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.
Key points
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Photoimmunology investigates the immunologic effects of UV radiation exposure.
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Photoimmunology originated from observations about the biologic behavior of nonmelanoma skin cancers and the recognition that immunosuppressed organ transplant recipients were at an increased risk for sunlight-induced skin cancers.
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Experiments in animal models showed that alterations in the host cell–mediated immune response are necessary for skin cancers to develop.
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UV mediates its effects by causing a disproportionate increase in regulatory T cells, altering the function of antigen-presenting cutaneous dendritic cells, and stimulating the production of soluble immunosuppressive mediators.
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Knowledge generated about the UV effects on the immune system has contributed to a broader understanding of the pathogenesis of several photosensitivity diseases and to the generation of more effective and safer forms of phototherapy.
The area of photodermatology that investigates the complex interrelationship between UV radiation and the body’s immune system is referred to as photoimmunology . Its foundation derives from clinical observations in patients with UV-induced skin cancers, but the acquisition of knowledge about the interactions of UV radiation with the immune system has implications beyond skin cancer. It has helped us to understand the mechanisms by which phototherapy is effective in psoriasis and other dermatologic diseases and, in so doing, has expanded the spectrum of illnesses amenable to UV radiation treatments. Furthermore, photoimmunology has enhanced our understanding of the role of the immune system in several different photodermatologic disorders.
Evidence of photoimmunologic effects of UV radiation in humans
The possibility that UV radiation, especially within the UVB range (290–320 nm), might modulate immunologic function was suspected long before there was supportive experimental evidence and was based on careful observations in individuals who developed solar UV radiation–induced skin cancers. In contrast to many of the cancers that arise in other organs, cutaneous squamous cell carcinomas (SCCs) develop gradually, rarely metastasize, and are associated with a chronic inflammatory infiltrate. SCCs develop from actinic keratoses, more than 25% of which undergo spontaneous regression, presumably by activation of cell-mediated immune defenses directed at antigens expressed by the preneoplastic cells.
It has also been observed that cutaneous SCC are more frequent in immunosuppressed individuals. More than 50% of renal transplant recipients on long-term immunosuppressive therapy have developed at least one nonmelanoma skin cancer. Although there is a 10-fold increased risk of basal cell carcinomas (BCCs) in organ transplant recipients, the likelihood of developing SCCs is even greater by 65 to 250 times, resulting in an inverted SCC/BCC ratio. The predisposition to skin cancer is not restricted to transplant patients. Patients with lymphoma and chronic lymphocytic leukemia, who also have subtle defects in cellular immune function, also have an increased incidence of BCCs and SCCs.
Immunologic abnormalities have been detected in patients with skin cancer who are otherwise immune competent. These patients demonstrate suppressed reactions to skin test antigens and decreased sensitization rates to the contact allergen dinitrochlorobenzene (DNCB), which are immune responses mediated by T lymphocytes. In addition, when BCCs are examined histologically, a disproportionate number of regulatory T cells are present in the inflammatory infiltrate. Finally, people who have received large numbers of psoralen plus UVA photochemotherapy (PUVA) treatments are known to have an increased incidence of skin cancer. These patients have been reported to have decreased immunization rates to contact allergens and reduced numbers of circulating peripheral blood CD4 + T cells.
Evidence of photoimmunologic effects of UV radiation in humans
The possibility that UV radiation, especially within the UVB range (290–320 nm), might modulate immunologic function was suspected long before there was supportive experimental evidence and was based on careful observations in individuals who developed solar UV radiation–induced skin cancers. In contrast to many of the cancers that arise in other organs, cutaneous squamous cell carcinomas (SCCs) develop gradually, rarely metastasize, and are associated with a chronic inflammatory infiltrate. SCCs develop from actinic keratoses, more than 25% of which undergo spontaneous regression, presumably by activation of cell-mediated immune defenses directed at antigens expressed by the preneoplastic cells.
