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Rick Allen
Effect of UV exposure on the skin (Rick)
Absorbance of UV
Different molecules obviously have different absorbance qualities (chromophore). In skin, the
primary chromophores are DNA, urocanic acid and aromatic amino acids. Chromophores take up the
photon (absorption) and the energy from the photon can cause it to become a new molecule (A
photoproduct). Chromophore often forms covalent bonds with another molecule.
Use of light for Vit D use
Plasma membrane bound chromophore 7-dehydrocholesterol is photoconverted to previtamin
D3 which then undergoes a slow thermal isomerisation to vit D3. Then enters the circulation.
Molecular level damage
UV absorption  when a thymine or cytosine absorbs UVB, the excited state can cause it to
bond to an adjacent cytosine or thymine forming a four-membered ring called a CPD. dipyrimidine
lesions cylcobutane pyrimidine dimers (CPDs) and pyrimidine (6-4 photoproducts) . If not repaired
speedily via nuclear excision repair (global genome repair and transcription coupled repair), lesions 
UVB signature mutations (CT or CCTT) [normally AT and CG]
Macroscopic level damage
Sunburn
Classic inflame signs (red, warm, pain, swelling) intensity based on UVR exposure dose
irrespective of time exposed over a few hours. Mast cell products are detected within 1 hour of UVR
exposure. Neutophils and T cells found in upper dermis within 3 hours, increasing rapidly till 48 hours.
Afferent sensory nerves release neuropeptides (substance P) after UVR exposure itch,
pain, inflam, immunomodulation. UVR also causes release of neutrophins and hormones from
melanocytes, keratinocytes, endothelial cells. These stimulate vasodialtion, mast cell degranulation, ↑
UVR induced cytokine production and other stuff that attracts inflam mediators.
Some endogenous chromophores and photosensitizers produce ROS. Mitochondria damage via
direct photon exposure also leads to ROS production. REDOX active proteins in keratinocytes and
fibroblasts produce ROS when the cell is exposed to UVA or UVB.
“UVA-induced responses in normal skin and in photosensitivity conditions are generally
dependent on production of ROS. Recent studies suggest that some UVB-initiated responses
also involve ROS.22 Antioxidants act by quenching (i.e., chemically reacting with and
removing) ROS and other free radicals before they can damage cellular molecules.”
Aging of skin
UVR (partly through ROS generationinhibit phosphatases which keep receptors inactive)
activate (phosphorylates) cell surface receptors (inc. epidermal GF, IL-1 nad TNF alpha) which induce
intracellular signalling  AP-1 activation (nuclear transcription complex)  blocks cytokines that
enhance collagen gene transcription, block receptors for transforming growth factor (TGF), blocks
retinoid effects in skin (reduce collagen promotion). UV directly induces synthesis of another cytokine
which reduces type I procollagen.
UV also causes a nuclear factor transcription factor which creates enzymes which promote MMP-1
(collagenase), also promoted by AP-1. Degrades the dermal matrix. MMP-8 Collagenase is also
secreted by local neutrophils called in.
PBL 3 – Jack and his Spots
Rick Allen
The collagen degradation is generally incomplete which leads to its accumulation in the dermis, which
reduces structural integrity and inhibits new collagen synthesis.
Final point is that the DNA of mitochondria in skin cells is damaged by the constant production of
ROS, causing mutations which are too big to be repaired,  drop in the cells ability to create energy,
further increase of ROS and hence death.
Mechanisms of skin aging. A. Reactive oxygen species (ROS) generated during aerobic metabolism
activate the transcription factor nuclear factor B (NF- B) that induces the expression of the proinflammatory cytokines, vascular endothelial growth factor (VEGF), and tumor necrosis factor (TNF). ROS also lead to the formation of carbonyl groups (C=O) in proteins, leading to the accumulation
of damaged proteins. Ultraviolet (UV) irradiation directly activates cell surface receptors (indicated
PBL 3 – Jack and his Spots
Rick Allen
by symbols on the cell membrane), initiating intracellular signaling that eventually activates the
nuclear transcription complex AP-1. AP-1 increases transcription of matrix metalloproteinases
(MMPs) and decreases expression of the procollagen I and III genes and transforming growth factor
(TGF)- receptors, with a final consequence of reduced dermal matrix formation. UV also activates
the NF- B transcription factor that induces the expression of multiple proteins and aggravates the
degradation of dermal matrix by increasing MMP levels. Matrix degradation is further exacerbated
by MMP-8 (collagenase) of neutrophil origin, following neutrophil infiltration into UV-irradiated skin.
Mitochondria display large DNA deletions and compromised function. Damaged proteins containing
carbonyl groups accumulate in the upper portions of the dermis. [From Halachmi S, Yaar M,
Gilchrest BA: Advances in skin aging/photoaging: Theoretic and practical implications (Part I). Ann
Dermatol Venereol 132:362, 2005, with permission.]
