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Molecular Basis Of Disease > Skin And Extracellular Matrix > Flashcards

Skin And Extracellular Matrix Flashcards

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1
Q

What is the cause Pemphigus

A

Antibodies attack cadherins and integrins in keratinocytes causing defects in cell to cell and cell to matrix adhesion

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2
Q

Key feature of Pemphigus and main types of the disease

A

Blisters on skin and in oral cavity

Two types:

  • Pemphigus vulgaris
  • Pemphigus foliaceus
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3
Q

Molecular basis of Pemphigus Volgaris

A

Autoantibodies attack cell surface antigens (desmogleins 1 and 3 - cadherins)

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4
Q

Symptoms and treatment of pemphigus vulgaris

A

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)
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5
Q

What is a key identifying feature in the histology of Pemphigus vulgaris

A

Tombstone rows

- due to single layer of basal cells still attached to dermis of skin

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6
Q

Molecular basis of Bullosa Pemphigoid

A

Autoantibodies attack BP 180 and BP 230 (basement membrane proteins) which connect hemidesmosome to intermediate filaments

Skin keratinocytes cannot attach to basement membrane

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7
Q

Symptoms and treatment of Bullosa Pemphigoid

A

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

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8
Q

What is keratin and what is it’s function?

A

Intermediate filament which forms alpha helices or beta sheets

Functions:

  • hold epithelial cells together through cell junctions
  • provides mechanical strength at hemidesmosomes and desmosomes
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9
Q

Keratin structure

A

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

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10
Q

Keratin subunits expressed in epithelium

A 
Basal layer (stratified epithelia) 
- keratins 5 and 14 
Suprabasal layers (layers above the basal layer) 
- keratins 1 and 10
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11
Q

Intermediate Filament assembly

A
  1. keratin polypeptide
  2. Another keratin monomer comes and coils with the first monomer to create a dimer
  3. Another dimer is created and joins with the first creating a tetramer
  4. Happens continuously until a protocol amend is formed
  5. Eight tetramers are then twisted into a rope like filament
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12
Q

What is the main cause of Karen in associated disease

A

If either one of a keratin pair is lost

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13
Q

What are the two keratin associated diseases

A

Epidermolysis bullosa

Epidermolysis hyperkeratosis

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14
Q

Epidermolysis bullosa simplex symptoms

A

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

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15
Q

Molecular basis of Epidermolysis bullosa simplex

A

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

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16
Q

Epidermolysis hyperkertosis symptoms and genetic inheritance

A

Symptoms in infants:

  • very red skin (erythroderma)
  • severe blisters

Symptoms in adults:

  • skin thickening
  • blisters and erythroderma less frequent

Genetic inheritance:
Autosomal dominant

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17
Q

Pathophysiology of epidermolytic hyperkeratosis

A

Mutations in KR1 and KR10

  • keratin aggregates in suprabasal cells (stratum corneum)
  • loss of strong intermediate filaments
  • increase in mitosis
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18
Q

Other keratin disorders

A

Keratin 6 and 16 mutations
- hair and nail disorders

Keratin 3 and 12 mutations
- cornea defects

Epidermodysplasia verruciformis (tree man)

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19
Q

Epidermodysplasia verruciformis symptoms, genetic inheritance

A

Autosomal recessive hereditary disorder

Symptoms:

  • wart like growths
  • scaly macules and papules
  • on hands and feet
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20
Q

Epidermodysplasia verruciformis molecular basis

A

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
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21
Q

What is the ECM and what is its function?

A

Network of proteins and polysaccharides

The ECM influences cell:

  • growth
  • movement
  • shape
  • proliferation
  • survival
  • development
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22
Q

Which cells produce the ECM?

A

Fibroblasts

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23
Q

What is the ECM composed of?