It has also been observed that cutaneous SCC are more frequent in immunosuppressed individuals. More than 50% of renal transplant recipients on long-term immunosuppressive therapy have developed at least one nonmelanoma skin cancer. Although there is a 10-fold increased risk of basal cell carcinomas (BCCs) in organ transplant recipients, the likelihood of developing SCCs is even greater by 65 to 250 times, resulting in an inverted SCC/BCC ratio. The predisposition to skin cancer is not restricted to transplant patients. Patients with lymphoma and chronic lymphocytic leukemia, who also have subtle defects in cellular immune function, also have an increased incidence of BCCs and SCCs.
Immunologic abnormalities have been detected in patients with skin cancer who are otherwise immune competent. These patients demonstrate suppressed reactions to skin test antigens and decreased sensitization rates to the contact allergen dinitrochlorobenzene (DNCB), which are immune responses mediated by T lymphocytes. In addition, when BCCs are examined histologically, a disproportionate number of regulatory T cells are present in the inflammatory infiltrate. Finally, people who have received large numbers of psoralen plus UVA photochemotherapy (PUVA) treatments are known to have an increased incidence of skin cancer. These patients have been reported to have decreased immunization rates to contact allergens and reduced numbers of circulating peripheral blood CD4 + T cells.
Experimental evidence for the photoimmunologic effects of UV radiation
More direct evidence of the ability of UV radiation to impair immune responses is derived from a classic series of experiments in animal models. Mice that are chronically exposed to UV radiation, like humans, develop UV-induced tumors ( Fig. 1 A). When these tumors are removed and are transplanted to the skin of genetically identical recipient mice, the tumors initially engraft but do not enlarge and ultimately regress because a host immune response develops against the tumors (see Fig. 1 B). On the other hand, when the same tumors are transplanted to genetically identical recipients that have received subcarcinogenic doses of UV radiation, the tumors grow progressively, are not immunologically eradicated, and ultimately kill their host (see Fig. 1 C). The conclusions that can be derived from these experiments are as follows: (1) UV radiation, in addition to causing mutations in keratinocytes, also prevents activation of host immune responses that have evolved to destroy mutant keratinocytes before they can develop into clinically apparent tumors. (2) Only when there are both mutant keratinocytes and UV-induced immunologic alterations is it possible for skin tumors to occur (see Fig. 1 D).
Mechanisms of UV-induced immune suppression
There has been great interest in determining the mechanisms by which UV radiation mediates its effects on the immune system. Those studies have focused on 5 features: (1) the role of regulatory T cells, (2) the contribution to alterations in antigen-presenting cell (APC) function, (3) the effect of UV-induced cytokines and soluble mediators, (4) the molecular target that initiates UV-induced immune suppression, and (5) the participation of toll-like receptors (TLRs) and innate immunity.
Regulatory T Cells
Studies have shown that UV radiation alters T cell–mediated immunity and, in so doing, causes immune suppression. Under normal circumstances, cutaneous exposure to antigens, such as contact allergens or tumor antigens expressed on skin cancers, results in the generation of both effector and regulatory T-lymphocytes, which are specific for the exposed antigen ( Fig. 2 A). Effector cells promote an immune response directed against the inciting antigen, whereas regulatory T cells dampen the reaction. The overall magnitude of the response depends on the ratio of effector to regulatory T cells that develop (see Fig. 2 C). When large numbers of effector T cells develop and small numbers of regulatory T cells are present, a vigorous immune response occurs, whereas in situations in which smaller numbers of effector T cells and proportionally larger numbers of regulatory T cells are generated, there is a modest immune response. Following UV exposure, the generation of regulatory T cells is unaffected, whereas the number of effector T cells is diminished (see Fig. 2 B). The disproportionate number of regulatory T cells relative to effector T cells leads to a suppressed immune response (see Fig. 2 C). The regulatory T cells that occur following UV exposure carry the phenotypic markers CD4 + , CD25 + , CTLA4 + , and FoxP3 + and secrete the immunosuppressive cytokine interleukin-10 (IL-10). In addition, a second population of cells called NKT cells have characteristics of both natural killer (NK) cells and T cells and express the CD4 + and DX5 + (CD49b + ) proteins. NKT cells suppress immune responses following UV radiation exposure and produce the Th2 cytokine IL-4, which suppresses antitumor immunity.
