Skin And Extracellular Matrix Flashcards
What is the cause Pemphigus
Antibodies attack cadherins and integrins in keratinocytes causing defects in cell to cell and cell to matrix adhesion
Key feature of Pemphigus and main types of the disease
Blisters on skin and in oral cavity
Two types:
- Pemphigus vulgaris
- Pemphigus foliaceus
Molecular basis of Pemphigus Volgaris
Autoantibodies attack cell surface antigens (desmogleins 1 and 3 - cadherins)
Symptoms and treatment of pemphigus vulgaris
Symptoms:
- intra-epidermal blisters (above dermis) which can rupture
- when ruptured causes bleeding and fluid leaking
- proteolytic enzymes produced breakdown enzymes in these cells
Treatment:
- immunosuppressive agents
- corticosteroids (decrease inflammation)
What is a key identifying feature in the histology of Pemphigus vulgaris
Tombstone rows
- due to single layer of basal cells still attached to dermis of skin
Molecular basis of Bullosa Pemphigoid
Autoantibodies attack BP 180 and BP 230 (basement membrane proteins) which connect hemidesmosome to intermediate filaments
Skin keratinocytes cannot attach to basement membrane
Symptoms and treatment of Bullosa Pemphigoid
Sub-epidermal bullae (blisters)
Blisters which appear on:
- abdomen
- groin
- upper thighs
- arms
- along creases in skin (e.g. inner elbow joint)
Treatment:
- immunosuppressants or steroids
What is keratin and what is it’s function?
Intermediate filament which forms alpha helices or beta sheets
Functions:
- hold epithelial cells together through cell junctions
- provides mechanical strength at hemidesmosomes and desmosomes
Keratin structure
Elongated molecule which N terminus (head) and C terminus (tail)
Composed of subunits
- Type 1 subunit pairs (acidic)
- type 2 subunit pairs (basic)
Different subunit compositions are expressed in different tissues
Keratin subunits expressed in epithelium
Basal layer (stratified epithelia) - keratins 5 and 14
Suprabasal layers (layers above the basal layer) - keratins 1 and 10
Intermediate Filament assembly
- keratin polypeptide
- Another keratin monomer comes and coils with the first monomer to create a dimer
- Another dimer is created and joins with the first creating a tetramer
- Happens continuously until a protocol amend is formed
- Eight tetramers are then twisted into a rope like filament
What is the main cause of Karen in associated disease
If either one of a keratin pair is lost
What are the two keratin associated diseases
Epidermolysis bullosa
Epidermolysis hyperkeratosis
Epidermolysis bullosa simplex symptoms
Blisters due to skin not being able to resist mechanical stress
- blisters appear primarily on hands and feet
- can usually heal without scarring
- sever cases have widespread blisters which can lead to secondary infections and dehydration
Mostly appears in infants and children
Molecular basis of Epidermolysis bullosa simplex
Genetic mutations = KRT5 or KRT14 genes
KRT14 mutation = non functioning keratin 14 molecule
KRT5 mutation = unstable keratin protein
Phenotype = keratin clumping or disorganised filaments
Because they are expressed in basal cells epidermis separated from dermis
Severity depends on type of mutations
Epidermolysis hyperkertosis symptoms and genetic inheritance
Symptoms in infants:
- very red skin (erythroderma)
- severe blisters
Symptoms in adults:
- skin thickening
- blisters and erythroderma less frequent
Genetic inheritance:
Autosomal dominant
Pathophysiology of epidermolytic hyperkeratosis
Mutations in KR1 and KR10
- keratin aggregates in suprabasal cells (stratum corneum)
- loss of strong intermediate filaments
- increase in mitosis
Other keratin disorders
Keratin 6 and 16 mutations
- hair and nail disorders
Keratin 3 and 12 mutations
- cornea defects
Epidermodysplasia verruciformis (tree man)
Epidermodysplasia verruciformis symptoms, genetic inheritance
Autosomal recessive hereditary disorder
Symptoms:
- wart like growths
- scaly macules and papules
- on hands and feet
Epidermodysplasia verruciformis molecular basis
Loss of function mutations in EVER1/TMC6 or EVER2/TMC8 (chromosome 17)
- code for membrane proteins which forms a complex with zinc transporter protein in ER membrane of keratinocytes
- these proteins also act as restriction factors for EV-specific HPV in keratinocytes (limit access of zinc to viral proteins) without the genes it increases risk of HPV
What is the ECM and what is its function?
