M+K Chapter 1 - Structure Flashcards
Plakoglobin and desmoplakins in desmosomes are the target for which acquired disease?
Paraneoplastic pemphigus
Desmoglein 3 in desmosomes is the targert for which acquired disease?
Pemphigus vulgaris
alpha-6, beta-4 intergrin in hemidesmosomes is affected in which congenital disease?
Junctional epidermolysis bullosa
Charolais cattle and Churra sheep
alpha-6, beta-4 intergrin in hemidesmosomes is the target for which acquired diseases?
Bullous pemphigoid, MMP
BPAG1e (BP230), collagen XVII (BP180, BPAG2, LAD-1) in hemidesmosomes are targeted in which acquired/autoimmune diseases?
Bullous pemphigoid, MMP, linear IgA bullous disease
Laminin alpha-3 beta-3 gamma 2 (laminin 5) in the lamina densa (BMZ) is affected in which congenital disease?
Junctional epidermolysis bullosa
Laminin alpha-3 beta-3 gamma 2 (laminin 5) in the lamina densa (BMZ) is the target in which acquired/autoimmune diseases?
MMP, acquired junctional epidermolysis bullosa
Type VII collagen in anchoring fibrils (BMZ) is affected in which congenital disease?
Dystrophic epidermolysis bullosa
Type VII collage in anchoring fibrils (BMZ) is the target in which acquired/autoimmune diseases?
Epidermolysis bullosa acquisita, type 1 bullous systemic lupus erythematosus
K5/K14 in intermediate filaments are affected in which congenital disease?
Epidermolysis bullosa simplex
K5/K14 in intermediate filaments are targets for which acquired/autoimmune disease?
Ocular cicatrical pemphigoid/MMP (people)
Which layer of the epidermis is intergrin expression normally confined to?
Basal layer
Name the three types of cytoplasmic filaments found in the keratinocyte cytoskeleton
Cytokeratin, actin, and microtubules (tubulin)
In which epidermal layer are lamellar bodies synthesised?
Stratum spinosum
An increase in calcium concentration in the stratum granulosum causes what to happen to lamellar bodies?
They fuse with the plasma membrane and secrete their contents into the intercellular space
Amide-linked fatty acids containing a long-chain amino alcohol (sphingoid base) are also know as what?
Ceramides
Which epidermal cells contain Birbeck granules?
Langerhans cells
What are Birbeck granules?
Invaginations of the plasma membrane and bound antigen
Laminin 332 (laminin 5) in anchoring fibrils binds intergrin alpha-6 beta-4 to which other element of the BMZ?
Collagen VII
BPAG2 (BP180, collagen XVII) is found in which part of the hemidesmosome?
Outer plaque of the hemidesmosome
Reticular fibres (reticulin - fine, branching structures) can be detected with which special stains?
Silver stains
Elastic fibers can be visualised with which stains?
Verhoff, Weigart and oxidised Weigart
What are elastic fibres made of?
Elastin (two unique cross-linked amino acids; desmosine and isodesmosine which give it it’s remarkable strength)
Microbfibrils (fibrillin and type VI collagen)
Which collagens make up 87%, 10% and 3% of the dermal collagen?
Collagen I 87%
Collagen III 10%
Collagen V 3%
Which cells are the major source of collagenases under normal remodeling conditions?
Dermal fibroblasts
Which cells, other than dermal fibroblasts, can produce collagenases?
Keratinocytes, neutrophils, eosinophils and macrophages
True or false, Shar Peis have higher levels of serum hyaluronic acid than other dogs?
True
Where are the below found? Collagen I, III and V Collagen IV and V Collagen VII Collagen XII and XIV
Collagen I, III and V - dermis
Collagen IV (lamina densa) and V (lamina lucida) - BMZ
Collagen VII - BMZ anchoring fibrils
Collagen XII and XIV - FACIT (fibril-associated collagens with interrupted triple helices), believed to be influential in limiting the diameter of the dermal collagen fibrils and to help organise a proper dermal collagen I network
In animals affected with epidermolysis bullosa, sloughing of hooves is common - true or false?
True
What is the initial histopathological finding in EBS?
What is seen on histopathology in more advance stages?
Subepidermal separation with a minimal neutrophilic inflammation.
