Chapter 26 PART IV: Molecular Pathology of Human Disease Molecular Basis of Skin Disease Companion...

Chapter 26PART IV: Molecular Pathology of Human Disease

Molecular Basis of Skin Disease

Companion site for Molecular PathologyAuthor: William B. Coleman and Gregory J. Tsongalis

Companion site for Molecular Pathology Copyright © 2009 by Academic Press. All rights reserved.

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Light microscopic appearances of normal human skin (hematoxylin and eosin; bar = 50 μm).

FIGURE 26.1


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Immune defense system in human skin.Microorganisms that breach the human epidermis are faced with a constitutive antimicrobial system, for example, psoriasin. Further protection is also provided by inducible antimicrobial peptides, such as the β-defensins RNASE7 and LL-37. Microorganisms may also be targeted by proinflammatory cytokines.

FIGURE 26.2


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The function of Langerhans cells in human skin.The photomicrograph (top left) shows the dendritic appearances of Langerhans cells in human epidermis (image kindly supplied by Dr. Rachel Mohr, University of Toledo, TX). Antigenic material from invading peptides or bacteria are phagocytosed and processed by Langerhans cells within the epidermis. These Langerhans cells then mature and migrate to regional lymph nodes. Antigen is presented to T-cells which are then activated, proliferate, and allow for adaptive immune responses.

FIGURE 26.3


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Diversity of immune sentinels in human skin.These include CD1a+ Langerin+ Langerhans cells located in the epidermis and various subtypes of dendritic cells and macrophages in the dermis. This figure illustrates some of the recent immunophenotypic and functional findings of these immune sentinels. The macrophage population expressing CD68 and CD14 can be further subdivided into classically activated macrophages (M1) and alternatively activated macrophages (M2), which develop under the influence of IL-4 and IL-10. Several cells have self-renewing potential under conditions of tissue homeostasis. Under inflammatory conditions, circulating blood-derived monocytes are potential precursors of Langerhans cells, dermal dendritic cells, and macrophages (based on an original figure by [86]).

FIGURE 26.4


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Genomic and functional domain organization of the transcription factor p63.At least 6 different isoforms can be generated by use of alternative translation initiation sites or alternative splicing. The main isoform expressed in human skin is ΔNp63α. Autosomal dominant mutations in the DNA binding domain of the p63 gene lead to ectrodactyly, ectodermal dysplasia, and clefting (EEC) syndrome. In contrast, autosomal dominant mutations in the SAM domain result in ankyloblepharon, ectodermal dysplasia, and clefting (AEC) syndrome. A number of other ectodermal dysplasia syndromes may also result from mutations in the p63 gene.

FIGURE 26.5


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(A)Localization of stem cells in human epidermis. Stem cells are located within the basal layer of interfollicular epidermis, as well as at the base of sebocytes and also in the bulge area of hair follicles. (B) These epidermal stem cells are associated with a number of cellular markers.

FIGURE 26.6A


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Illustration of the integral structural macromolecules present within hemidesmosome-anchoring filament complexes and the associated forms of clinical epidermolysis bullosa that result from autosomal dominant or autosomal recessive mutations in the genes encoding these proteins.

FIGURE 26.7


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Clinicopathological consequences of mutations in the gene encoding keratin 14 (KRT14), the major intermediate filament protein in basal keratinocytes.(A) The clinical picture shows autosomal dominant Dowling-Meara epidermolysis bullosa simplex. (B) The electron micrograph shows keratin filament clumping and basal keratinocyte cytolysis (bar = 1 μm).

FIGURE 26.8


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Spectrum of clinical abnormalities associated with dominant mutations in keratin 5 (KRT5).(A) Missense mutations in the nonhelical end domains result in the most common form of EB simplex, which is localized to the hands and feet (Weber-Cockayne variant). (B) A specific mutation in keratin 5, p.P25L, is the molecular cause of epidermolysis bullosa simplex associated with mottled pigmentation. (C) Heterozygous nonsense or frameshift mutations in the KRT5 gene leads to Dowling-Degos disease.