Network of proteins and polysaccharides
The ECM influences cell:
- growth
- movement
- shape
- proliferation
- survival
- development
Which cells produce the ECM?
Fibroblasts
What is the ECM composed of?
3 major macromolecules:
- Proteoglycans and glycosaminoglycans (GAGs)
- produce polysaccharide chains - Fibrous proteins
- help with structure
- collagen for strength and elastin for stretch - Glycoproteins
- helps with adhesion
- fibronectin (helps adhere fibroblasts to matrix)
- laminin (adhere epithelium to basal lamina)
What is the basal lamina and what are its macromolecules components?
Specialised ECM which lies beneath epithelial cells
Components:
- laminin to adhere
- type 4 collagen
Glycosaminoglycan (GAG) structure
Unbranched polysaccharide chains of repeated disaccharides
Disaccharide:
- Always an amino sugar (N-acetylglucosamine or N-acetyalgalactosamine)
- Always uronic acid
Sulphate in most cases (has a sulphate group on each block
Glycosaminoglycan (GAG) chemical features
Hydrophilic (likes water)
Negatively charged
- attract positive ions (Na) in water
- form hydrated gels
Helps withstand compressive forces (swelling)
What are proteoglycans and what is it’s structure
A proteoglycan are Glycosaminoglycan (GAG) covalently linked to a protein
Structure:
Protein - linkage tetrasaccharide - GAGs
Types of Proteoglycans and their main functions
Decorin:
- 1-10 GAG chains
- influences fibrillogenesis
- assists in assembly of collagen fibrils
Aggrecan:
- 100 GAGs
- resists compression
Ribonuclease (RNase)
- catalyses degradation of RNA into smaller components
Proteoglycan Functions
Mechanical
Filter
- regulate molecules getting in and out of the cell by charge or size
Chemical signalling (syndecans) - bind to growth factors for cell growth and proliferation
Regulate protein or enzyme activity
4 classes of proteoglycans
Intracellular
Transmembrane
Pericellular
ECM
Where is collagen produced? Where is it mostly found?
It’s a fibrous protein secreted by fibroblasts
Major component in hair and skin (can lasts up to 10 years compared to other proteins)
What are the classes of collagen?
- Fibrillar collagens
- Fibril-associated collagens
- Network forming collagens
Fibrillar Collagen Class
- types
- where is it found
Type 1,2,3,5,11
Found in:
- skin
- bone
- tendons
- ligaments
- cornea
- organs
Fibril-associated class collagens
- types
- where is this found
- function
Type 9 and 12
9 - cartridge and cornea
12 - tendons and other tissues
Function: link Fibrillar collagens together
Network Forming class of collagens
- types
- where is it found/function
Type 4 and 7
4 - form mesh networks in the basal lamina
7 - anchoring
Collagen structure
Long, stiff, triple stranded helix
3 collagen alpha chains wound together
- 42 types of alpha chains
- 40 combinations of different alpha chains wound together
Rich in proline and glycine
Synthesis and secretion of collagen pathway
- Synthesis of pre collagen alpha chains on ribosomes
- Hydroxylation of proline and lysine
- Release from ribosome and glycosylation of selected hydroxylysines = pro collagen
- Formation of triple helix and folding of globular domains
- Secretion from cell
- Remove pro-sequences from N and C terminals = tropocollagen
- Deamination of lysine residues to form aldehyde cross links = collagen
- Aggregation and self-assembly into collagen fibrils which make collagen fibres
How is collagen organised
In bundles
What is the purpose of elastin
For tissues to stretch and recoil
What is the chemical components and features of elastin
- 750 amino acids
- hydrophobic (don’t like water)
- rich in proline and glycine (not glycosylated)
- loose random coil formation
How is elastin synthesised?