Extensive areas of intact full thickness epidermis are separated from the dermis, forming large clefts containing eosinophilic fluid, extravasated erythrocytes and occasional neutrophils
Can you see acantholytic keratinocytes in EBS?
Yes
In all animal species with JEB, oral multifocal ulcers are observed - true or false?
True
In the study by Nakai and Nasu, what were the ultrastructural properties of Merkel cells?
- Arrangement in clusters in the basal layer of the epidermis, oral mucosa and external follicular root sheath
- Inconstant link with nerve terminal
- Oval cell shape with large lobulated nuclei
- Spine-like and thick cytoplasmic processes interdigitating with surrounding keratinocytes
- Presence of desmosomes in the cell body or at the base of spine-like processes attaching to neighbouring keratinocytes
- Cytoplasm containing loosely arranged intermediate filaments and numerous dense-core granules arranged in the basal portion of the cytoplasm - cytoplasmic filaments in MKs were fewer and finer than those of keratinocytes.
Which vasoactive compounds are released from damaged cells causing a transient vasoconstriction and then vasodilation to allow fluids and cells to pass into the extravascular site of injury?
Histamine, serotonin and catecholamines
Dermal fibroblasts are stimulated to differentiate into alpha-smooth muscle actin expressing myofibroblasts by what?
transforming growth factor (TGF)-beta
The eventual result of the maturation phase is an acellular scar consisting of mostly which type of collagen?
Mostly collagen I
Which vitamin has been reported to significantly reverse the effects of corticosteroids on wound healing, and could be considered for adjunctive treatment in wound patients on chronic corticosteroid therapy?
Vitamin A
Positioning of ILCs in the epidermis is CCR6-dependent, and the maintenance requires which cytokines?
IL-7 and thymic stromal lymphopoietin (TSLP)
Produced by epithelial cells.
Which fibres link oxytalan (thin, most superficial) to elastic fibres (thicker, deepest)?
Elaunin
Which stain can demonstrate elastic, elaunin and oxytalan fibres?
Oxidised Weigert
What is the difference in composition of oxytalan, elaunin and elastic fibres?
Oxytalan is predominantly fibrillin microfibrils
Elaunin is a mixture of fibrillin and elastin
Elastic fibres are predominantly made of elastin
Tropoelastin is encoded by which gene?
Elastin (ELN)
Name two inflammatory/degenerative diseases of elastic fibres in veterinary species
Chronic progressive lymphoedema (of draught horses)
Solar elastosis
Erythema ab igne
Glucocorticoid effects
Marfan syndrome, a hereditary fibrillinopathy with lax and hyperelastic skin, has been reported in which veterinary species and affects which protein?
Cattle
Fibrillin 1
Which cytokine is sequestered in fibrillin fibres via LTBP?
TGF-beta (when released it stimulates collagen production by fibroblasts)
LTBP = latent TGF-beta binding protein
How do you differentiate cutis laxa from Ehlers-Danlos?
The hyperextensible skin rapidly moves back after stretching with Ehlers-Danlos and there is skin fragility and impaired wound healing
Cutis laxa has redundant skin and excessive folds (not reported in vet species yet)
Why do elastin fibres in solar elastosis stain with PAS?
There is an increased production and deposition of versican (a proteoglycan) on elastic fibres
Glucocorticoids reduce transcription of which dermal components?
Collagen I and III
Elastin
What is the role of tight junctions and adherence junctions?
Prevent diffusion of molecules between cells
What is the role of gap junctions?
Allow the diffusion of small molecules (e.g. calcium) between keratinocytes
Desmosomes link keratinocytes together by which intracellular structure?
Keratin filaments
What links intermediate filaments to plakoglobin and plakophlin in the desmosome?
Desmoplakin
Name the two cadherins that are in desomosomes
Desmogleins and desmocollins
Which is the more flexible protein, plakoglobin or plakophilin?
Plakophilin - it has a different segment between armadillo repeats which makes it more flexible
Name the epidermal plakins
Spectraplakins
BPAG1e/BP230
Envoplakin (corneodesmosomes and cornified envelope)
Periplakin (corneodesmosomes and cornified envelope)
Epiplakin
Desmoplakin
Plectin
True or false, plakophilin 1 (PKP1), desmocollin 1 (DSC1) and desmoglein 1 (DSG1) are expressed in the more superficial layers of the epidermis
True
What is epigenetics?
