l-Histidine Supplementation in Adults and Young Children with Atopic Dermatitis (Eczema).

Atopic dermatitis (AD) is an incurable, inflammatory skin condition that is prevalent (∼20%) in young children. There is an unmet clinical need, particularly in children, for safe interventions that target the etiology of the disease. Deficiencies in the skin barrier protein, filaggrin (FLG) have been identified as major predisposing factors in AD. In mammals, l-histidine is rapidly incorporated into epidermal FLG and subsequent FLG proteolysis releases l-histidine as an important natural moisturizing factor (NMF). It has therefore been hypothesized that l-histidine supplementation would be a safe approach to augment both FLG and the NMF, enhance skin barrier function, and reduce AD severity. In a clinical pilot study, adult subjects (n = 24) with AD took either a placebo or 4 g oral l-histidine daily for 8 wk. Unlike the placebo, l-histidine reduced AD (34% reduction in SCORing Atopic Dermatitis scores; P < 0.003) after 4 wk. Nine and 8 adverse events (AEs), and 1 and 0 severe AEs were recorded in the l-histidine or placebo groups, respectively, with no AE being causally related to l-histidine ingestion. A survey of adults (n = 98) taking 4 g l-histidine daily reiterated a lack of causal AEs and also reported a 33% reduction in topical corticosteroid use. A placebo-controlled, clinical pilot study conducted in young children with AD (n = 49; mean age 3.5 y) taking 0.8 g l-histidine daily, showed that eczema area and severity index scores were reduced by 49% (P < 0.02) at 12 wk, whereas a placebo had no effect. The children taking l-histidine had 50 minor AEs (compared with 39 on placebo), with 78% considered as "not," 18% "unlikely," and 4% "possibly" related to l-histidine ingestion. These studies indicate that at the levels reported, oral l-histidine supplementation is well tolerated and has potential as a safe intervention for long-term use in the management of AD in all age groups.

Selective proteolysis by matrix metalloproteinases of photo-oxidised dermal extracellular matrix proteins.

Photodamage in chronically sun-exposed skin manifests clinically as deep wrinkles and histologically as extensive remodelling of the dermal extracellular matrix (ECM) and in particular, the elastic fibre system. We have shown previously that loss of fibrillin microfibrils, a key elastic fibre component, is a hallmark of early photodamage and that these ECM assemblies are susceptible in vitro to physiologically attainable doses of ultraviolet radiation (UVR). Here, we test the hypotheses that UVR-mediated photo-oxidation is the primary driver of fibrillin microfibril and fibronectin degradation and that prior UVR exposure will enhance the subsequent proteolytic activity of UVR-upregulated matrix metalloproteinases (MMPs). We confirmed that UVB (280-315 nm) irradiation in vitro induced structural changes to both fibrillin microfibrils and fibronectin and these changes were largely reactive oxygen species (ROS)-driven, with increased ROS lifetime (D2O) enhancing protein damage and depleted O2 conditions abrogating it. Furthermore, we show that although exposure to UVR alone increased microfibril structural heterogeneity, exposure to purified MMPs (1, -3, -7 and - 9) alone had minimal effect on microfibril bead-to-bead periodicity; however, microfibril suspensions exposed to UVR and then MMPs were more structurally homogenous. In contrast, the susceptibly of fibronectin to proteases was unaffected by prior UVR exposure. These observations suggest that both direct photon absorption and indirect production of ROS are important mediators of ECM remodelling in photodamage. We also show that fibrillin microfibrils are relatively resistant to proteolysis by MMPs -1, -3, -7 and - 9 but that these MMPs may selectively remove damaged microfibril assemblies. These latter observations have implications for predicting the mechanisms of tissue remodelling and targeted repair.

Feeding filaggrin: effects of l-histidine supplementation in atopic dermatitis.

