Matthias Schmuth, Gil Yosipovitch, Mary L

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Presentation transcript:

Pathogenesis of the Permeability Barrier Abnormality in Epidermolytic Hyperkeratosis1 Matthias Schmuth, Gil Yosipovitch, Mary L. Williams, Florian Weber, Helmut Hintner, Susana Ortiz-Urda, Klemens Rappersberger, Debra Crumrine, Kenneth R. Feingold, Peter M. Elias Journal of Investigative Dermatology Volume 117, Issue 4, Pages 837-847 (October 2001) DOI: 10.1046/j.0022-202x.2001.01471.x Copyright © 2001 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Pathogenesis flow chart for the analysis of the barrier abnormality in disorders of keratinization. First, functional assessments are used to determine TEWL levels in ichthyotic skin. If TEWL abnormalities are present, lanthanum perfusion is employed to distinguish transcellular from intercellular permeability pathways. In the case of an inter cellular abnormality, a battery of ultrastructural methods is then applied to detail the morphologic basis for the intercellular defect. aElias et al, 1981; bElias et al, 2001; cElias et al, 2000b; dpresent study. Journal of Investigative Dermatology 2001 117, 837-847DOI: (10.1046/j.0022-202x.2001.01471.x) Copyright © 2001 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Barrier recovery after tape stripping is accelerated in EHK epidermis. The volar forearm of EHK and normal subjects was tape-stripped, and TEWL was measured with time following barrier disruption (time 0). Accelerated barrier recovery, although evident at all early time points after disruption (i.e., 0–48 h), was significant only at 48 h, because of the small number of patients (*p <0.05 vs normal control values). At later time points, barrier recovery of EHK individuals paralleled the recovery of normal skin, and at 2-5 d, barrier recovery slowed, resulting in the higher-than-normal baseline TEWL levels characteristic of EHK. Journal of Investigative Dermatology 2001 117, 837-847DOI: (10.1046/j.0022-202x.2001.01471.x) Copyright © 2001 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Increased water movement occurs via intercellular pathways. Freshly obtained biopsies from EHK were exposed for 1 h to 4% colloidal lanthanum nitrate tracer in 0.05 M Tris buffer, pH 7.4, containing 2% glutaraldehyde and 2% paraformaldehyde, followed by postfixation in OsO4. (A), (B) Tracer is observed throughout the SC interstices (arrows), but was excluded from the corneocyte cytosol. OsO4 postfixation. Scale bars: 0.5 µm. Journal of Investigative Dermatology 2001 117, 837-847DOI: (10.1046/j.0022-202x.2001.01471.x) Copyright © 2001 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 Extracellular lamellar bilayer structures are abnormal in EHK. (A–C) Clefts and lacunae are present througout the SC interstices (asterisks). (C) Overall, the amount of bilayer material is reduced. (A, B, D,) Stretches of intact, normal-appearing bilayers are only focally present (arrows). RuO4 postfixation. Scale bars: 0.5 µm. Journal of Investigative Dermatology 2001 117, 837-847DOI: (10.1046/j.0022-202x.2001.01471.x) Copyright © 2001 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 5 CE and CLE appear normal in EHK. (A) CE (arrows) in EHK appear largely normal, although there is some variation in thickness. (B) CLE (arrowheads) also appear completely normal in EHK. (A) OsO4 postfixation; (B) OsO4 postfixation after pyridine pretreatment (see Methods). Scale bars: 0.25 µm. Journal of Investigative Dermatology 2001 117, 837-847DOI: (10.1046/j.0022-202x.2001.01471.x) Copyright © 2001 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 6 Arrays of LB beneath plasma membrane indicate a secretory defect in EHK. Although the overall number of LB is normal in EHK, arrays of individual organelles remain restricted beneath the apical plasma membrane of outermost granular (SG) cells (A, B, arrows). (C) Lack of LB secretion results in a paucity of extracellular deposits at the SG–SC interface (asterisks). RuO4 postfixation. Scale bars: 0.5 µm. Journal of Investigative Dermatology 2001 117, 837-847DOI: (10.1046/j.0022-202x.2001.01471.x) Copyright © 2001 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 7 LB content is entombed within corneocyte cytosol. (A, B) Entombed LB are found within the cytosol of corneocytes (A, B, short open arrows; C, solid arrow). Note again the presence of lacunae (asterisks) and areas of reduced and abnormal bilayer structures (B, C). (C) The encased LB contents focally form bilayer structures within the cytosol. RuO4 postfixation. Scale bars: 0.25 µm. Journal of Investigative Dermatology 2001 117, 837-847DOI: (10.1046/j.0022-202x.2001.01471.x) Copyright © 2001 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 8 Further evidence of impaired secretion in EHK: acid lipase is retained within corneocytes. (A, B) The LB hydrolase, acid lipase, is largely retained within the cytosol of corneocytes in EHK (arrowheads). (C) Retained activity is colocalized with entombed LB. (D) Normal human skin demonstrates hydrolase solely in the SC interstices, indicative of effective secretion. OsO4 postfixation. Scale bars: 0.5 µm. Journal of Investigative Dermatology 2001 117, 837-847DOI: (10.1046/j.0022-202x.2001.01471.x) Copyright © 2001 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 9 Basis for accelerated barrier recovery in EHK epidermis. (A, B) (6 h post-tape stripping): No LB remain in cytosol of granular cells (SG), indicated by release of lipase activity into the intercellular spaces (B, arrows). Extent of release of contents also is shown at level of SC: no entombed organelles or cytosolic lipase activity remain in corneocyte cytosol. (C) (3 d post-tape stripping): Reappearance of additional foci of replete lamellar bilayers at time point when barrier recovery is accelerated (cf. Figure 2). (D) (6 h post-tape stripping): Lanthanum perfusion demonstrates substantial blockade of tracer movement at SG–SC interface, although foci of tracer (arrow) continue to penetrate the SC interstices. (A, B, D) OsO4 postfixation; (C) RuO4 postfixation. Scale bars: (A, B, D) 0.5 µm; (C) 0.25 µm. Journal of Investigative Dermatology 2001 117, 837-847DOI: (10.1046/j.0022-202x.2001.01471.x) Copyright © 2001 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 10 Baseline Ca2+ distribution and loss of Ca2+ gradient is similar to normals in EHK. (A, B) A comparable Ca2+ gradient, with the highest Ca2+ levels in the outer SG with lower levels in subjacent layers and SC, is evident in both normal (A) and EHK (B) skin at baseline. (C, D) Loss of Ca2+ gradient after tape stripping (C) or acetone treatment (D) is accompanied by secretion of LB (SC, stratum corneum, OSG, outer stratum granulosum). OsO4 postfixation. Scale bars: 1 µm. Journal of Investigative Dermatology 2001 117, 837-847DOI: (10.1046/j.0022-202x.2001.01471.x) Copyright © 2001 The Society for Investigative Dermatology, Inc Terms and Conditions