- Tropoelastin is secreted into extra cellular environment
- These become cross linked to form elastin fibres
- Networks of these fibres come together to make a sheet
- These sheets are then covered with microfibrils
Common disorders of the extra cellular matrix
- arthritis
- scurvy
- Marian syndrome
- osteogenesis imperfecta
- chondrodysplasias
- Euler see-Danilo’s syndrome
What is arthritis and what are the 2 types?
Irreversible destruction of cartilage, tendon and bone
Types:
- Rheumatoid arthritis (autoimmune disease)
- Osteoarthritis (due to injury)
What macromolecules are found in cartridge?
Proteoglycans and type 2 collagen
Which joints are mostly affected by osteoarthritis?
Hip
Hand
Foot
Knee
What are some features of rheumatoid arthritis in the knee joint?
- subchondral cysts and sclerosis (bone hardening)
Difference between osteoarthritis and rheumatoid arthritis in synovial joints
Osteoarthritis:
- thinning of cartridge which leads to bone ends rubbing together
Rheumatoid:
- synovial membrane becomes inflamed which causes bone erosion
Rheumatoid arthritis aetiology
- Due to the inflammation of synovial membrane inflammatory cytokines (TNF alpha and interleukins) are released
- This stimulates the production of matrix metalloproteinases (MMP’s) which degrade the ECM
- MMP 13 plays a key role
Collagen related disorders
- Ehlers-Danilo’s syndrome
- scurvy
- Chondrodysplasias
- osteogenesis imperfecta
Scurvy symptoms
- swelling and bleeding of gums
- easily bruised and bleeding
- pain and swelling of joints
- hair and tooth loss
- small bleeding around hair follicles and under nails
- fatigue
- dry and pale skin
Scurvy Aetiology
Vitamin C deficient
Vitamin C needed for collagen processing (proline and lysine hydorxylation)
- without this pro-collagen alpha chains degrade
Leads to:
- fragile blood vessels (explains the bleeding)
- loose teeth
Osteogenesis imperfecta aetiology
Results from mutations in collagen 1 gene
- collagen 1 needed for skin, tendons and bones to provide tensile strength
Severity of disease depends on location of mutation
Severity vs gene mutation location in osteogenesis imperfecta
Ranges from normal quality collagen but insufficient quantities
To
Mutations encoding middle to C terminal part of protein which is lethal
- e.g. glycine substituted for a bulkier amino acid = collagen fibrils cannot be formed
8 different types
Osteogenesis imperfecta symptoms
- Blue whites of the eyes
- bones fracture easy (due to missing strength)
- slight spinal curvature
- loose joints
- poor muscle tone
- early loss of hearing in some children
Chondrodysplasia mutation and symptoms
Mutation in collagen 2 which is needed in cartilage
Symptoms
- abnormal cartilage, bone and joint deformities
- shortening of fingers and toes
Ehlers-danlo’s syndrome aetiology
Mutations in 20 different collagen and collagen related genes
- collagen 1,2, 5
- collagen biogenesis/interacting proteins
Leads to abnormal assembly of collagen fibres
Ehlers- Danlos syndrome symptoms and complications
Symptoms:
- hyper-flexible joints
- stretchy skin
Complications:
- aortic dissection
- joint dislocations
- chronic pain
- early osteoarthritis
Elastin related disorders
Marian syndrome
Marian syndrome symptoms
- tall stature
- arachnodactyly (excessively long fingers and toes)
- defects of heart (valves and aorta)
- chest malformation
- eye problems (dislocation of lens)
- flexible joints
- scoliosis (curvature of the spine)
Death can occur due to rupture of the aorta (thinning of elastin in aorta)
Marian Syndrome cause
Autosomal dominant (hereditary)
Mutation in FBN1 gene on chromosome 15
- encodes for Fibrillin-1
Fibrillin 1 forms microfibrils which forms a sheath around elastin fibres
- when this is lost elastin is degraded
