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Case 1: Histophysiology, image image, image …
Case 1: Histophysiology
Skin and Basic FunctionThe skin is the largest and heaviest organ forming the external covering of the body.List the function of the Skin
- Protection from external influences: Dehydration, Radiation, Pathogens, Injury
- Sensation: The skin has receptors for Pain, Pressure, Touch, and Temperature.
- Heat Regulation
- Excretion of waste products via sweat glands.
What is the Epidermis ?The epidermis is a Keratinized Stratified Squamous Epithelium. The epidermis is composed of 4 cell types:
- Keratinocytes
- Melanocytes
- Langerhans Cells
- Merkel Cells
List the layers of the Epidermis
- Stratum Corneum
- Stratum Lucidum
- Stratum Granulosum
- Stratum Spinosum
- Stratum Basale
What are Keratinocytes ?
90% of the total cells in the epidermis are Keratinocytes
Keratinocytes migrate from the Basal Layer to the Superficial Layer over a 3-4 week period.
Through differentiation, Keratinocytes undergo characteristic changes as they move upwards from the Basal Layers.
Keratinocytes are filled with Keratin (Protein)
What are the functions of the Keratinocytes ?
Keratinocytes provide a barrier to water loss.
Keratinocytes form a protective barrier against environmental damage (eg: pathogens, heat, UV radiation and water loss)
Keratinocytes are responsible for wound healing - through the migration of these cells into the wound area
Describe the differentiation of Keratinocytes1.Stratum BasaleThe basal layer of the epidermis consist of Viable Undifferentiated, Mitotic Keratinocytes that are attached to the basement membrane through Hemidesmosomes. Keratinocytes have a distinct nucleus. Protein keratin 5 and 14 are produced
- Stratum Spinosum
Keratinocytes detach from the basal membrane and start to undergo differentiation.Cells flatten through cytoskeleton re-arrangementKeratinocytes have a distinct nucleus.Differentiated protein Keratin 1 and 10 are produced.These cells are attached at the Desmosomes.
- Stratum Granulosum
This layer is characterized by the presence of Keratohyalin Granules. The Keratin Filament network is cross-linked by Filaggrin, DNA is degraded and organelles are destroyed.Keratinocyte nucleus is flattened.Plasma membrane is replaced by the cornified envelope.Lamellar produce Lipids and Enzymes.Protein keratin 2e and 9 are produced.
- Stratum Lucidum
The cornified layer consists of dead, flat cells No nucleus is present in KeratinocytesFormation of cornified cell envelope on inside.On the outside Lamellar bodies produce complex of lipids forming the compound cornified envelope.
- Stratum Corneum
The cells are shed into the environment during DESQUAMATION.
The Clinical relevance of Keratinocytes and Keratin
What is Ichthyosis bullosa of Siemens ?
Ichthyosis bullosa of Siemens (IBS) is caused by the defects of Keratin 2e
What is Epidermolytic Palmoplantar Keratoderma (EPPK) ?
Epidermolytic Palmoplantar Keratoderma is caused by a defect in Keratin 9.
What is Epidermolytic Hyperkeratosis (EHK)?
Epidermolytic Hyperkeratosis is caused by a mutation in Keratin 1 and 10.
What is Epidermolysis bullosa simplex (EBS) ?
Epidermolysis bullosa simplex is caused by a mutation in Keratin 5 and 14.
List the components of the Epidermal permeability Barrier
- Multi-lamellar Lipid
- Cornified Cell Envelope
- Keratin-Filaggrin Complex
- Tight Junctions
Outline the Cell Junctions in the Skin
- Hemi-Desmosomes: Responsible for Cell to Extracellular Matrix communication.
- Desmosomes: Are cell-to-cell junctions and mediate strong adhesions between the epidermal keratinocytes. (appear as spines)
- Adherens Junctions: aka Belt Desmosomes are responsible for strong adhesion and intercellular anchoring.
- Tight Junctions: Are formed by two closely associated areas of two cell membranes forming an impermeable barrier to fluid.
- Gap Junction: Are intercellular channels, which are involved in cell to cell communication
Gap junctions are important in Keratinocyte growth and differentiation.Is the skin waterproof ?
Why does the skin on the fingers and toes wrinkle during a bath ?They don't wrinkle in people with nerve damage to their fingers. This helps grip wet objects.