FIGURE 26.9


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Laminin-332 mutations result in junctional epidermolysis bullosa.(A) Laminin-332 consists of 3 polypeptide chains: α3, β3, and γ2. (B) Immunogold electron microscopy shows laminin-332 staining at the interface between the lamina lucida and lamina densa subjacent to a hemidesmosome (bar = 50 nm). (C) Loss of function mutations in any one of these genes encoding the 3 polypeptides chains results in Herlitz junctional epidermolysis bullosa, which is associated with a poor prognosis, usually with death in early infancy.

FIGURE 26.10


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Clinicopathological abnormalities in the dystrophic forms of epidermolysis bullosa.(A) This form of epidermolysis bullosa is associated with variable blistering and flexion contraction deformities, here illustrated in the hands. (B) The disorder results from mutations in type VII collagen (COL7A1 gene), the major component of anchoring fibrils at the dermal-epidermal junction. This leads to blister formation below the lamina densa (lamina densa indicated by arrow). (C) In contrast, in normal human skin there is no blistering, and the sublamina densa region is characterized by a network of anchoring fibrils.

FIGURE 26.11


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Squamous cell carcinoma (SCC) in recessive dystrophic epidermolysis bullosa.(A) Affected individuals have a 70-fold increased risk of developing SCC, here illustrated on the mid-back. (B) Light microscopy revealsa moderately differentiated SCC.

FIGURE 26.12


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Protein composition of the desmosome linking two adjacent keratinocytes a moderately differentiated SCC.The major transmembranous proteins are the desmogleins and the desmocollins. Several desmosomal plaque proteins, including desmoplakin, plakophilin, and plakoglobin provide a bridge that links binding between the transmembranous cadherins and the keratin filament network within keratinocytes.

FIGURE 26.13


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Clinical abnormalities associated with inherited gene mutations in desmosome proteins.(A) Recessive mutations in plakophilin 1 result in nail dystrophy and skin erosions. (B) Woolly hair is associated with several desmosomal gene abnormalities, particularly mutations in desmoplakin. (C) Recessive mutations in plakophilin 1 can result in extensive neonatal skin erosions, particularly on the lower face. (D) Recessive mutations in desmoplakin can lead to skin blistering. (E) Autosomal dominant mutations in desmoplakin do not result in blistering but can lead to striate palmoplantar keratoderma.

FIGURE 26.14


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Clinicopathological abnormalities in atopic dermatitis.(A) Clinically, there is inflammation in the antecubital fossa with erythema erosions and lichenification. (B) Genetic or acquired abnormalities that lead to reduction in filaggrin expression in the granular layer disrupt the skin barrier permeability, which allows penetration of external allergens and presentation to Langerhans cells. Reduced filaggrin in skin may be a major risk factor for atopic dermatitis and increases susceptibility to atopic asthma and systemic allergies.

FIGURE 26.15


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Loss of function mutations in the filaggrin gene result in several common disease associations or susceptibilities.

FIGURE 26.16


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Abnormalities and therapeutic potential for inflamed skin in psoriasis.There is increasing evidence for a role of tissue-resident immune cells in the immunopathology of psoriasis. New therapies may be developed by (1) antagonizing local cytokines and chemokines, such as IFN-α; (2) blocking of adhesion molecules (e.g., integrins) and co-stimulatory molecules within the tissue; (3) modification of keratinocyte proliferation and differentiation (e.g., use of corticosteroids or vitamin D preparations); (4) blocking of entry of dermal T-cells into the epidermis, and (5) modification of the microenvironment, including the extracellular matrix (based on original figure published by [87]).

FIGURE 26.17


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Clinical pathology resulting from autoantibodies against desmosomes or hemidesmosomes.(A) Pemphigus vulgaris resulting from antibodies against desmoglein 3; (B) Bullous pemphigoid associated with antibodies against type XVII collagen; (C) Mucous membrane pemphigoid associated with antibodies to laminin-332.

FIGURE 26.18


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Illustration of hemidesmosomal structural proteins and the autoimmune diseases associated with antibodies directed against these individual protein components.

FIGURE 26.19


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Salt-split skin technique to diagnose immunobullous disease.Incubation of normal human skin in 1M NaCl overnight at 4 °C results in cleavage through the lamina lucida. This results in separation of some proteins to the roof of the split and some to the base (above and below pink line on the schematic). In the skin labeling shown, immunoglobulin from a patient's serum binds to the base of salt-split skin. Further analysis revealed that the antibodies were directed against type VII collagen. This technique is useful in delineating bullous pemphigoid from epidermolysis bullosa acquisita, both of which are associated with linear IgG at the dermal-epidermal junction in intact skin.

