198 - PHOTOTHERAPY - not done Flashcards
most common short term adverse effect of phototherapy
sunburn-like reactions
UVB phottoxicity usually peaks at
12- 24 hours
PUVA reaction sually peaks at
24 to 48 to even 72 hrs
The main phototherapeutic devices that are in use today (aside from lasers, high-output incoherent light sources, and visible light sources employed for photodynamic therapy)
- broadband ultraviolet B (BB-UVB),
- narrowband UVB (NB-UVB),
- ultraviolet A (UVA) 1, and
- UVA for psoralen photochemotherapy (PUVA)
Wavelength of UVB
290 to 320 nm
Most UVB radiation (290 to 320 nm) is absorbed by what structures?
Most UVB radiation (290 to 320 nm) is absorbed superficially by the epidermis and superficial dermis
Effects of UVB radiation
This particular wavelength of radiant energy produces many different types of DNA damage, including pyrimidine dimers and 6,4-pyrimidine-pyrimidone photoproducts. These by-products are thought to be particularly important for both UVB’s efficacy and toxicity. 4 UVB also causes photochemical changes in trans-urocanic acid, converting it into the cis form of the molecule. Urocanic acid is a breakdown product of histidine and is present in large amounts in the stratum corneum. Originally considered to be a natural photoprotectant, there is now substantial evidence that cis-urocanic acid is a mediator of UVB-induced immunosuppression. 5 In addition, urocanic acid levels can also affect vitamin D production. Specifically, upon NB-UVB exposure, there is an accompanied increase in hydroxyvitamin D synthesis that inversely correlates with the baseline levels of trans-urocanic acid. 6 A third direct target of UVB radiation is the amino acid tryptophan. UVB converts tryptophan into 6-formylindololo[3,2-b]carbazole, which binds to the intracellular aryl hydrocarbon hydroxylase receptor, initiating a series of events that culminates in activation of signal transduction pathways. One such pathway results in expression of cyclooxygenase-2, an enzyme required for synthesis of prostaglandin E2 . 7 Finally, there is evidence that UVB exposure leads to the generation of reactive oxygen intermediates, which has downstream effects such as DNA damage in the form of 8-oxo-deoxyguanosine, lipid peroxidation, activation of signal transduction pathways, and stimulation of cytokine production.
UVA wavelength
320 to 400 nm
depth of penetration of UVA
UVA radiation (320 to 400 nm) can reach the mid- or lower dermis to a depth of 140 microns
effects of UVA
Like UVB, UVA radiation can produce pyrimidine dimers in DNA, but, on a per-photon basis, it is much less effective at doing so. 9 In most situations, the major biologic effects of UVA radiation are from the generation of reactive oxygen intermediates. 10 Following UVA exposure, reactive oxygen intermediates are formed in mitochondrial enzyme complexes during oxidative phosphorylation. Although the skin contains antioxidants, reactive oxygen intermediates formed during phototherapy exceed the amount that can be neutralized by endogenous photoprotective activities. UVAinduced oxidants are capable of harming DNA, lipids, structural and nonstructural proteins, and organelles such as mitochondria. The generation of oxidants following UV exposure also has been implicated in photoaging of the skin and skin cancer. Interestingly, animal studies show that exposure to UVA’s longer wavelength (UVA1, 340-400 nm) has immunoprotective properties via the generation of heme oxygenase-1, which exerts antioxidant and antiinflammatory effects while also decreasing UVB-induced damage.
depth of penetration of PUVA
In psoralen photochemotherapy, psoralen photosensitizers are activated by UVA radiation, and the depth of penetration of PUVA is the mid-dermis.