Atopic dermatitis (AD), also known as eczema, is one of the most common chronic skin conditions worldwide, affecting up to 16% of children and 10% of adults. It is incurable and has significant psychosocial and economic impacts on the affected individuals. AD etiology has been linked to deficiencies in the skin barrier protein, filaggrin. In mammalian skin, l-histidine is rapidly incorporated into filaggrin. Subsequent filaggrin proteolysis releases l-histidine as an important natural moisturizing factor (NMF). In vitro studies were conducted to investigate the influence of l-histidine on filaggrin processing and barrier function in human skin-equivalent models. Our further aim was to examine the effects of daily oral l-histidine supplementation on disease severity in adult AD patients. We conducted a randomized, double-blind, placebo-controlled, crossover, nutritional supplementation pilot study to explore the effects of oral l-histidine in adult AD patients (n=24). In vitro studies demonstrated that l-histidine significantly increased both filaggrin formation and skin barrier function (P<0.01, respectively). Data from the clinical study indicated that once daily oral l-histidine significantly reduced (P<0.003) AD disease severity by 34% (physician assessment using the SCORingAD tool) and 39% (patient self-assessment using the Patient Oriented Eczema Measure tool) after 4 weeks of treatment. No improvement was noted with the placebo (P>0.32). The clinical effect of oral l-histidine in AD was similar to that of mid-potency topical corticosteroids and combined with its safety profile suggests that it may be a safe, nonsteroidal approach suitable for long-term use in skin conditions that are associated with filaggrin deficits such as AD.

Effect of oral eicosapentaenoic acid on epidermal Langerhans cell numbers and PGD2 production in UVR-exposed human skin: a randomised controlled study.

Langerhans cells (LCs) are sentinels of skin's immune system, their loss from epidermis contributing to UVR suppression of cell-mediated immunity (CMI). Omega-3 polyunsaturated fatty acids show potential to reduce UVR suppression of CMI in mice and humans, potentially through modulation of LC migration. Our objectives were to examine whether eicosapentaenoic acid (EPA) ingestion influences UV-mediated effects on epidermal LC numbers and levels of immunomodulatory mediators including prostaglandin (PG)D2 , which is expressed by LC. In a double-blind randomised controlled study, healthy individuals took 5-g EPA-rich (n=40) or control (n=33) lipid for 12 weeks; UVR-exposed and unexposed skin samples were taken pre- and postsupplementation. Epidermal LC numbers were assessed by immunofluorescence for CD1a, and skin blister fluid PG and cytokines were quantified by LC-MS/MS and Luminex assay, respectively. Presupplementation, UVR reduced mean (SEM) LC number/mm2 from 913 (28) to 322 (40) (P<.001), and mean PGD2 level by 37% from 8.1 (11.6) to 5.1 (5.6) pg/µL; P<.001), while IL-8 level increased (P<.001). Despite confirmation of EPA bioavailability in red blood cells and skin in the active group, no between-group effect of EPA was found on UVR modulation of LC numbers, PGD2 or cytokine levels postsupplementation. Thus, no evidence was found for EPA reduction of photoimmunosuppression through an impact on epidermal LC numbers. Intriguingly, UVR exposure substantially reduced cutaneous PGD2 levels in humans, starkly contrasting with reported effects of UVR on other skin PG. Lowered PGD2 levels could reflect LC loss from the epidermis and/or altered dendritic cell activity and may be relevant for phototherapy of skin disease.

A potential role for endogenous proteins as sacrificial sunscreens and antioxidants in human tissues.

Excessive ultraviolet radiation (UVR) exposure of the skin is associated with adverse clinical outcomes. Although both exogenous sunscreens and endogenous tissue components (including melanins and tryptophan-derived compounds) reduce UVR penetration, the role of endogenous proteins in absorbing environmental UV wavelengths is poorly defined. Having previously demonstrated that proteins which are rich in UVR-absorbing amino acid residues are readily degraded by broadband UVB-radiation (containing UVA, UVB and UVC wavelengths) here we hypothesised that UV chromophore (Cys, Trp and Tyr) content can predict the susceptibility of structural proteins in skin and the eye to damage by physiologically relevant doses (up to 15.4 J/cm(2)) of solar UVR (95% UVA, 5% UVB). We show that: i) purified suspensions of UV-chromophore-rich fibronectin dimers, fibrillin microfibrils and ß- and γ-lens crystallins undergo solar simulated radiation (SSR)-induced aggregation and/or decomposition and ii) exposure to identical doses of SSR has minimal effect on the size or ultrastructure of UV chromophore-poor tropoelastin, collagen I, collagen VI microfibrils and α-crystallin. If UV chromophore content is a factor in determining protein stability in vivo, we would expect that the tissue distribution of Cys, Trp and Tyr-rich proteins would correlate with regional UVR exposure. From bioinformatic analysis of 244 key structural proteins we identified several biochemically distinct, yet UV chromophore-rich, protein families. The majority of these putative UV-absorbing proteins (including the late cornified envelope proteins, keratin associated proteins, elastic fibre-associated components and ß- and γ-crystallins) are localised and/or particularly abundant in tissues that are exposed to the highest doses of environmental UVR, specifically the stratum corneum, hair, papillary dermis and lens. We therefore propose that UV chromophore-rich proteins are localised in regions of high UVR exposure as a consequence of an evolutionary pressure to express sacrificial protein sunscreens which reduce UVR penetration and hence mitigate tissue damage.