FIGURE 26.20


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Mucous membrane pemphigoid may be associated with autoantibodies against either type XVII collagen or laminin-332.Distinction between the two may have clinical relevance since antilaminin-332 antibodies in mucous membrane pemphigoid can be associated with malignancy (especially of the upper aero-digestive tract) in some patients.

FIGURE 26.21


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Clinical consequences of disruption of desmoglein 1 in human skin.(A) Staphylococcal toxins cleave the extracellular part of desmoglein 1 and result in staphylococcal scalded skin syndrome. (B) Inherited autosomal dominant mutations in desmoglein 1 can result in striate palmoplantar keratoderma. (C) Autoantibodies against desmoglein 1 result in pemphigus foliaceus, which is associated with superficial blistering and crusting in human skin.

FIGURE 26.22


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The SHH signaling pathway.(A) In the absence of SHH, PATCHED constitutively represses smoothened, a transducer of the SHH signal. (B) Binding of the ligand SHH to PTCH relieves its inhibition of SMO and transcriptional activation occurs through the GLI family of proteins, resulting in activation of target genes.

FIGURE 26.23


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Potential for targeted therapies in melanoma.Recent improvement in defining the genetics of melanoma has led to the development of targeted therapeutic agents that are directed at specific molecular aberrations involved in tumor proliferation and resistance to chemotherapy. (Based on an original figure published by [89]).

FIGURE 26.24


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Clonal T-cell expansion in a patient with mycosis fungoides (cutaneous T-cell lymphoma).The clinical stage of the patient is Stage 1b. This figure shows single-strand conformational polymorphism (SSCP) analysis and demonstrates an identical clonal T-cell receptor gene rearrangement in two lesional skin biopsies. The matched blood sample is polyclonal.

FIGURE 26.25


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Impact of molecular diagnostics on clinical management.(A) Clinical appearances of multiple cutaneous leiomyomas. (B) Light microscopic appearances show a spindle cell tumor within the dermis (bar = 100 μm). (C) Immunostaining with smooth muscle actin identifies the dermal tumor as a leiomyoma (bar = 100 μm). In patients with multiple cutaneous leiomyomas and an autosomal dominant family history, detection of fumarate hydratase (FH gene mutations) may indicate a diagnosis of specific syndromes that can have implications for fertility as well as the risk of developing rare forms of renal cancer.

FIGURE 26.26


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Options for prenatal testing for severe inherited skin diseases.(A) Chorionic villus samples taken at 10–12 weeks; (B) Preimplantation genetic diagnosis, here illustrating single cell extraction from a 72-hour-old embryo; (C) Fetal skin biopsy performed at 16–22 weeks gestation, here showing the appearances of normal human fetal skin at 18 weeks (bar = 25 μm).

FIGURE 26.27


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Roles for chemokine receptors and possible therapeutic manipulation in cutaneous T-cell lymphoma.Chemokine receptors may have important roles in enabling malignant T-cells to enter and survive in the skin. (1) Homing: Activation of T-cell integrins permits T-cell adhesion to endothelial cells in the skin and subsequent binding to extracellular matrix proteins. T-cells can then migrate along a gradient of chemokines, e.g., CCL17 and CCL27 to the epidermis. (2) Activation: chemokine receptors allow T-cells to interact with dendritic cells such as Langerhans cells, leading to T-cell activation and release of inflammatory cytokines. (3) Inhibition of apoptosis: chemokine receptor engagement can lead to upregulation of PI3K and AKT, which are prosurvival kinases. T-cells can therefore survive and proliferate in the skin. (4) Chemokine-antigen fusion proteins can be used to target tumor antigens from cutaneous T-cell lymphoma cells to CCR6+ presenting dendritic cells that can stimulate host antitumor immunity. (5) Chemokine toxin molecules can also target specific chemokine receptors found on cutaneous T-cell lymphoma cells to mediate direct killing. (Based on an original figure published by [76]).

FIGURE 26.28

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Chapter 26 PART IV: Molecular Pathology of Human Disease Molecular Basis of Skin Disease Companion...

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