Vitamin D3 (Cholecalciferol)
What is Vitamin D3 ?
Vitamin D3 is important for Calcium Homeostasis. eg: the absorption of Calcium from the intestine.
What are the functions of Vitamin D3 ?
Vitamin D3 enhances macrophage immune function.
How does the body deal with Calcium Deficiency ?
The skeleton serves as a Calcium reservoir.
Therefore, if the calcium levels drop, then the Parathyroid Hormone is released to cause re-absorption of calcium from the Bones.
What are the results of Vitamin D3 deficiency in young kids ?
The deficiency in Vitamin D3 in infants and children results in Rickets.
Rickets are weak soft bones.
In adults the deficiency of Vitamin D3 results in Osteomalacia.
Low Vitamin D3 can increase risk of TB progression. This is treated through Sanatoria: Sunshine to Treat TB.
How is Vitamin D3 (Cholecalciferol) produced ?The skin is important for Vitamin D3 production.Vitamin D3 is produced as follows:
- In the skin there is 7-Dehydrocholesterol.
When the Ultra Violet radiation from the sun hits the skin: 7-Dehydrocholesterol is converted to Pre-Vitamin D3 in the skin.
- When the Pre-Vitamin D3 in the skin is hit by heat, it is converted into Vitamin D3 in the skin.
In places with minimal sunlight, many foods are stocked with this Vitamin D3, to promote function of Vitamin D3.
- The Vitamin D3 in the skin then moves into the blood.
- The Vitamin D3 is then catalysed by 25-Hydroxylase (enzyme) in the Liver and Pancreas to form 25-HydroxyVitamin D3.
- 25-HydroxyVitamin D3 in the blood is then catalysed by 1Alpha-Hydroxylase in the Kidney to form 1Alpha, 25 - Hydroxyvitamin D3 in the blood.
1alpha,25 - Hydroxyvitamin D3 is known as Calcitriol.
- The 1alpha,25 - Hydroxyvitamin D3 then binds to Vitamin D3 receptors in the classical targets such as: Intestine, Kidney, Bone and Parathyroid Gland.
Vitamin D3 is essential for the absorption of Calcium and Phosphorus from the intestine.
What are Melanocytes ?Melanocytes are cell of neural crest origin.Where are Melanocytes found ?Melanocytes sit on the basement membrane in the Stratum Basale and in the Hair Follicles.What are the functions of Melanocytes ?Melanocytes are responsible for the production of Melanin through the process of Melanogenesis.Melanocytes give colour to skin (Skin pigmentation)In addition they add melanin to Keratinocytes in order to protect the skin from Ultra Violet Radiation.NOTE: Skin colour is based on the amount of melanin produced (activity of melanocytes) and not on the number of melanocytes.Describe the different types of MelaninDifferent types of Melanin:
- Eumelanin is found in the hair and skin.
Eumelanin colours hair black, yellow and brown.
It is more abundant in people with dark skin.
- Pheomelanin is found in the skin and the hair.
Pheomelanin is found in large quantities in red hair.
It is present both in darker skinned and light skinned people.
- Neuromelanin is a dark pigment.
Neuromelanin is present in pigment bearing neurons of deep brain
nuclei (Substantia nigra)
How is Melanin Synthesised ?Melanin Synthesis:
- When melanocytes are activated by Ultra-violet Radiation, melanin granules are formed near the nucleus in the melanocyte.
These are known as Pre-melanosomes.
- Pre-melanosomes mature into Melanosomes.
Melanosomes are transported along the microtubules and actin filaments to the cell periphery.
- Melanosomes bind to the plasma membrane and are internalised by Keratinocytes to protect DNA from UV-damage.
Where does Melanin Synthesis take place ?Melanin synthesis takes place in the melanosomes.
- Melanin Synthesis begins in the liver: Phenylalanine is converted to Tyrosine by Phenylalanine Hydroxylase.
- The oxidation of Tyrosine to DOPA is then catalysed by Tyrosine (Tyr) enzyme with in the melanosomes.
- Next DOPA is oxidised to DOPAquinone
- From DOPAquinone the pathway converges to produce either Eumelanin or Pheomelanin.
NOTE: melanin production depends on the amino acid: Tyrosine. Mutation in the gene for Tyrosine leads to less melanin, which leads to Albinism.
