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Biomedical subjects

M Norval

Publications and source records attributed to M Norval.

At least 37 records · Page 2Linked to original sources
PubMed1999

Isomerization of urocanic acid after ultraviolet radiation is influenced by skin pigmentation.

Exposure to ultraviolet (UV) radiation may induce erythema, DNA damage and suppression of immune responses. Melanin pigmentation offers protection against the first two of these effects, but immunosuppression seems to occur irrespective of the subject's pigmentation. Cis-urocanic acid (cis-UCA), produced by isomerization of trans-UCA in the stratum corneum on UV exposure, initiates some of the immunomodulatory effects of UV radiation. In the present study the relationship between skin pigmentation and UCA isomerization has been examined in 28 healthy individuals of skin types I-IV. Pigmentation is measured in five areas of not recently exposed back skin before irradiation with 0, 0.45, 0.9, 1.8 and 3.6 standard erythema dose (SED) of filtered broadband UV-B (1 SED = 10 mJ cm-2 at 298 nm). The concentration of UCA isomers is measured immediately after the irradiation. With 3.6 SED, the relative production of cis-UCA is close to the maximum obtainable, irrespective of skin type. A significant negative correlation is found between pigmentation and relative production of cis-UCA at 0.45 and 1.8 SED, and between pigmentation and absolute production of cis-UCA at 0.45 SED. At doses of 0.45 and 0.9 SED the relative and absolute production of cis-UCA are higher in the group with skin types I and II when compared with the group with skin types III and IV. The higher isomerization in the lightly pigmented subjects than in the more pigmented ones may indicate that people with fair skin are at a relatively higher risk of immunosuppression when exposed to low doses of UV radiation.

Adolescent↗
PubMed1999

The effects of ultraviolet radiation on the human immune system.

The adverse outcome of increased ultraviolet (UV) irradiation on human health is currently of concern. While many experiments have been carried out in rodent models, fewer have been designed to test the effects of UV exposure in human subjects. This review concentrates on the modulations induced in the human immune system by UV, and outlines changes in antigen presentation by Langerhans cells and macrophages, in the activities of natural killer cells and T cells, and in cytokine regulation. Precautionary measures which might be taken to help protect people against the immunosuppressive action of UV irradiation are considered.

Animals↗
PubMed1999

The role of urocanic acid in UVB-induced suppression of immunity to Trichinella spiralis infection in the rat.

The naturally occurring trans-isomer of urocanic acid (trans-UCA), found in the stratum corneum, absorbs ultraviolet light (UV) and isomerizes to the cis-form. Cis-UCA has been shown to impair some cellular immune responses, and has been proposed as an initiator of the suppression that follows UV irradiation. UVB exposure leads to an increase in cis-UCA in the skin of rats from about 10% to 40% of the total UCA. Previously it has been demonstrated that UVB lowers immune responses to Trichinella spiralis after oral infection of rats with the parasitic worm. In the present study we investigated the role of cis-UCA in the control of this parasitic infection. Rats were infected orally with T. spiralis and injected with different doses of cis- or trans-UCA subcutaneously. Mitogenic responses and the mixed lymphocyte reaction were not affected by either isomer. In contrast, the number of T. spiralis larvae in muscle tissue of infected rats was increased significantly in the cis-UCA-treated animals compared with the trans-UCA-treated animals. In addition, delayed-type hypersensitivity (DTH) to T. antigen in infected rats was significantly impaired by cis-UCA but not by trans-UCA. If rats were injected with a monoclonal antibody with specificity for cis-UCA 2 hr prior to UVB exposure, the UVB-induced suppression in DTH to T. spiralis and the increase in larvae counts were significantly inhibited compared with rats that were similarly injected with a control antibody. Thus cis-UCA can inhibit the specific resistance to parasitic infections and acts as an important mediator of UVB-induced suppression of immunity to T. spiralis in the rat.

Analysis of Variance↗
PubMed1999

The UV waveband dependencies in mice differ for the suppression of contact hypersensitivity, delayed-type hypersensitivity and cis-urocanic acid formation.

