What are the two main compartments of the skin?
the dermis and the epidermis
What are the embryologic origins of the dermis and epidermis?
Epidermis = ectoderm Dermis = mesoderm
What are the 4 layers of the epidermis? What is their composition?
- Stratum basale: single cell later of dividing keratinocytes
- Stratum spinosum: the spinous layer in which the desmosomal attachments between keratinocytes are prominent
- Stratum granulosum: granular cell layer where terminal keratin and lipid organization occurs and lysosomes are prominent
- Stratum corneum: 15-20 layers of flattened, non-nucleated cells called corneocytes
Keratinization (cornification) refers to…
The process by which the principle fibrous proteins of the keratinocyte are formed. Begins in the basal layer where dispersed keratin filaments are synthesized and as the cell matures, thicker filaments are deposited that increase structural integrity and UV filtration
What layer of the epidermis forms the main diffusion barrier of the skin?
the stratum corneum
What 2 compartments of the stratum corneum are vital for maintaining the diffusion barrier of the skin?
- protein rich corneocytes
2. lipid rich intercellular material
How is the diffusion barrier of the skin formed?
- proteins and lipids are synthesized by keratinocytes
- proteins and lipids are modified as keratinocytes mature
- keratolyalin is formed in the granular layer from keratin and profilaggrin
- an envelope of highly cross-linked proteins forms a corneocyte exoskeleton with the intercellular cement produced by lamellar bodies (Odland bodies) which are lipid rich lysosomal bodies secreted into the intercellular space.
What can occur if there are abnormalities in the formation of the skin barrier?
ichthyosiform = “scaly” disorders like atopic dermatitis!
What separates the epidermis and the dermis?
The basement membrane
What are 2 functions of the basement membrane?
- Scaffold for tissue organization and repair
2. physical barrier between cell types
What components make up the basement membrane of the skin?
- Type IV collagen
- Laminin
- Heparin sulfate proteoglycans
- hemidesmosomes/anchoring filaments/anchoring fibrils
- these are unique and required for the skin BM
Alterations in the formation of the basement membrane can lead to what type of disorders?
blistering disorders
What are the the two types of UV light that can damage the skin? How do they cause damage?
- UVA: penetrates the skin more deeply that UVB and causes formation of cytotoxic free radicals
- causes wrinkling and aging of skin - UVB: “sunburn” UV light that damages both proteins and nucleic acids
What are the two primary barriers the skin has to UV radiation?
- Protein barrier in the stratum corneum (keratins)
- Melanin barrier dispersed throughout the epidermis
* both melanin and keratin absorb UV photons
What are the 4 pigments that contribute to skin colour? Where are they?
- brown: melanin in epidermis
- red: oxygenated Hbg in dermis
- Blue: reduced Hbg in dermis
- Yellow: carotenoids in the epidermis
What is melanin?
A high molecular weight polymer produced by melanocytes and localized in subcellular membrane bound organelles called melanosomes
What are the 3 functions of melanin?
- protection against UV radiation
- Scavenging of cytotoxic radicals
- Participating in neurologic development
Where do melanocytes originate from?
neural crest cells that migrate to the epidermal/dermal junction
Abnormalities in the migration of neural crest cells can lead to what kinds of dysfunctions?
Pigmentary as well as neurologic
What are melanocytes? Where are they found?
A form of dendritic cell that are in the basal layer of the epidermis and have cellular processes that extend between keratinocytes
How is melanin distributed from the melanocyte to the keratinocytes?
Melanin is sequestered in melanosomes that are transported along dendrites to the keratinocytes. There they are phagocytosed and incorporated
Whats the ratio of melanocyte: keratinocyte?
about 1:36 in an “epidermal melanin unit”
Is there a variation in melanocyte number among humans of differing racial backgrounds?
no, is it differences in # and size of melanosomes, the amount of melanin within them and the rate of degradation
Describe the difference between immediate pigment darkening and delayed tanning
immediate pigment darkening occurs around 20 minutes after UV exposure and is due to the redistribution of melanosomes
Delayed tanning occurs 2-4 days after UV exposure and is due to increased numbers of melanocytes, dendricity, and melanosome number in response to the SOS response initiated by light damage to DNA
What growth factors (besides light) do melanocytes respond to? What can this mean pathology wise
multiple forms of growth factors present in the body
inflammatory skin conditions can therefore lead to pigment changes if there is an increase in there growth factors
How is vitamin D3 produced in the epidermis?