Nutritional abrogation of photoimmunosuppression: in vivo investigations.

Skin cancer is a major public health concern, and the primary aetiological factor in the majority of skin cancers is ultraviolet radiation (UVR) exposure. UVR not only induces potentially mutagenic DNA damage but also suppresses cell-mediated immunity (CMI), allowing cancerous cells to escape destruction and progress to tumours. A considerable proportion of an individual's annual sun exposure is obtained outside the vacation period when topical and physical measures for photoprotection are irregularly used. Certain nutrients could provide an adjunctive protective role, and evidence is accruing from experimental studies to support their use in abrogation of photoimmunosuppression. Moreover, developments in clinical research methods to evaluate impact of solar-simulated radiation on cutaneous CMI allow the immune protective potential of nutritional agents to be examined in humans in vivo. This article summarises the mediation of CMI and its suppression by UVR, evaluates the methodology for quantitative assessment in vivo, reviews the human studies reported on nutritional abrogation of photoimmunosuppression including recent randomized controlled trials and discusses the mechanisms of photoprotection by the nutrients. This includes, in addition to antioxidants, novel studies of omega-3 polyunsaturated fatty acids and nicotinamide.

Damage to skin extracellular matrix induced by UV exposure.

SIGNIFICANCE: Chronic exposure to environmental ultraviolet radiation (UVR) plays a key role in both photocarcinogenesis and induction of accelerated skin aging. Although the spatiotemporal consequences of UVR exposure for the composition and architecture of the dermal extracellular matrix (ECM) are well characterized, the pathogenesis of photoaging remains poorly defined. Given the compelling evidence for the role of reactive oxygen species (ROS) as mediators of photoaging, UVR-exposed human skin may be an accessible model system in which to characterize the role of oxidative damage in both internal and external tissues. RECENT ADVANCES: Although the cell-mediated degradation of dermal components via UVR-induced expression of ECM proteases has long been identified as an integral part of the photoaging pathway, the relative importance and identity of cellular and extracellular photosensitizers (direct hit and bystanders models, respectively) in initiating this enzymatic activity is unclear. Recently, both age-related protein glycation and relative amino-acid composition have been identified as potential risk factors for photo-ionization and/or photo-sensitization. Here, we propose a selective multi-hit model of photoaging. CRITICAL ISSUES: Bioinformatic analyses can be employed to identify candidate UVR targets/photosensitizers, but the action of UVR on protein structure and/or ROS production should be verified experimentally. Crucially, in the case of biochemically active ECM components such as fibronectin and fibrillin, the downstream effects of photo-degradation on tissue homeostasis remain to be confirmed. FUTURE DIRECTIONS: Both topical antioxidants and inhibitors of detrimental cell signaling may be effective in abrogating the effects of specific UVR-mediated protein degradation in the dermis.

Photoimmunosuppression: a brief overview.

Exposure to ultraviolet radiation can lead to suppression of many adaptive immune responses, both to antigens encountered within a short period of the irradiation (primary) and to antigens previously encountered (memory). The pathways involved are complex and not completely elucidated. This brief review summarizes the information available currently regarding the multiple steps involved, with the aim of providing a general overview of the main aspects of photoimmunosuppression and its clinical consequences.

Randomized controlled trial of oral omega-3 PUFA in solar-simulated radiation-induced suppression of human cutaneous immune responses.