APCs
The recognition that regulatory T cells contribute to the suppressed immune response following UV exposure coincided with the discovery that T cells are only activated when antigen is presented to them by APCs. The skin contains several populations of APCs, including epidermal Langerhans cells, different types of dermal dendritic cells, and macrophages/monocytes, some of which migrate into the skin after UVB exposure. Depending on the type and status of the APC, different subpopulations of T cells are activated. UV radiation has been shown to have a deleterious influence on cutaneous dendritic cell function for effector T-cell activation and less of an effect on APC function for regulatory T cells (see Fig. 2 ). Recent evidence from animal models indicates that epidermal Langerhans cells are required for the generation of regulatory T cells following UV exposure. UV radiation produces its effects on cutaneous dendritic cells both through indirect and direct effects on the cells ( Fig. 3 ). The indirect effects include stimulation of keratinocytes to produce immunosuppressive soluble mediators, such as IL-4, IL-10, tumor necrosis factor (TNF)-α, and prostaglandin (PGE2), and stimulation of the migration of immunosuppressive macrophages into sites of UV injury. Also, the regulatory T cells that are generated following UV exposure have a negative influence on the presentation of antigen to effector T cells, thereby serving as a positive feedback loop for immunosuppression.
Initial Molecular Events
DNA is now generally considered to be the molecular structure within cells that initiates the immunosuppressive effects of UV radiation. Those wavelengths within the solar spectrum that are most effective at causing immunosuppression lie primarily within the UVB range and correspond closely with those that are most damaging to DNA. In fact, patients with xeroderma pigmentosum (XP), a disease in which there is an inherited defect in DNA repair, have an increased propensity to develop actinic keratoses, BCCs, SCCs, and melanomas at an unusually early age. Patients with XP also have impaired delayed-type hypersensitivity (DTH) responses, reduced circulating CD4/CD8 T-cell ratios, defective NK cell function, and impaired production of interferon-γ, further supporting the concept of DNA as the molecular target of UVR-induced immunosuppression. In animal models, UV-induced immune suppression can be reversed by topical application of enzymes that repair DNA damage. When used in patients with XP, topical application of DNA repair enzymes prevents the development of actinic keratoses and BCCs.
Transurocanic acid is present in large amounts in the stratum corneum of the skin and undergoes photoisomerization to its cis-urocanic acid conformation following UV exposure. Cis-urocanic acid has been shown to be a mediator of UV-induced immunosuppression. Recent studies have shown that cis-urocanic acid mediates its immunosuppressive effects by interfering with the repair of UV-induced DNA damage.
Cytokines and Other Soluble Mediators
UV radiation is known to stimulate epidermal production of a variety of soluble mediators. These mediators include TNF-α ; PGE2 ; serotonin ; platelet-activating factor ; and neuropeptides, such as calcitonin gene–related peptide (CGRP) and α-melanocyte-stimulating hormone (α-MSH). UVR is also proficient at generating reactive oxygen intermediates. These molecules have been shown to be important mediators of UV-induced immunosuppression, and interfering with their activity reverses their immunosuppressive effects in experimental animal models ( Fig. 4 ). Many of these agents, including cis-urocanic acid, platelet-activating factor, and serotonin, produce their immunosuppressive effects by interfering with repair of DNA damage. CGRP inhibits the Langerhans cell antigen-presenting function, and this may be the mechanism by which it causes UV-induced immune suppression. α-MSH is a stimulus for IL-10 production by keratinocytes and monocytes.
Two other cytokines that play a prominent role in UV-induced immunosuppression are IL-10 and IL-12. IL-10 is an immunosuppressive cytokine produced by UV-irradiated keratinocytes, macrophages that migrate into UV-irradiated skin, and regulatory T cells that are generated following UV exposure. IL-10 acts on dendritic cells in such a manner as to enhance the generation of UV-induced regulatory T cells. IL-12, on the other hand, promotes T cell–mediated immunity by supporting the production of effector T cells, which produce the proinflammatory cytokine interferon-γ. Studies in animal models have shown that the administration of IL-12 will reverse the immunosuppressive effects of UV radiation. IL-12 stimulates the production of enzymes that repair UV-damaged DNA, which may also contribute to its ability to abrogate the immunosuppressive effects of UV. Polyphenols present in green tea and other natural and dietary products have been shown to prevent UV-induced immunosuppression and carcinogenesis, at least in part, by stimulating the production of IL-12.