The study of changes in organisms caused by modification of gene expression rather than alteration of the genetic code itself.
Based on NGS studies, what are the main bacterial phyla found across different body sites in dogs?
Proteobacteria, Actinobacteria, Firmicutes, Bacteroidetes and Fusobacteria
Similar findings in cats although Bacteroidetes was more abundant
This EM image shows which structure? What do ODP and IDP stand for?
Desmosome
Outer dense plaque
Inner dense plaque
Midline
Plasma membrane
Name the structures of the desmosome
Keratin intermediate filaments
Dedmoplakin
Plakophilin and plakoglobin
Desmogleins and desmocollins
What makes up the outer dense plaque of the desomosme?
Desmoplakin heads, plakophilins, plakoglobin, cadherin cytoplasmic tails
What makes up the inner plaque of the desmosome?
Desmoplakin tails and keratin intermediate filaments
Which autoimmune diseases associated with desmoglein -1 have been reported in the dog?
PF
Mucocutaneous PV
Pemphigus vegetans
Which autoimmune diseases associated with desmocollin -1 have been reported in the dog?
Pemphigus Foliaceus (major antigen)
Name the epidermal members of the plakin family?
BPAG1-e (BP230), plectin, desmoplakin I/II, envoplakin, periplakin and epiplakin(-1)
Which autoimmune diseases associated with desmoplakin-1/2, envoplakin and periplakin have been reported in the dog?
PNP
Is this an image of footpad/haired skin or buccal mucosa?
Footpad/haired skin
Is this an image of footpad/haired skin or buccal mucosa?
Buccal mucosa
What are the green and yellow structures connecting microtubules and intermediate filaments?
Plectin
Which genetic diseases are associated with these structures?
In Chesakpeake Bay retrievers with ectodermal dysplasia and skin fragility, a mutation in which desomsomal structure leads to acantholysis?
Plakophilin-1
Loss of connection of desmoplakin to plakoglobin
Genetic EBS suprabasal form is reported in cows and associated with changes to which proteins?
Transglutaminase-5
Plakophilin-1
Desmoplakin
Plakoglobin
Name the hemidesmosome structures
Name the BMZ structures
Junctional epidermolysis bullosa in Charolais cattle and Churra sheep is associated with a mutation in ITGB4 gene and affects which protein?
alpha-6 beta-4 integrin
Which chain of alpha-6 beta-4 integrin is mostly extracelluar?
alpha-6 mostly extracellular
beta-4 mostly intracellular
Collagen XVII forms the bulk of the anchoring fibrils in the BMZ and is a helix of which chains?
Homotrimer of alpha-1 chains
Which vitamin is a cofactor for collagen formation?
Name another mineral that is a cofactor for collagen formation.
Vitamin C (ascorbic acid)
Copper
__________ control and prevent the premature aggregation of triple helices and the formation of fibrils in the endoplasmic reticulum
Chaperones
Extracellularly, procollagen ends are removed by which enzymes?
Metalloproteases
- ADAMTS2: procollagen I amino-proteinase (procollagen I N-proteinase)
- BMP1: procollagen I carboxy-proteinase (procollagen C-proteinase, Bone Morphogenetic Protein-1),
Cross linking of tropocollagen monomers via lysyl oxidase enzyme to form microfibrils requires which mineral?
Copper
True or false; Collagen III is the main component of reticulated (reticulin) fibrils, especially in lymphatic tissues
True
Name the FACIT (Fibril-Associated Collagens with Interrupted Triple Helices) collagens and describe their role
Collagen XII and XIV
Influential in limiting the diameter of the dermal collagen fibrils and to help organize a proper dermal collagen I network (help regulate space between collagens)
Which amino acid is important for triple helix formation in collagenogenesis?
Glycine
What is removed from procollagen during processing?
N- and C-propeptides
Where does lateral aggregation of collagen occur?
Golgi apparatus
Where does propeptide assembly occur?
Endoplasmic reticulum
Which enzymes cleave terminal peptides?
N: ADAMTS2
C: BMP1
What are the extracellular steps of collagen fibril formation?