BACKGROUND: Skin cancer is a major public health concern, and the majority of cases are caused by solar ultraviolet radiation (UVR) exposure, which suppresses skin immunity. Omega-3 (n-3) PUFAs protect against photoimmunosuppression and skin cancer in mice, but the impact in humans is unknown. OBJECTIVES: We hypothesized that EPA-rich n-3 PUFA would abrogate photoimmunosuppression in humans. Therefore, a nutritional study was performed to assess the effect on UVR suppression of cutaneous cell-mediated immunity (CMI) reflected by nickel contact hypersensitivity (CHS). DESIGN: In a double-blind, randomized controlled study, 79 volunteers (nickel-allergic women, 22-60 y old, with phototype I or II) took 5 g n-3 PUFA-containing lipid (70% EPA plus 10% DHA) or a control lipid daily for 3 mo. After supplementation, nickel was applied to 3 skin sites preexposed on 3 consecutive days to 1.9, 3.8, or 7.6 J/cm(2) of solar-simulated radiation (SSR) and to 3 unexposed control sites. Nickel CHS responses were quantified after 72 h and the percentage of immunosuppression by SSR was calculated. Erythrocyte [red blood cell (RBC)] EPA was measured by using gas chromatography. RESULTS: SSR dose-related suppression of the nickel CHS response was observed in both groups. Photoimmunosuppression appeared less in the n-3 PUFA group than in the control group (not statistically significant [mean difference (95% CI): 6.9% (-2.1%, 15.9%)]). The difference was greatest at 3.8 J/cm(2) SSR [mean difference: 11% (95% CI: 0.5%, 21.4%)]. Postsupplementation RBC EPA was 4-fold higher in the n-3 PUFA group than in the control group (mean difference: 2.69% (95% CI: 2.23%, 3.14%), which confirmed the EPA bioavailability. CONCLUSION: Oral n-3 PUFAs appear to abrogate photoimmunosuppression in human skin, providing additional support for their chemopreventive role; verification of study findings is required. This trial was registered at clinicaltrials.gov as NCT01032343.

The 3T3 neutral red uptake phototoxicity test: practical experience and implications for phototoxicity testing--the report of an ECVAM-EFPIA workshop.

This is the report from the "ECVAM-EFPIA workshop on 3T3 NRU Phototoxicity Test: Practical Experience and Implications for Phototoxicity Testing", jointly organized by ECVAM and EFPIA and held on the 25-27 October 2010 in Somma Lombardo, Italy. The European Centre for the Validation of Alternative Methods (ECVAM) was established in 1991 within the European Commission Joint Research, based on a Communication from the European Commission (1991). The main objective of ECVAM is to promote the scientific and regulatory acceptance of alternative methods which are of importance to the biosciences and which reduce, refine and replace the use of laboratory animals. The European Federation of Pharmaceuticals Industries and Association (EFPIA) represent the pharmaceutical industry operating in Europe. Through its direct membership of 31 national associations and 40 leading pharmaceutical companies, EFPIA is the voice on the EU scene of 2200 companies committed to researching, developing and bringing to patients new medicines that improve health and the quality of life around the world. The workshop, co-chaired by Joachim Kreysa (ECVAM) and Phil Wilcox (GSK, EFPIA) involved thirty-five experts from academia, regulatory authorities and industry, invited to contribute with their experiences in the field of phototoxicology. The main objectives of the workshop were: -to present 'in use' experience of the pharmaceutical industry with the 3T3 Neutral Red Uptake Phototoxicity Test (3T3 NRU-PT), -to discuss why it differs from the results in the original validation exercise, -to discuss technical issues and consider ways to improve the usability of the 3T3 NRU-PT for (non-topical) pharmaceuticals, e.g., by modifying the threshold of chemical light absorption to trigger photo-toxicological testing, and by modifying technical aspects of the assay, or adjusting the criteria used to classify a positive response. During the workshop, the assay methodology was reviewed by comparing the OECD Test Guideline (TG 432) with the protocols used in testing laboratories, data from EFPIA and JPMA 'surveys' were presented and possible reasons for the outcomes were discussed. Experts from cosmetics and pharmaceutical industries reported on their experience with the 3T3 NRU-PT and evidence was presented for phototoxic clinical symptoms that could be linked to certain relevant molecules. Brainstorming sessions discussed if the 3T3 NRU-PT needed to be improved and whether alternatives to the 3T3 NRU-PT exist. Finally, the viewpoint from EU and US regulators was presented. In the final session, the conclusions of the meeting were summarized, with action points. It was concluded that the 3T3 NRU-PT identifies phototoxicological hazards with a 100% sensitivity, and thus is accepted as the tier one test that correctly identifies the absence of phototoxic potential. Consequently, positive results in the 3T3 NRU-PT often do not translate into a clinical phototoxicity risk. Possible ways to improve the practical use of this assay include: (i) adaptation of changed UV/vis-absorption criteria as a means to reduce the number of materials tested, (ii) reduction of the highest concentration to be tested, and (iii) consideration of modifying the threshold criteria for the prediction of a positive call in the test.

