Photoimmunology

Abstract

The discipline that investigates the biologic effects of ultraviolet radiation on the immune system is called photoimmunology. Photoimmunology evolved from an interest in understanding the role of the immune system in skin cancer development and why immunosuppressed organ transplant recipients are at a greatly increased risk for cutaneous neoplasms. In addition to contributing to an understanding of the pathogenesis of nonmelanoma skin cancer, the knowledge acquired about the immunologic effects of ultraviolet radiation exposure has provided an understanding of its role in the pathogenesis of other photodermatologic diseases.

Keywords: Chronic actinic dermatitis; Cutaneous lupus erythematosus; Nonmelanoma skin cancer; Photoimmunology; Photosensitivity; Phototherapy; Polymorphous light eruption; Ultraviolet radiation.

Figure 1

UV-induced immune suppression and photocarcinogenesis. (A) Chronic exposure of mice, as in humans, results in the development of UV-induced non-melanoma skin cancers. (B) UV-induced tumors that are transplanted to genetically identical recipients that have not been exposed to UV radiation results in rejection of the tumor by the host immune response. (C) UV-induced tumors that are transplanted to genetically identical recipients that have received subcarcinogenic doses of UV radiation grow progressively and ultimately result in death of the recipient. (D) UV-induced tumors only develop when mutations in keratinocytes and UV-induced immunosuppression occurs.

Figure 2

Cell-mediated immune responses reflect the balance between regulatory and effector T-cells. (A) When antigens, including tumor antigens, are present in the skin, they are taken up by cutaneous dendritic cells, which is a necessary precondition for the generation of effector and regulatory Tlymphocytes. (B) When the skin has been UV-irradiated and then encounters an antigen, the generation of regulatory T-cells proceeds unimpeded, but the generation of effector T-cells is diminished. (C) The overall magnitude of the cutaneous cell-mediated immune response represents the balance between the effector and regulatory T-cells that are generated. Following UV exposure, there are relatively more regulatory T-cells, resulting in a more modest response.

Figure 3

Direct and indirect effects of UV radiation on the antigen presenting function of cutaneous dendritic cells. Following UV exposure, the antigen presenting function of cutaneous dendritic cells is altered by direct effects on the antigen presenting cell itself and by indirect effects. The indirect effects are mediated by UV-irradiated keratinocyte production of soluble mediators such as IL-10, prostaglandin E2, and TNF-α, which then act on cutaneous dendritic cells. In addition, macrophages, which migrate into the skin following UV exposure, and regulatory T-cells both secrete the immunosuppressive molecule IL-10, which diminishes the capacity of cutaneous antigen presenting cells to activate effector T-cells.

Figure 4

Mechanism of by which UV radiation suppresses cutaneous cell-mediated immune responses. Following UV exposure, DNA damage occurs, which, in addition to its other effects, initiates photoimmunosuppression. Furthermore, UV exposure of the skin results in the generation of soluble mediators including serotonin (5-HT), cis-urocanic acid (Cis-UCA) and platelet activating factor (PAF), all of which antagonize activation of DNA repair enzymes. In addition, UV exposure prompts keratinocytes to produce immunosuppressive mediators which alter the antigen presenting function of cutaneous dendritic cells. Regulatory T-cells are generated that produce IL-10, which suppresses host T-cell mediated defense mechanisms and facilitates the growth and development of UV-induced tumors. Solid line: stimulatory. Dashed line: inhibitory.

Figure 5

Proposed photopathogenesis of polymorphous light eruption (PMLE). In contrast to normal individuals who have a suppressed immune response following UV exposure, the immune response in patients with polymorphous light eruption is not suppressed.

Figure 6

Two proposed models of the photopathogenesis of cutaneous lupus. (A) In subjects with Ro positive lupus, UV exposure of the skin results in translocation of the Ro protein to the surface of the keratinocyte, which enables anti-Ro antibodies to bind. Cytotoxic cells that express Fc receptors for the IgG molecule bind to the Fc portion of the anti-Ro antibody, which is attached to UV-irradiated keratinocytes expressing the Ro antigen on their surface. Thus, cytotoxicity occurs, leading to keratinocyte lysis. (B) Following UV exposure, apoptotic keratinocytes (sunburn cells) result. Apoptotic blebs are released from the dying keratinocytes. In unaffected individuals, these apoptotic blebs are removed by macrophages via non-inflammatory mechanisms. In lupus patients, the apoptotic bodies are taken up by dendritic cells and enter a pro-inflammatory pathway.