers were used to assess the effects of cis- and trans-UCA on dendritic cell phenotype by using flow cytometry (n = 11). RESULTS: Epidermal APCs from FLG-null subjects had increased CD11c expression. Confocal microscopy confirmed this and additionally revealed an increased number of epidermal CD83(+) Langerhans cells in FLG-null subjects. In vitro differentiation in the presence of cis-UCA significantly reduced costimulatory molecule expression on monocyte-derived dendritic cells from healthy volunteers and increased their ability to induce a regulatory T-cell phenotype in mixed lymphocyte reactions. CONCLUSIONS: We show that subjects with FLG-null mutations have more mature Langerhans cells in nonlesional skin irrespective of whether they have AD. We also demonstrate that cis-UCA reduces maturation of dendritic cells and increases their capacity to induce regulatory T cells, suggesting a novel link between filaggrin deficiency and immune dysregulation.
Cell Differentiation/genetics , Intermediate Filament Proteins/genetics , Langerhans Cells/cytology , Langerhans Cells/metabolism , Mutation , Adult , Antigen-Presenting Cells/cytology , Antigen-Presenting Cells/immunology , Antigen-Presenting Cells/metabolism , Biomarkers , CD11c Antigen/metabolism , Cell Communication , Coculture Techniques , Dermatitis, Atopic/diagnosis , Dermatitis, Atopic/genetics , Dermatitis, Atopic/immunology , Dermatitis, Atopic/metabolism , Epidermis/immunology , Epidermis/metabolism , Epidermis/pathology , Female , Filaggrin Proteins , Flow Cytometry , Humans , Immunoglobulin E/immunology , Langerhans Cells/immunology , Leukocytes, Mononuclear/cytology , Leukocytes, Mononuclear/immunology , Leukocytes, Mononuclear/metabolism , Male , Middle Aged , Phenotype , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , Young Adult
Biological Therapy/methods , Psoriasis/therapy , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized , Dermatologic Agents/therapeutic use , Etanercept , Humans , Immunoglobulin G/therapeutic use , Immunologic Factors/therapeutic use , Infliximab , Receptors, Tumor Necrosis Factor/therapeutic use
Skin Diseases/etiology , Acquired Immunodeficiency Syndrome/complications , Connective Tissue Diseases/complications , Diabetes Complications , Digestive System Diseases/complications , Drug Eruptions , Humans , Neoplasms/complications , Porphyrias/complications , Sarcoidosis/complications , Thyroid Diseases/complications