Chemical consequences of cutaneous photoageing.

Human skin, in common with other organs, ages as a consequence of the passage of time, but in areas exposed to solar ultraviolet radiation, the effects of this intrinsic ageing process are exacerbated. In particular, both the severity and speed of onset of age-related changes, such as wrinkle formation and loss of elasticity, are enhanced in photoaged (also termed extrinsically aged) as compared with aged, photoprotected, skin. The anatomy of skin is characterised by two major layers: an outer, avascular, yet highly cellular and dynamic epidermis and an underlying vascularised, comparatively static and cell-poor, dermis. The structural consequences of photoageing are mainly evident in the extracellular matrix-rich but cell-poor dermis where key extracellular matrix proteins are particularly susceptible to photodamage. Most investigations to date have concentrated on the cell as both a target for and mediator of, ultraviolet radiation-induced photoageing. As the main effectors of dermal remodelling produced by cells (extracellular proteases) generally have low substrate specificity, we recently suggested that the differential susceptibility of key extracellular matrix proteins to the processes of photoageing may be due to direct, as opposed to cell-mediated, photodamage.In this review, we discuss the experimental evidence for ultraviolet radiation (and related reactive oxygen species)-mediated differential degradation of normally long lived dermal proteins including the fibrillar collagens, elastic fibre components, glycoproteins and proteoglycans. Whilst these components exhibit highly diverse primary and hence macro- and supra-molecular structures, we present evidence that amino acid composition alone may be a useful predictor of age-related protein degradation in both photoexposed and, as a consequence of differential oxidation sensitivity, photoprotected, tissues.

Urocanic acid in the skin: a mixed blessing?

Located in the stratum corneum, urocanic acid is a major epidermal chromophore for UVR. This simple molecule has attracted a great deal of research interest over the past half century, initially as a putative "natural sunscreen" and later as a mediator of photoimmunosuppression with a consequent role in photocarcinogenesis. For the first time, Barresi and colleagues provide robust evidence for the photoprotective role of endogenous urocanic acid and reopen the debate on the relative "beneficial" and "detrimental" properties of this molecule.

Low-dose ultraviolet radiation selectively degrades chromophore-rich extracellular matrix components.

Photoageing of human skin due to chronic exposure to ultraviolet radiation (UVR) is characterized histologically by extensive remodelling of the dermal elastic fibre system. Whilst enzymatic pathways are thought to play a major role in mediating extracellular matrix (ECM) degeneration in UV-exposed skin, the substrate specificity of UVR-up-regulated and activated matrix metalloproteinases (MMPs) is low. It is unclear, therefore, how such cell-mediated mechanisms alone could be responsible for the reported selective degradation of elastic fibre components such as fibrillin-1 and fibulin-5 during the early stages of photoageing. Here we use atomic force microscopy (AFM) and scanning transmission electron microscopy (STEM) to demonstrate that physiologically attainable doses (20-100 mJ/cm(2)) of direct UV-B radiation can induce profound, dose-dependent, changes in the structure of, and mass distribution within, isolated fibrillin microfibrils. Furthermore, using reducing and native PAGE in combination with AFM, we show that, whilst exposure to low-dose UV-B radiation significantly alters the macromolecular and quaternary structures of both UV chromophore (Cys, His, Phe, Trp and Tyr)-rich fibrillin microfibrils (fibrillin-1, 21.0%) and fibronectin dimers (fibronectin, 12.9%), similar doses have no detectable effect on UV chromophore-poor type I collagen monomers (2.2%). Analysis of the published primary amino acid sequences of 49 dermal ECM components demonstrates that most elastic fibre-associated proteins, but crucially neither elastin nor members of the collagen family, are rich in UV chromophores. We suggest, therefore, that the amino acid composition of elastic fibre-associated proteins [including the fibrillins, fibulins, latent TGFbeta binding proteins (LTBPs) and the lysyl oxidase family of enzymes (LOK/LOXLs)] may predispose them to direct degradation by UVR. As a consequence, this selective acellular photochemical pathway may play an important role in initiating and/or exacerbating cell-mediated ECM remodelling in UVR-exposed skin.