- Nucleators (e.g. collagen V) initiate fibril assembly at the fibroblast surface
- Protofibril deposition in the extracellular matrix
- Stabilisation by interaction with SLRPs and FACITs
- Fibril growth and maturation
- Linear and lateral growth to mature banded fibrils
Name small leucine rich proteoglycans (SLRPs)
Decorin Biglycan Fibromodulin Lumican Tenascin
What is the role of small leucine rich proteoglycans (SLRPs)?
Steric hindrance
Collagen linking
Selection of lysine cross-links
A form of classical Ehlers Danlos syndrome has been reported in the cat with skin tears, skin hyperextensibility, hip subluxation and perineal hernias; which gene was mutated?
COL5A1
Dermatosparaxis is associated with a mutation in which enzyme?
ADAMTS2
Which species has dermatosparaxis been reported in?
Cats
Cattle
Sheep
True or false; collagen abnormalities can be variable in canine Ehlers Danlos syndrome
True
Collagen fibers can be relatively normal to short to almost no normal fibers
Are elastic fibers affected in Ehlers Danlos syndrome?
No
HERDA (Hereditary Equine Regional Dermal Asthenia) is seen in which breeds of horses?
Quarter Horse
American Paint
Which images shows normal collagen?
Left: normal
Right: irregular and loosely organised fibrils
HERDA is associated with a mutation in the gene encoding cyclophilin B; what is its role?
- Role in triple helix formation
- Affects the folding of the carboxyl-terminal propeptide and collagen trimer formation
In vivo studies have shown that topically administered glucocorticoids inhibit the transcription of mRNA encoding which types of collagen?
Collagen I and III
What effect does photodamage have on dermal collagen?
Increased collagen degradation
Decreased collagen production
What are the histopathological changes seen with photodamage?
Superficial alterations in dermal collagen usually include a hypocellular and homogeneous pale appearance.
What are the three main reasons for reduced collagen in the dermis?
Genetic diseases
Glucocorticoids
Photodamage/ageing
Feline skin fragility syndrome can be associated with spontaneous hyperadrenocorticism (48% of patients in one series), after iatrogenic glucocorticoid administration and with which other diseases?
Cholangiocarcinoma
Hepatic lipidosis,
Multiple endocrine neoplasia with hyperadrenocorticism
Chronic cholangiohepatitis with lipidosis
FIP infection
Generalized histoplasmosis
Multicentric follicular lymphoma
What are the histopathological changes seen in feline skin fragility syndrome?
- Thin epidermis and a severely atrophic dermis
- Profound attenuation of dermal collagen fibers with pale staining and disorganized appearance
In GDSs with renal cystadenocarcinomas and nodular dermatofibrosis, what is seen in the dermis?
Increased normal collagen fibers
In GDSs with renal cystadenocarcinomas and nodular dermatofibrosis, what is the mode of inheritance?
Autosomal dominant (homozygosity is lethal)
Musladin-Lueke Syndrome - associated with a mutation in ADAMTSL2 - causes what clinical signs?
Failure to thrive Short stature Thick, tight and inelastic skin Restricted joint mobility with a tiptoed gait Craniofacial changes Gregarious temperament
Appears to stabilise around one year of age
In GDSs with renal cystadenocarcinomas and nodular dermatofibrosis, a missense mutation occurs in which gene?
The folliculin (FLCN) gene encoding the protein folliculin
What are the clinical signs in morphea (Localized Scleroderma)?
Well-circumscribed alopecic, smooth and sclerotic patches with a fairly shiny and hypopigmented skin appearance
What is the prognosis for morphea?
They spontaneously regress
What is an important differential for morphea?
Care must be taken to differentiate a morphea-like lesion from that of a post-traumatic scarring (cicatricial) alopecia.
Morphea-like lesions do not follow skin ulceration!
Acquired reactive perforating collagenosis in cats causes exophytic adherent crusted papules and may be associated with wound healing; how can it be prevented?
Topical betamethasone
What are flame figures?
Eosinophilic degranulation surrounding collagen fibers - not collagen degradation!
Name the three fibers from superficial to deep
Oxytalan, elaunin and elastic
Where does fibrillin microfibril assembly occur?
Bound to receptors on the fibroblast cell membrane where mature fibrillins assemble linearly (head-to-tail) and laterally (side-by-side; 8 molecules) to form polymers
Marfan syndrome, associated with a fibrillin-1 mutation, is seen in which breeds of cattle?