- 7-dehydro-cholesterol absorbs UV radiation (under 320 nm) and is converted to pre-vitamin D3
- Pre-vitamin D3 then isomerizes to form vitamin D which is bound to a binding protein the capillaries
Describe the difference in frequency/intensity of unprotected sun exposure and the cancer risks associated.
Episodes of intense sun exposure = increase risk of melanoma and basal cell carcinoma
Prolonged episodes of lower intensity sun exposure = increased risk of squamous cell carcinoma
What is photoaging?
the pigmentary abnormalities and the atrophy/decrease in elasticity of the skin as a result of sustained UV radiation assault
What cells are responsible for producing cytokines in the skin?
keratinocytes
What kinds of cytokines are released? what cell types can they activate (broadly)
Interleukins, interferons, Growth factors, TNFalpha, and CSF
Can activate innate and adaptive immune cell subtypes
What other chemical mediators do keratinocytes produce to protect against microbial infection?
- antimicrobial peptides and xenobiotic enzymes
- Eicosanoids: PGE2 and LTB4
- Neuropeptides
What are Langerhans cells?
bone marrow derived dendritic cells that act as specialized antigen presenting cells and coordinate the immune response
What are unique features of Langerhans cells?
- efficient antigen trapping
- presentation to naive T cells in regional LN (activate with costim molecultes CD80/86)
- Can actively inhibit immune responses
What is the composition of the dermis? How does this relate to the immune response?
- Blood vessels and lymphatics that allow transit of inflammatory cells
- Fibroblasts that secrete chemokines to attract T cells
- Dermal DCs also present antigen to T cells
What is the proportion of cutaneous T cells that are found in the epidermis?
small : 2-3%
What types of T cells are cutaneous T cells
Mostly regulatory T cells, others are memory T cells resident in the dermis
How does the skin thermoregulate (4 main ways)
- skin thermoreceptors: play a minor role compared to the hypothalamus
- body insulation through subcutaneous fat
- Vasoconstriction/Dilation
- Sweating
What are the 3 mechanisms of health loss when core temp is elevated?
- Vasodilation
- Sweating
- Decrease in thermogenesis
What are the 3 main mechanisms of heat conservation when core temp is decreased
- vasoconstriction
- Piloerection (sympathetic stimulation)
- Thermogenesis: shivering, chemical ,and thyroxine secretion
What plexi are involved in blood flow in the skin ?
- superficial papillary plexus
- deeper cutaneous plexus
- Glomus bodies: AV anastamoses in the exposed areas (hands, feet, ears).
What is the blood flow like through the skin?
Highly variable! Can be almost 0 to up to 30% of cardiac output.
Under basal conditions, about 8.5% of total blood flow passes through the skin
What brain structure is responsible for coordinating the response to decreased body temp? What happens in increased temp conditions?
The sympathetic centres in the posterior hypothalamus which control vasoconstriction
If temp increases, these centres are inhibited and heat transfer can increase
Stimulation of what brain centre by excess heat will cause sweating?
anterior hypothalamic preoptic area which stimulates eccrine sweat glands
What types of nerves stimulate eccrine sweat glands?
Cholinergic (Ach) receptors as well as adrenergic stimuli during exercise
Describe the physiology of sweating at the level of the duct
Normally precursor solution (similar to NaCl) secreted in coiled portion and mostly reabsorbed in ductal portion.
When sweating is stimulated, the ductal reabsorption decreases due to changes in transporters
What are apocrine sweat glands?
Glands located in the axillary and anogenital regions and open into hair follicles. They are under the control of adrenergic receptors and function as scent glands
What is the difference between encapsulated and free nerve endings?
Free nerve endings: pain and temp
Encapsulated: touch