Vitiligo
What is Vitiligo ?
Vitiligo is an autoimmune loss of Melanocytes.
Vitiligo results in white patches on otherwise normal skin.
Vitiligo is a largely a cosmetic issue.
What are some of the outcomes of Vitiligo ?
Some individuals with Vitiligo pursue complete depigmentation of the skin to generate a uniform skin colour.
Langerhans CellsWhat are Langerhans Cells ?Langerhans cells are bone marrow derived dendritic cells.They are associated with Keratinocytes through E-cadherinAnd they are responsible for antigen presenting.Where are Langerhans Cells located ?Langerhans cells are dendritic cells found mainly in the Stratum Spinosum, in the Epidermis.Langerhans Cells may also be present in the Dermis.Describe the mode of action for Langerhans Cells
- The Langerhans Cells are derived from monocyte precursor of the bone marrow.
Monocytes in the epidermis become Langerhans Cells (dendritic cells)Langerhans cells interact with keratinocytes through E-Cadherins on their surface.
- Langerhans cells take up an epidermal antigen through langerin and CD1a
- Langerhans cells leave the epidermis , enter the Lymphatic system, and are transported to a regional Lymph Node.
- In the Lymph node, Langerhans cells interact with T cells in the deep cortex.
T cells become activated by epidermal antigen, re-enter the blood circulation, extravasate at the site where the epidermal antigen is present, and secrete pro-inflammatory cytokines.
Sensory Receptors in The SkinMechanoreceptors mediate touch.List the Types of Sensory Receptors of the SkinMeissner CorpuscleMerkel CellRuffini CylinderPacinian Corpuscle Free Nerve EndingsDescribe the Properties of mechanoreceptorsAdapting Properties for Mechanoreceptors:
- Slowly Adapting
Slowly adapting mechanoreceptors fire continuously as long as the stimulus is applied.Eg: Merkel Receptor and Ruffini Corpuscle
- Rapidly Adapting
Rapidly adapting mechanoreceptors fire at onset and offset of simulation.Eg: Meissner Receptor and Pacinian CorpuscleTypes of Receptor Fields of mechanoreceptors
- Surface receptors have small receptive fields
Eg: Meissner Corpuscle and Merkel receptor
- Deep receptors have large receptor fields
Eg: Ruffini Corpuscle and Pacinian Corpuscle
Describe Meissner Corpuscles based on structure, location, mechanism, effective stimuli, sensory function
- Structure: Meissner Corpuscle is an encapsulated tactile mechanoreceptor
- Location: Meissner Corpuscle is located in the Dermal papilla, below the Epidermis.
They are present in the fingers, foot, lips and tongue, glabrous and hairy skin
- Mechanism:
Meissner Corpuscle are fast adapting
And they have a small receptor field
- Stimuli: Meissner Corpuscle are stimulated by skin motion.
- Sensory Function: Motion detection and grip control.
Describe Merkel Receptor based on structure, location, mechanism, effective stimuli, sensory function
- Structure: Merkel Receptor is a neural crest derived cell, it is a non-encapsulated receptor.
- Location: Merkel Receptor is located in the basal layer of the Epidermis.
It is present in the fingertip and lips.
- Mechanism: Merkel Receptor is slowly adapting.
And has a small receptive field, with high resolution for reading Braille.
- Effective Stimuli: Merkel Receptor is stimulated by edges, points, corner, and curvatures.
- Sensory Function: Is shape and texture perception.
Describe Ruffini Cylinder based on structure, location, mechanism, effective stimuli, sensory function
- Structure: Ruffini Cylinder is made up of branched fibres in cylindrical capsule.
- Location: Ruffini Cylinder are located deeper into the dermis, in the skin and joint capsule.
- Mechanism: Ruffini Cylinder are slowly adapting.
And have a larger receptive field.
- Effective Stimuli: Ruffini Cylinder is stimulated skin stretch and also warmth.
- Sensory function: is Tangential force, hand shape, motion direction.
Describe Pacinian Corpuscle based on structure, location, mechanism, effective stimuli, sensory function
- Structure: Pacinian Corpuscle is an onion-like capsule
- Located: Pacinian Corpuscle is located deep in the hypodermis, and deep fascia.
- Mechanism: Pacinian Corpuscle is Rapidly Adapting
And has a Large Receptive field.