Limousin crosses
Japanese black
What is the main difference in clinical signs between cutis laxa and Ehlers-Danlos syndrome?
Decrease in skin elasticity in cutis laxa, and hyperelasticity in Ehlers-Danlos
Mucinosis in Shar-Pei dogs is due to an excess secretion of high molecular weight HA following overtranscription or hyperactivity of which enzyme?
HAS2 enzyme
Low copy number = mucinosis
High copy number = familial Shar Pei fever
What is abnormal in this image?
More, thicker, distorted elastic fibers are present
Will be PAS positive as versican (glycosaminoglycan) is present
Which dermal collagen associated disease is this?
Erythema ab igne
Does not cause ulcers!
Is hyaluronic acid (a GAG), sulphated?
No - the other GAGs are
SLRPs bind to collagen I and are involved in regulating its fibril diameter and interfibrillar spacing; what is their other role?
- Involved in fibrillin-1 fibrillogenesis.
- Serve as signaling molecules, for example via their effect on TBF-beta, to regulate the deposition of extracellular matrix fibrils such as collagen type I.
- Appear to regulate the intermolecular cross-linking of collagen, either directly or via binding to lysyl oxidase
What are the clear spaces?
Mucin deposition
Mucinosis in Shar-Pei dogs is due to an excess secretion of high molecular weight HA following overtranscription or hyperactivity of which enzyme?
HAS2 enzyme
What is in the granules?
Hyaluronic acid
Shar Peis with Shar-Pei Auto-Inflammatory Disease
(SPAID) have mutations associated with which genes?
MTBP - forms a complex that stabilizes MDM2, a protein that induces sterile inflammation and that inhibits the p53 pro-apoptotic tumor suppressor gene, thus promoting apoptosis
Transmitted with HAS2
Mucinosis in hypothyroidism is associated with increased dermal deposition of what?
Hyaluronic acid
What effect does UVB have on hyaluronic levels in the dermis?
Increases dermal hyaluronic acid
What effect do glucocorticoids have on HAS2?
GCs inhibit the transcription of HAS2 mRNA - might be due to interference of GC with TGF signaling pathways
In dogs, how many hair follicles make up a follicular compound?
10-30
What separates the outer root sheath from the inner root sheath?
The companion layer
What does the middle picture show?
Transition from infundibulum to isthmus (ring of tricholemmal keratin, opening of SG duct)
Which part of the hair follicle is this?
Border of infundibulum and isthmus
What are the arrows pointing to?
Top: Henle’s layer (cornifies first)
Bottom: Huxley’s layer
At which part of the hair follicle is the inner root sheath fully cornified?
Isthmus
Which image is the inferior portion of the hair follicle and why?
Bottom
Huxley layer not cornified
Which growth phase are these hairs in?
Catagen
Retracting strand, apoptotic cells, different shape to dermal papilla, tricholemmal keratin anchoring the hair
Anagen or telogen?
Anagen
Anagen or telogen
Telogen
Bright eosinophilic keratin
Which structures are part of intercellular cohesions in the hair shaft?
Desmogleins and desmocollins
Do puppies have secondary or primary hair follicles at birth?
Primary only - secondary develop ~12 weeks
KRT71 is associated with which coat phenotype?
Curly
Hairlessness in Sphynx cats
FGF5 is associated with which coat phenotype?
Long hair
RSPO2 is associated with which coat phenotype?
Wire hair/furnishings
LPAR6 is associated with which coat phenotype in cats?
Curly coat in Cornish Rex and German Rex
Naked foal syndrome in Akhal Teke horses is inherited as a monogenic autosomal recessive trait and a nonsense variant of which gene?
ST14
Mutations in which gene cause hairlessness in American terriers and Scottish deerhounds?
SGK3
A mutation of which gene leads to colour dilution?
MLPH (melanophilin gene)
Are there increased number of kenogen follicles seen in dogs with endocrinopathies compared to normal dogs?
Yes
Witches feet follicles are seen with which cause of alopecia in dogs?
Recurrent flank alopecia
Glucocorticoids and oestrogens have what effects on the hair growth cycle?
- Induce premature catagen
- Induce premature telogen
- Inhibit onset of anagen
T4/T3 have what effects of the hair growth cycle?