major photochemical effect of psoralen photochemotherapy
damage to DNA
Psoralen photochemotherapyinduced changes in DNA differ from those of UVB and UVA without psoralens. 12 Psoralens used for photochemotherapy have 2 double bonds that can absorb UVA radiation. When administered to an individual, these compounds intercalate with DNA. Following UVA exposure, they form a single adduct with DNA and then become a bifunctional adduct, crosslinking the DNA strands in the double helix, when a second photon is absorbed. There is also some evidence that photochemotherapy augments the production of reactive oxygen intermediates such as singlet oxygen. This effect has been implicated in induction of the cyclooxygenase enzyme and activation of arachidonic acid pathways
Effects of phototherapy on the immune system
The photoimmunologic effects of phototherapy are thought to provide an explanation, at least in part, for phototherapy’s efficacy in cutaneous diseases in which T-cell hyperactivity predominates (eg, psoriasis, atopic dermatitis, lichen planus). Under normal circumstances, both effector and regulatory T cells are generated, with the overall intensity of the immune response dependent on the relative proportion of effector and regulatory T-cell populations that are present. UVB exposure inhibits activation of effector T cells, whereas it leaves the development of regulatory T cells unaltered. 14 Consequently, the equilibrium of effector and regulatory T cells is biased toward a diminished cell-mediated immune response. This perturbation in the balance of effector and regulatory T cells reflects disruption of the activities of dendritic cells within the skin, the major function of which is to present antigen to T-lymphocytes. This is a result of the direct effects of UVB on dendritic cells and indirectly through the production of interleukin (IL)-10 and prostaglandin E2 , both of which diminish the capacity of dendritic cells to present antigen to effector T cells leading to suppressed T-cell responses. 15 Increased levels of IL-10 have been found after UVB, UVA1, and PUVA exposure. Prostaglandin E 2 production occurs through
UVB effects on keratinocytes16-18 ; UVB is an inductive stimulus for cyclooxygenase-2, which is important for prostaglandin E 2 production. UV exposure also significantly lowers levels of immunomodulatory factors such as prostaglandin D2 , possibly reflecting a loss of Langerhans cells from the epidermis upon UV exposure.19
Other immunosuppressive soluble mediators that are reported to be increased following UVB exposure include agonists of the platelet activating factor receptor, 20 melanocyte-stimulating hormone, and calcitonin gene–related peptide. 21 In addition, in the setting of inflammation, FoxP3-positive regulatory T cells can convert into IL-17–producing cells and lose FoxP3. UVB radiation, however, increases FoxP3 expression by binding the transcription factor, p53, and stabilizing the FoxP3-positive regulatory T-cell population.22,23 The epidermal growth factor–like growth factor amphiregulin influences the activity of regulatory T cells and basophil-derived amphiregulin is implicated in mediating UVB-induced immune suppression in murine models, which supports the notion that growth factors have immunomodulatory properties relevant to skin biology and disease.24,25
PUVA has effects that are similar to UVB with respect to antigen-presenting cells within the skin, the balance between effector and regulatory T cells, and the production of soluble immunosuppressive mediators. 14 However, there is limited information on the effect of UVA1 on antigen-presenting cells and on effector and regulatory T cells. In acute skin lesions of atopic dermatitis, UVA1 appears to increase IL-4 and thymus-regulated and activation-regulated chemokine messenger RNA expression, but has little effect on expression of human beta defensin-1, thymic stromal lymphopoietin, IL-5, IL-10, IL-13, or IL-31.26,27
In addition to its actions on cutaneous antigenpresenting cells, phototherapy causes cell death by apoptosis of T cells in cutaneous lymphoid infiltrates. This has been demonstrated for UVA1 phototherapy in the lymphocytic infiltrate in atopic dermatitis, 28 and for NB-UVB in psoriasis. 29 Another immunologic effect of phototherapy is on expression of CD54 (intercellular adhesion molecule-1) and other adhesion molecules. Intercellular adhesion molecule-1 is not normally present on epidermal keratinocytes, but can be induced in a variety of inflammatory skin conditions. It facilitates T-cell binding to keratinocytes, through its interaction with lymphocyte function–associated antigen-1 that is present on T cells. Because UVB, UVA1, and PUVA all interfere with keratinocyte expression of CD54, this effect of phototherapy may contribute to phototherapy’s efficacy in diseases that have increased keratinocyte CD54 expression.