- Effective Stimuli: Pacinian Corpuscle is stimulated by Vibration
- Sensory Function: is the perception of distant events through transmitted vibrations, tool use.
List the types of Nerve EndingsFree Nerve Ending mediates pain, temperature, non-discriminative touch.
- Free Nerve Endings
- Peritrichial Nerve Endings
List the types of Thermoreceptors
- Krause End Bulb
Describe the Free Nerve Ending based on structure, location, effective stimuliFree Nerve Ending mediates pain, temperature, non-discriminative touch.
- Structure: Free Nerve Ending is an Un-encapsulated nerve ending.
It lacks Myelin or Schwann Cells
- Location: Free Nerve Ending is found in the Epidermis, and Corneal Epithelium
- Effective Stimuli: Free Nerve Ending responds to pain and temperature.
Describe the Peritrichial Nerve Ending based on structure, location, effective stimuli
- Structure: Peritrichial Nerve Ending are nerve fibres wrapped around the base of the hair follicle.
- Location: Peritrichial Nerve Ending is found in the Dermis (Base of hair follicle).
- Effective Stimuli: Peritrichial Nerve Ending is stimulated by hair movement.
Describe the Krause End Bulb based on structure, location, effective stimuli
- Structure: Krause End Bulb is an encapsulated thermoreceptor.
- Location: Conjunctiva of the eye, mucosa of the lips and tongue, and in the epineurium.
- Effective stimuli: Krause End Bulb is stimulated by cold.
The Pathophysiology of Cystic FibrosisOutline the Appendages of the SkinHair
- Hair Follicles
Glands
- Sebaceous Glands
- Sweat glands
NailsDescribe the structure of Merocrine/Eccrine Sweat GlandsThe Merocrine/Eccrine Sweat Glands have:
- Apical Dark Cells
Cells secrete glycoproteins by exocytosis (merocrine secretion).
- Basal Clear cells
Cells secret water and electrolytes into intercellular canaliculi.Water and electrolytes reach the lumen of the Acinus through intercellular spaces between the apical dark cells.Mitochondria and basal folding in clear cells are typically found in the cells involved in fluid and electrolyte transport.
- Myoepithelial Cells
Cells are found between the Basil Lamina and Basal Domain of Clear cells.
What is Cystic Fibrosis ?
Cystic Fibrosis is the production of an unusually thick secretion of mucus which can obstruct the lungs and pancreas.
Cystic Fibrosis results in an abnormally high NaCl content in the sweat.
Cystic Fibrosis is a genetic autosomal recessive disorder due to the mutation of the CFTR gene (Cystic Fibrosis Transmembrane conductance Regulator)
This mutation affects the epithelial transport of the Chloride ion (Cl-)
Outline the Na+ and Cl- Transport in Normal Sweat Duct
- As the primary sweat moves along the duct, most of the NaCl is re-absorbed into the duct wall.
- This is driven by a large inward gradient for Na+, which flows into the cell via the Epithelial Na+ channel (ENaC) in the apical membrane.
- This Na+ is then transported out of the cell and into the blood via the Basolateral Sodium pump. (Na+/K+ ATPase)
- Because Cl- is electrically attracted to Na+:
Cl- follows the Na+ by flowing through the CFTR Cl- channels.
- The result is the production of dilute sweat, so that we can be cooled by evaporation without losing an undue amount of sweat.
Na+ and Cl- Transport in Sweat Ducts of an individual affected by Cystic Fibrosis
- In Cystic Fibrosis sweat ducts, the Cl- conductance is completely abolished because of defective CFTR.
- When Na+ attempts to flow out of the Cystic Fibrosis duct through the remaining sodium-selective pathway, it is unaccompanied by Cl-.
- This creates an excessive amount of negative charge in the cystic fibrosis ducts.
The build up of negative charge attracts Na+ and prevents further absorption of Na+.
- Therefore little NaCl is re-absorbed, resulting in a high salt content in Cystic Fibrosis sweat.
Individuals with Cystic fibrosis will have a salt content of more than 100mMWhereas, Healthy individuals have a salt content of 20-30mM.The sweat chloride concentration is the most reliable single physiological marker of Cystic fibrosis.
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Sebaceous Gland (Holocrine)
Merocrine and Apocrine Sweat Glands
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