Initiate and prolong anagen
Which types of alopecia can be classified as ischemia not associated with primary vascular pathology?
Canine traction alopecia
Post-traumatic alopecia
Which types of alopecia can be classified as ischemic dermatopathies (cutaneous vasculitis / vasculopathy)?
- Canine familial dermatomyositis
- Juvenile-onset ischemic dermatopathy without proven breed predilection
- Generalized postrabies vaccination-associated disease
- Adult onset generalized idiopathic ischemic dermatopathy
- Jack Russel Terrier vasculitis
Plectin through its actin-binding domains connects keratin filaments to nucleus by binding to _________
Nesprin-3
Curly coat in Fleckvieh and German angus cattle is due to mutation on keratin ____.
KRT 27
How many extracellular domains do the desmosomal cadherins have?
4 (EC1 TO EC4)
Which hormones initiate and prolong anagen?
Thyroid Corticotropin Melatonin Androgens Growth hormone
Which hormones inhibit the hair cycle?
Cortisol Oestrogen Corticotropin-releasing hormone Corticotropin Prolactin Parathyroid-related peptide
Name three growth factors that induce or prolong anagen
FGF 7 Hepatocyte growth factor Insulin-like growth factor 1 Sonic hedgehog Keratinocyte growth factor, WNTs, beta-catenin, TGF-alpha Nerve growth factor GDNF
Name two growth factors that inhibit the hair cycle
Epidermal growth factor FGF 2, FGF 5 Brain derived neurotropic factor Neurotrophin 3, 4 TGF-alpha TGF-beta 1/2
What effect does ciclosporin have on the hair cycle?
Stimulates it
Which cells are thought to be the primary target to hormones affecting the hair cycle?
Dermal papilla cells
If activation of melanocortin 1 receptors (MCR1) on melanocytes leads to eumelanin production, what does inhibition of MCR1 lead to?
Pheomelanin production
Fatty acids are converted to what products by keratinocytes?
Phospholipids
Ceramides (sphingomyelin, glucosylceramide)
Which essential fatty acid forms part of ceramides 1, 4 and 9?
Linoleic acid
Polyunsaturated fatty acids are precursors of what?
Eicosanoids
How are phospholipids metabolised to prostaglandins and leukotrienes?
Phospholipase A metabolises phospholipids to polyunsaturated fatty acids. They are subsequently metabolised by cyclooxygenase and lipoxygenase to prostaglandins and leukotrienes
What is the arrow pointing to?
Merkel cells in a tylotrich pad
Merkel cells contain a large cytoplasmic vacuole that displaces the nucleus dorsally. They are found in/just below the basal layer
What does this EM image show?
Birbeck granule in a Langerhans cell
The inner root sheath keratinises and disintegrates at which level of the follicle?
When it reaches the isthmus
Which hairs are slow- and which hairs are rapid-adapting mechanoreceptors?
Sinus hairs = slow
Tylotrich hairs = rapid
Sebaceous glands are not found at which body sites?
Footpad and nasal planum
Androgens cause sebaceous gland hypertrophy; which hormones cause sebaceous gland involution?
Oestrogen and glucocorticoids
Where do epitrichial sweat gland ducts open in the hair follicle?
The pilary canal in the infundibulum, above the sebaceous gland duct
Which parts of the skin do the deep, middle and superficial plexus of blood vessels supply?
Deep: subcutis, lower portion of the hair follicle and sweat glands
Middle: arrector pili, middle portion of the hair follicle and sebaceous glands
Superficial: upper portion of the hair follicle and epidermis
What regulators of leukocyte trafficking are found on endothelial cells?
E- and P-selectin
ICAM1
VCAM1
Substance P, released by sensory nerve fibres and keratinocytes, binds to tachykinin and neurokinin 1 receptors and has what function in the skin?
- Inflammation
- Upregulation of cell adhesion molecules
- Priming of mast cells
- Pruritus
Keratinocytes and _____________ are important sources of nerve growth factor
Mast cells
What are these structures?
Pacinian corpuscles
Which type of opioids are pruritic at spinal level?
u-opioids
Which interleukins are pruritogenic?
IL-2 and IL-31
Damage to which part of the hair follicle leads to lack of capability to grow?
Stem cell bulge (isthmus)
