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Chapter 26
PART IV: Molecular Pathology of Human Disease
Molecular Basis of Skin Disease
Companion site for Molecular Pathology
Author: William B. Coleman and Gregory J. Tsongalis
FIGURE 26.1
Light microscopic appearances of normal human skin (hematoxylin and eosin; bar = 50 μm).
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FIGURE 26.2
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.
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FIGURE 26.3
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.
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FIGURE 26.4
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]).
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FIGURE 26.5
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.
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FIGURE 26.6A
(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.
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FIGURE 26.7
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.
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FIGURE 26.8
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).
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FIGURE 26.9
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 DowlingDegos disease.
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FIGURE 26.10
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.
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FIGURE 26.11
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.
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FIGURE 26.12
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 midback. (B) Light microscopy revealsa moderately differentiated SCC.
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FIGURE 26.13
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.
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FIGURE 26.14
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.
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FIGURE 26.15
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.
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FIGURE 26.16
Loss of function mutations in the filaggrin gene result in several common disease associations or
susceptibilities.
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FIGURE 26.17
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]).
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FIGURE 26.18
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.
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FIGURE 26.19
Illustration of hemidesmosomal structural proteins and the autoimmune diseases associated with
antibodies directed against these individual protein components.
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FIGURE 26.20
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.
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FIGURE 26.21
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.
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FIGURE 26.22
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.
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FIGURE 26.23
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.
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FIGURE 26.24
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]).
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FIGURE 26.25
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.
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FIGURE 26.26
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.
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FIGURE 26.27
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).
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FIGURE 26.28
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 Tcells 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]).
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