A

3 major macromolecules:

  1. Proteoglycans and glycosaminoglycans (GAGs)
    - produce polysaccharide chains
  2. Fibrous proteins
    - help with structure
    - collagen for strength and elastin for stretch
  3. Glycoproteins
    - helps with adhesion
    - fibronectin (helps adhere fibroblasts to matrix)
    - laminin (adhere epithelium to basal lamina)
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24
Q

What is the basal lamina and what are its macromolecules components?

A

Specialised ECM which lies beneath epithelial cells

Components:

  • laminin to adhere
  • type 4 collagen
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25
Glycosaminoglycan (GAG) structure
Unbranched polysaccharide chains of repeated disaccharides Disaccharide: 1. Always an amino sugar (N-acetylglucosamine or N-acetyalgalactosamine) 2. Always uronic acid Sulphate in most cases (has a sulphate group on each block
26
Glycosaminoglycan (GAG) chemical features
Hydrophilic (likes water) Negatively charged - attract positive ions (Na) in water - form hydrated gels Helps withstand compressive forces (swelling)
27
What are proteoglycans and what is it’s structure
A proteoglycan are Glycosaminoglycan (GAG) covalently linked to a protein Structure: Protein - linkage tetrasaccharide - GAGs
28
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
29
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
30
4 classes of proteoglycans
Intracellular Transmembrane Pericellular ECM
31
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)
32
What are the classes of collagen?
1. Fibrillar collagens 2. Fibril-associated collagens 3. Network forming collagens
33
Fibrillar Collagen Class - types - where is it found
Type 1,2,3,5,11 Found in: - skin - bone - tendons - ligaments - cornea - organs
34
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
35
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
36
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
37
Synthesis and secretion of collagen pathway
1. Synthesis of pre collagen alpha chains on ribosomes 2. Hydroxylation of proline and lysine 3. Release from ribosome and glycosylation of selected hydroxylysines = pro collagen 4. Formation of triple helix and folding of globular domains 5. Secretion from cell 6. Remove pro-sequences from N and C terminals = tropocollagen 7. Deamination of lysine residues to form aldehyde cross links = collagen 8. Aggregation and self-assembly into collagen fibrils which make collagen fibres
38
How is collagen organised
In bundles
39
What is the purpose of elastin
For tissues to stretch and recoil
40
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
41
How is elastin synthesised?
1. Tropoelastin is secreted into extra cellular environment 2. These become cross linked to form elastin fibres 3. Networks of these fibres come together to make a sheet 4. These sheets are then covered with microfibrils
42
Common disorders of the extra cellular matrix
- arthritis - scurvy - Marian syndrome - osteogenesis imperfecta - chondrodysplasias - Euler see-Danilo’s syndrome
43
What is arthritis and what are the 2 types?
Irreversible destruction of cartilage, tendon and bone Types: 1. Rheumatoid arthritis (autoimmune disease) 2. Osteoarthritis (due to injury)
44
What macromolecules are found in cartridge?
Proteoglycans and type 2 collagen
45
Which joints are mostly affected by osteoarthritis?
Hip Hand Foot Knee
46
What are some features of rheumatoid arthritis in the knee joint?
- subchondral cysts and sclerosis (bone hardening)
47
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
48
Rheumatoid arthritis aetiology
1. Due to the inflammation of synovial membrane inflammatory cytokines (TNF alpha and interleukins) are released 2. This stimulates the production of matrix metalloproteinases (MMP’s) which degrade the ECM - MMP 13 plays a key role
49
Collagen related disorders
- Ehlers-Danilo’s syndrome - scurvy - Chondrodysplasias - osteogenesis imperfecta
50
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
51
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
52
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
53
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
54
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
55
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
56
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
57
Ehlers- Danlos syndrome symptoms and complications
Symptoms: - hyper-flexible joints - stretchy skin Complications: - aortic dissection - joint dislocations - chronic pain - early osteoarthritis
58
Elastin related disorders
Marian syndrome
59
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)
60
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

Molecular Basis Of Disease (17 decks)

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