Recent advances in urocanic acid photochemistry, photobiology and photoimmunology.

Urocanic acid (UCA), produced in the upper layers of mammalian skin, is a major absorber of ultraviolet radiation (UVR). Originally thought to be a 'natural sunscreen', studies conducted a quarter of a century ago proposed that UCA may be a chromophore for the immunosuppression that follows exposure to UVR. With its intriguing photochemistry, its role in immunosuppression and skin cancer development, and skin barrier function, UCA continues to be the subject of intense research effort. This review summarises the photochemical, photobiological and photoimmunological findings regarding UCA, published since 1998.

Psychologic distress in polymorphous light eruption and its relationship to patients' beliefs about their condition.

BACKGROUND: Skin disease can cause psychologic difficulties, but information is lacking on the emotional impact of the common photosensitivity condition, polymorphous light eruption (PMLE). OBJECTIVE: We sought to examine the emotional impact of PMLE, and its relationships with patients' beliefs about their PMLE and health-related variables. METHODS: Patients with PMLE who had attended a hospital dermatology department were mailed the Illness Perception Questionnaire-Revised during the summers of 2002 to 2004. RESULTS: Questionnaires were returned by 150 of 302 patients. Emotional distress attributable to PMLE was found in more than 40% of individuals. The emotional impact of PMLE was principally predicted by patients' beliefs about their condition (>50% of the variance), particularly regarding its consequences, whereas health-related variables played a lesser role. Women associated more severe consequences with their PMLE (z = -2.27, P = .02) and were more emotionally distressed (z = -2.17, P = .03) than men. LIMITATIONS: Hospital-based patients with PMLE may not be representative of the community. CONCLUSIONS: Psychologic factors should receive greater attention in PMLE management.

Selenomethionine inhibits ultraviolet radiation-induced p53 transactivation.

BACKGROUND: Ultraviolet (UV) radiation damages the cellular DNA of skin cells. In response, wild-type p53 protein accumulates in irradiated cells and the stabilized and transactivated protein can then induce genes involved in cell cycle arrest in G1, or in the initiation of apoptosis. Selenium protects cells from UVB-induced cell death and apoptosis by mechanisms which are unclear, although recent reports suggest that selenium protects against UV-induced cell damage by inducing DNA repair enzymes and transactivating p53. METHODS: We examined whether selenomethionine could protect human skin cells from UV radiation-induced p53 transactivation, using a pRGCDeltafos-lacZ p53-dependent reporter construct stably transfected in an amelanotic melanoma cell line (Arn-8) which expresses wild-type p53. Cells were pretreated with or without selenomethionine and then irradiated with broadband UVB (approximately 270-350 nm); 0-30 mJ/cm2 from a Phillips TL100 W/12 lamp. RESULTS: The percentage of cells with transcriptionally active p53 increased dose dependently up to 20 mJ/cm2 UVB. Treatment with 50 microM selenomethionine for 24 h both pre- and post-irradiation, significantly diminished p53 activation by 30-43% across the UV dose range (P=0.0085, n=5 independent experiments) and decreased UV-induced p53 protein accumulation as assessed by Western blotting. CONCLUSIONS: We conclude that selenomethionine inhibits broad band UVB-induced p53 transactivation and protein accumulation and that this effect correlates with reported protective effects of selenium against UV-induced DNA damage.

An action spectrum for the production of cis-urocanic acid in human skin in vivo.

Urocanic acid (UCA) is present at millimolar concentrations in mammalian epidermis and undergoes photoisomerization from the naturally occurring trans-isomer to the cis-isomer on exposure to ultraviolet radiation (UVR). Cis-UCA causes downregulation of various immune responses in mouse and human experimental models and has been proposed as both a chromophore and a mediator of UV-induced immune suppression. In this study, the wavelength dependence from 260-340 nm for trans to cis-UCA photoisomerization in human skin was analyzed in five healthy volunteers. The resulting action spectrum demonstrated maximal cis-UCA production in the UVB spectral region of 280-310 nm. This spectral peak is red-shifted to longer wavelengths compared with the erythemal action spectrum. The cis-UCA action spectrum can be used to predict the ability of sunscreens to protect against UVR-induced cis-UCA formation and may assist in explaining discrepancies between sunscreens' abilities to protect against erythema and photoimmunosuppression.