Light, including ultraviolet

Abstract

Ultraviolet (UV) light is intricately linked to the functional status of the cutaneous immune system. In susceptible individuals, UV radiation can ignite pathogenic inflammatory pathways leading to allergy or autoimmunity. In others, this same UV radiation can be used as a phototherapy to suppress pathogenic cutaneous immune responses. These vastly different properties are a direct result of UV light's ability to ionize molecules in the skin and thereby chemically alter them. Sometimes these UV-induced chemical reactions are essential, the formation of pre-vitamin D(3) from 7-dehydrocholesterol, for example. In other instances they can be potentially detrimental. UV radiation can ionize a cell's DNA causing adjacent pyrimidine bases to chemically bond to each other. To prevent malignant transformation, a cell may respond to this UV-induced DNA damage by undergoing apoptosis. Although this pathway prevents skin cancer it also has the potential of inducing or exacerbating autoreactive immune responses by exposing the cell's nuclear antigens. Ultraviolet-induced chemical reactions can activate the immune system by a variety of other mechanisms as well. In response to UV irradiation keratinocytes secrete cytokines and chemokines, which activate and recruit leukocytes to the skin. In some individuals UV-induced chemical reactions can synthesize novel antigens resulting in a photoallergy. Alternatively, photosensitizing molecules can damage cells by initiating sunburn-like phototoxic reactions. Herein we review all types of UV-induced skin reactions, especially those involving the immune system.

Figure 1. The electromagnetic spectrum

Ultraviolet radiation can be further devided into UVC, UVB, and UVA. Wavelength decreases as the frequency of the electromagnetic waves increases. As the frequency increases the energy of the emitted photons also increases. With a shorter wavelength, UVB radiation possesses much more energy than UVA.

Figure 2. UVB induces a 6-electron conrotatory electrocyclic reaction to synthesize pre vitamin D₃ from 7-dehydrocholesterol, a derivative of cholesterol

Figure 3. Penetrating abilities of UVA, UVB and UVC

A) Approximately 90% of UVB and nearly all of UVC is absorbed by O₃, O₂, and H₂O in the Earth’s atmosphere. UVA makes up 95% of the UV radiation that reaches the Earth. B) With its longer wavelength, UVA can penetrate deeper into the skin than UVB.

Figure 4. Mechanisms by which UV radiation can activate the immune system

A) In response to UV irradiation keratinocytes secrete a variety of different cytokines including TNF-α and IL-1β. B) Ionizing radiation from ultraviolet light can induce chemical reactions in the skin. Depicted here is a drug forming a covalent bond to a self-protein resulting is a novel antigen. In this example the drug can be considered a hapten. C) In response to UV-induced DNA damage, keratinocytes undergo apoptosis as a definitive mechanism to prevent malignant transformation. Following UV irradiation there is a redistribution of nuclear antigens to the surface of the keratinocyte.

Figure 5. Formation of cyclobutane pyrimidine dimers and (6-4) photoproducts photoproducts

A) Two normal thymidine residues. B&C) DNA can absorb the ionizing radiation of ultraviolet light and undergo chemical modifications including the formation of cyclobutane pyrimidine dimers (CPD) or 6-4 photoproducts (6-4PPs).

Figure 6. Following UV irradiation there are several pathways to eliminate DNA-damaged keratinocytes

Damaged cells can undergo apoptosis and be engulfed by macrophages. To facilitate this process UV-irradiated cells secrete pro-inflammatory cytokines. These cytokines help recruit the leukocytes to the skin that participate in the disposal of the dying keratinocytes. T cells can also recognize and destroy the damaged keratinocytes. Receptors that target T cells for migration to the skin include the cutaneous lymphocyte antigen (CLA) and the chemokine receptors CCR4 and CCR6. Finally, if a DNA damaged keratinocye escapes these mechanisms a malignancy may develop. These malignancies almost always have mutations in the p53 tumor suppressor gene.

Figure 7. Mechanisms of UV-induced immunosuppression

UV irradiation disrupts Langerhans cell function by: inducing apoptosis, altering their surface phenotype, or by increasing their migration to the lymph nodes. The altered Langerhans cells can induce anergy or deletion of Th1 cells. Urocanic acid is present in large amounts in the epidermis. UV radiation can induce the isomerization of trans-urocanic acid to the cis-isomer that has immunosuppressive properties. Lastly, skin-infiltrating macrophages secrete IL-10, an anti-inflammatory cytokine.

Figure 8. Phototoxic and photoallergic reactions

In photoallergic reactions small photosensitizer can act as a haptens using UV light to attach themselves to larger molecules, forming photoallergens. In PMLE it is believed that there is an endogenous protein or other molecule that can absorb ultraviolet light and be chemically modified by it. The resulting antigen then initiates an immune response. Phytophotodermatitis and phototoxic drug eruptions are examples of phototoxic reactions. In these types of reactions reactive oxygen species can be synthesized by the energy released from light absorbing photosensitizers, such as psoralens. Psoralens can also bind to DNA forming monoadducts or crosslinks.

Figure 9

A) Phytophotodermatitis in response to lemonade and UV radiation; The linear areas of this rash reveal a likely external cause. B) Picture of hand of the same patient with phytophotodermatitis. The eruption is similar to an exaggerated sunburn, presenting with erythema and bullae. C) A milder case of phytophotodermatitis; The sometimes linear nature of the eruption is more apparent in this photo. D) Phototoxic drug eruption; Note the erythematous photodistributed plaque with hemorrhagic crust. E) Polymorphous light eruption; Notice the photodistribution of this rash. F) Subacute cutaneous lupus; Annular plaques with a ridge of scale and some central clearing or hyperpigmentation. The patient has a positive anti-Ro titer. G) Systemic lupus erythematosus; Acute photodistributed erythematous plaque with very light scale. The patient has a positive anti-Ro titer. Photos A, B and D are courtesy of Daniel B. Eisen, M.D.