Mechanisms of abnormal lamellar body secretion and the dysfunctional skin barrier in patients with atopic dermatitis Peter M. Elias, MD, Joan S. Wakefield

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Presentation transcript:

Mechanisms of abnormal lamellar body secretion and the dysfunctional skin barrier in patients with atopic dermatitis Peter M. Elias, MD, Joan S. Wakefield Journal of Allergy and Clinical Immunology Volume 134, Issue 4, Pages 781-791.e1 (October 2014) DOI: 10.1016/j.jaci.2014.05.048 Copyright © 2014 Terms and Conditions

Fig 1 Multifunctional effect of secreted lamellar body contents. Modified from Elias et al.10 Journal of Allergy and Clinical Immunology 2014 134, 781-791.e1DOI: (10.1016/j.jaci.2014.05.048) Copyright © 2014 Terms and Conditions

Fig 2 Cytokine cascade leads to multiple vicious cycles in patients with AD. NF-κB, Nuclear factor κB; TSLP, thymic stromal lymphopoietin; VEGF, vascular endothelial growth factor. Journal of Allergy and Clinical Immunology 2014 134, 781-791.e1DOI: (10.1016/j.jaci.2014.05.048) Copyright © 2014 Terms and Conditions

Fig 3 Multiple downstream consequences of filaggrin deficiency in patients with AD. *Trans-urocanic acid (trans-UCA) is the most potent endogenous UV-B filter in lightly pigmented skin. Loss of t-UCA could account for the higher incidence of nonmelanoma skin cancers in patients with AD. NMF, Natural moisturizing factor. Modified from Elias et al.10 Journal of Allergy and Clinical Immunology 2014 134, 781-791.e1DOI: (10.1016/j.jaci.2014.05.048) Copyright © 2014 Terms and Conditions

Fig 4 Abnormalities that lead to paracellular barrier abnormality in FLG-deficient epidermis. A and B, Lanthanum perfusion in patients with double-allele IV (Fig 4, B) versus wild-type (Fig 4, A) human epidermis. C, Retraction of cytoskeleton (asterisk) in patients with double-allele IV. D (and inserts), Impaired loading and secretion of lamellar body cargo in double-allele IV. E, Normal (wild-type) human epidermis. Ruthenium textroxide post-fixation. F and G, Postsecretory abnormalities in lamellar bilayer organization and maturation in double-allele IV (arrows). SG, Stratum granulosum; wt, wild-type. Modified from Gruber et al.26 Journal of Allergy and Clinical Immunology 2014 134, 781-791.e1DOI: (10.1016/j.jaci.2014.05.048) Copyright © 2014 Terms and Conditions

Fig 5 Lessons from NS: proposed roles for increased pH and KLK activation in producing lipid abnormalities in patients with AD. AMP, Antimicrobial peptide; Cer, ceramide; FA, fatty acid; TSLP, thymic stromal lymphopoietin. Journal of Allergy and Clinical Immunology 2014 134, 781-791.e1DOI: (10.1016/j.jaci.2014.05.048) Copyright © 2014 Terms and Conditions

Fig 6 How inherited abnormalities converge to produce defective permeability and antimicrobial barriers in patients with AD. FA, Fatty acid; Fatp4, fatty acid transport protein 4; hBD2, human β-defensin 2; Hrn, hornerin; LB, lamellar body. Journal of Allergy and Clinical Immunology 2014 134, 781-791.e1DOI: (10.1016/j.jaci.2014.05.048) Copyright © 2014 Terms and Conditions

Fig E1 Abnormalities in the lamellar body secretory system in flaky tail mice. A and C, Partial failure of lamellar body exocytosis is evident in flaky tail (FT) epidermis, with loss of mattrin. Note lamellar bodies lined up in peripheral cytosol (Fig E1, A, multiple thin arrows), decreased secreted material at the stratum granulosum (SG)–SC interface (Fig E1, A and C, short fat arrows), decreased numbers of lamellar bilayers (Fig E1, C), delayed maturation of lamellar bilayers (Fig E1, C), and entombed lamellar body contents within the corneocyte cytosol (Fig E1, C, short thin arrows). B and D, Normal lamellar body secretion (Fig E1, B, arrows) and extracellular lamellar bilayers in wild-type (WT) epidermis (Fig E1, D, thin arrows). Fig E1, A and B, Osmium tetroxide postfixation; Fig E1, C and D, ruthenium tetroxide postfixation. Reproduced from Scharschmidt et al.71 Journal of Allergy and Clinical Immunology 2014 134, 781-791.e1DOI: (10.1016/j.jaci.2014.05.048) Copyright © 2014 Terms and Conditions