Immunosupression (Th – T suppressor)
CPD is a direct cause of immunosuppression. UVB creates CPDs in APCs, impairing their antigenpresenting capacity. Damage persists for several days, while it migrates to lymph nodes. Unable to
repair the damage because we lack the DNA repair enzyme T4 endonuclease V.
Generation of ROS is likely to also be involved.
Cell membrane – UVB exposure leads to clustering and internalisation of cell surface receptors for
epidermal GF, TNF and IL-1. Clustering also causes activation of stress induced mitogen kinases.
Membrane lipids can be oxidised to a state where it will bind to prostaglandin activating factor (PAF)
receptors and activate cytokine synthesis (inc. IL-10).
UVB alters keratinocyte surface molecule expression and induces cytokine production and secretion;
notably TNF – alpha and IL-10; immunosuppressive cytokines. IL-10 is also a TH2 cytokine that
suppresses the production of TH1 cytokines (notably IFN – gamma). Therefore shift from TH1 to TH2
immunity. IL-10 also inhibits the APC abilities of langerhan cells and promotes their migration to
lymph nodes, therefore decreasing contact hypersensitivity reactions (CHS). Also promotes their
activation of Th2 over Th1 and causes Th1 anergy.
Induces T suppressor cells (shut down activated T cells). Natural Killer T cells also observed with
regulatory powers.
Th1 cytokine responses are suppressed. Therefore sensitization and elicitation of immune system is
inhibited. Deplete Langerhans cells, recruit APC macrophages and release inflam mediators. All this
altered normal antigen presentation process  highly specific regulatory T cells that specifically
inhibit cell mediated immunity to newly encountered antigens.
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Rick Allen
Ultraviolet B (UVB) radiation–induced immunosuppression: Illustration of the presumed molecular and cellular
events at the irradiated skin site. ATPase = adenosine triphosphatase; DC = dendritic cell; DLN = draining
lymph node; IL = interleukin; ICAM = intercellular adhesion molecule; MAPK = mitogen-activated protein
kinase; MHC = major histocompatibility complex; NFB = nuclear factor
B; PAF = plateletactivating factor; PGE2 = prostaglandin E2; ROS = reactive oxygen species; TGF = transforming growth factor;
TNF = tumor necrosis factor; UCA = urocanic acid.
Adaptive responses -Tanning
Hyperplasia of the dermis and stratum corneum. UVR triggered, protective.
Melanin is composed of pheomelanin (light, alkali soluble, sulphur) and eumelanin (darker, insoluble).
UVA  immediate pigment darkening (via photooxidation of existing melanin)
Melanogenesis (UVB response) = ↑activity and # of melanocytes. Melanocyte dendrites elongate and
branch
Evidence suggests that DNA photodamage and its repair initiates melanogenesis. Tyrosinase is the
rate limiting enzyme for melanogenesis who’s activity increases upon UV exposure. UVR damage
also upregulates cell surface receptors for keratinocyte-derived melanogenic factors.
Antioxidant defences are utilised in the skin to reduce the damage caused by ROS released by UVR
exposure.
References
http://www.accessmedicine.com/content.aspx?aID=2868631&searchStr=ultraviolet+rays#2868631
Major skin chromophores include DNA, urocanic acid (UCA), and aromatic amino acids (proteins)
that absorb primarily in the UVC/UVB region;
http://www.accessmedicine.com/content.aspx?aID=2966157
http://www.accessmedicine.com/content.aspx?aID=2987235
PBL 3 – Jack and his Spots
Rick Allen
Table 89-1 A Classification of Skin Phototypes Based on Susceptibility to
Sunburn in Sunlight, Tanning Ability, and Skin Cancer Risk
Skin
Sunburn
Phototype Susceptibility
Tanning
Ability
Skin
Cancer
Risk
No. Standard
Erythema Dosea
Required for
Minimal Erythema
I
High
None
High
1–3
II
High
Poor
High
III
Moderate
Good
Low
IV
Low
Very good
Low
V
Very low
Excellent
Very low
VI
Very low
Excellent
Very low
3–7
7–>12
aA
standard erythema dose is equivalent to an erythemally effective radiant exposure of 100
J/m2.62 Approximately three standard erythema doses are required to produce just perceptible or
minimal erythema in unacclimatized skin of the most common Caucasian American and northern
European skin types.2
Molecular level studies have shown that photosensitivity responses are mediated by reactive oxygen
species (ROS), which are small molecules and free radicals that rapidly oxidize cellular molecules.
Examples of ROS include singlet oxygen, hydrogen peroxide, superoxide anion, hydroxyl radical, and
nitric oxide. These ROS oxidize unsaturated lipids, certain amino acids in proteins (histidine,
methionine, tryptophan, cysteine), and nucleic acids. The products formed initiate signal
transduction processes, leading to production of inflammatory mediators such as prostaglandin E2
(PGE2) and cytokines [e.g., tumor necrosis factor (TNF)-
, interleukin (IL)-1
].