TLRs and Innate Immunity
TLRs are highly conserved molecules that are present on the surface of immune cells and epithelial cells including epidermal keratinocytes. They are important in the activation of several pathways of the innate immune response. TLRs recognize patterns within antigens that are foreign to the immune system, which include foreign pathogens; pathogen-associated molecular patterns; as well as endogenous antigens that are altered from their normal state, damage-associated molecular patterns. Of the 13 TLRs that have been identified thus far, 2 (TLR3 and TLR4) have been shown to be involved in the recognition of UV radiation–induced damage of RNA and DNA, respectively. These receptors initiate pathways that ultimately enhance UV-induced immunosuppression.
TLR3 is a cell surface receptor, present on keratinocytes. Following UV exposure, damage to keratinocytes occurs, which results in the release of double-stranded, small nuclear RNA (snRNA). Once released, these snRNAs induce the expression of TLR3 on nonirradiated cells and then bind to the same TLR3 receptors, the expression of which they have provoked. TLR3 activation causes keratinocytes to produce proinflammatory cytokines, such as IL-6 and TNF-α. TNF-α is a known mediator of UV-induced immune suppression. Direct evidence of TLR3 in UV-induced immune suppression has come from studies in experimental animal models. UV-irradiated mice expressing TLR3 develop a suppressed T cell–mediated allergic contact hypersensitivity response, whereas the immune response in mice that are genetically deficient in TLR3 is normal.
A receptor involved in the recognition of UV-induced DNA damage is TLR4. As was mentioned, UV-damaged DNA can be repaired by DNA repair enzymes. In the skin, TLR4 is found primarily on dendritic cells. Following UV exposure, dendritic cells in the skin that express the TLR4 molecule have a diminished capacity to synthesize IL-12. As was mentioned (see above), IL-12 stimulates the synthesis of DNA repair enzymes. The decrease in DNA repair in cutaneous dendritic cells renders them unable to effectively activate effector T cells and leads to suppression of the cell-mediated immune response. In contrast, in experimental systems, TLR4-deficient animals repair UV-damaged DNA normally and do not exhibit UV-induced immune suppression.
Photoimmunologic diseases
The information derived from animal models about the photoimmunologic effects of UV radiation, coupled with observations made in patients, have been the basis for theories about the immunopathogenesis of several photodermatologic disorders, including polymorphous light eruption (PMLE), chronic actinic dermatitis, and cutaneous lupus erythematosus.
PMLE
PMLE is the most common photodermatosis, with prevalence rates ranging from 1% to 21%, depending on the geographic location surveyed. Wavelengths within the UVA are most commonly reported to prompt the inflammatory reaction, although in some patients, UVB and even UVC have been associated with flares of the disease. PMLE has many features in common with DTH reactions in the skin. Within a few hours of sun exposure, CD4 + T cells can be detected infiltrating the UV-exposed site. The CD4 + T cell infiltrate is followed over the next few days by an influx of CD8 + T cells. In addition, the adhesion molecules E-selectin (CD62), vascular cell adhesion molecule 1 (CD106, also known as VCAM1), and intercellular adhesion molecule-1 (CD54, also known as ICAM1), all of which facilitate the migration and retention of T cells into inflamed skin, can easily be detected in PMLE skin, whereas they are not found in normal skin. Although they are not first-line therapies for the disease, the fact that PMLE can be controlled with immunosuppressive agents, such as azathioprine and cyclosporine, is also consistent with the concept that it is an immunologically mediated disease.
It has been proposed that UV is less effective at suppressing cell-mediated immune responses in patients with PMLE ( Fig. 5 ). There is decreased migration of CD11b + macrophages, which are known to secrete IL-10, into UV-irradiated skin in patients with PMLE. Moreover, a series of studies in which attempts were made to sensitize PMLE and normal control subjects to the contact allergen DNCB through UV-irradiated skin, demonstrated that UV-induced suppression of the contact allergic reaction was more effective in control subjects than in patients with PMLE. In other words, patients with PMLE are resistant to the immunosuppressive effects of UV radiation.