Solar radiation contains ultraviolet B (280-315 nm) and ultraviolet A (ultraviolet AII, 315-340 nm; ultraviolet AI, 340-400 nm) wavebands. Ultraviolet B is known to suppress certain aspects of cell mediated immunity. Using three ultraviolet lamps (the broad-band ultraviolet B TL-12, the narrow-band ultraviolet B TL-01 and an ultraviolet AI source), we investigated the dose and waveband dependencies for the suppression of contact hypersensitivity to oxazolone and delayed-type hypersensitivity to herpes simplex virus, plus the formation of cis-urocanic acid in C3H/HeN mice. A single exposure of 1500 J/m2 TL-12 or 10,000 J/m2 TL-01 or 500,000 J/m2 ultraviolet AI corresponded to 1 minimum erythema dose in this mouse strain. The percentage of cis-urocanic acid of the total urocanic acid rose from a background level of 1.7% to 40% with 1000 J/m2 TL-12 or 10,000 J/m2 TL-01, but only 17% cis-urocanic acid was obtained with 500,000 J/m2 ultraviolet AI. The contact hypersensitivity response was significantly suppressed after a minimum dose of 5000 J/m2 TL-12 or 50,000 J/m2 TL-01 or 500,000 J/m2 ultraviolet AI. The delayed-type hypersensitivity response was suppressed by a minimum dose of 100 J/m2 TL-12 or 10,000 J/m2 TL-01 or 1000 J/m2 ultraviolet AI. So, whereas a low dose of ultraviolet AI reduced the delayed-type hypersensitivity response, a 500-fold higher dose was required to suppress contact hypersensitivity. There was no correlation between the suppression of these responses and the concentration of cis-urocanic acid in the skin. Thus different mediators may modulate the various immune responses affected by ultraviolet exposure, depending on the wavelength of the radiation.

Animals↗
PubMed1999

Sunscreen protection against cis-urocanic acid production in human skin.

Commercial sunscreens may offer some protection from immunosuppression induced by ultraviolet (UV) radiation, but agreement concerning the degree of protection is lacking. Cis-urocanic acid, formed by the photoisomerization of transurocanic acid is considered an important mediator of the cutaneous immunomodulation resulting from exposure to UV radiation. We investigated the effect of sunscreens on the isomerization of urocanic acid in 17 human subjects. Two sunscreens containing chemical filters, sun protection factor (SPF) 4 and SPF 10, and a SPF 10 sunscreen with a physical filter were applied at a thickness of 2 mg/cm2. The effect of a thin layer (0.5 mg/cm2) of the chemical SPF 10 sunscreen was also evaluated, as the amount of sunscreen applied in practice may be considerably less than recommended. All areas were irradiated with a single UV dose of 3.6 SED (standard erythema doses). In irradiated unprotected skin the median net production of cis-urocanic acid was 52% (relative amount). In the sites treated with the chemical sunscreens, the production of cis-urocanic acid was 7.4% (SPF 4) and 3.5% (SPF 10), and isomerization was thus reduced more efficiently at a higher SPF (p<0.01). The physical sunscreen reduced the formation of cis-UCA to 15%, and was significantly less effective than both the chemical SPF 10 sunscreen (p<0.01) and the SPF 4 sunscreen (p<0.01). The production of cis-urocanic acid in the area treated with the thin layer of the chemical SPF 10 sunscreen was 22%. The protection against the production of cis-urocanic acid was therefore reduced significantly (p<0.01) when the sunscreen was applied in an amount lower than recommended.

Administration, Cutaneous↗
PubMed1999

UV-induced changes in the immune response to microbial infections in human subjects and animal models.

Exposure to UV is a recognised risk factor for skin cancer and it also induces immunosuppression to a variety of antigens encountered following the irradiation. The latter property has been demonstrated in rodent models of infections with the microbial agents including viruses, bacteria, protozoa and helminths. In the majority of cases the severity of the symptoms and the microbial load in the host are increased as a result of the immunomodulation. UV can also affect the pathogenesis of some natural microbial infections of human subjects, such as causing recrudescence of herpes simplex virus and contributing to the oncogenic potential of papillomaviruses. Sufficient data have been generated from the animal models to construct a risk assessment in humans for suppression of microbial immune responses induced by sunlight exposure. This estimation requires verification from epidemiological studies and from further work to assay modulation in human immunity to particular pathogens experienced before and after the UV radiation.

Animals↗
PubMed1998

Estimation of the effect of increasing UVB exposure on the human immune system and related resistance to infectious diseases and tumours.

Exposure to UV light has, besides some beneficial effects (vitamin D production), many harmful effects on human health. UVB irradiation has been shown to suppress both systemic and local immune responses to a variety of antigens, including some microorganisms. However, it is still not known whether such immunomodulating effects may lead to an increase in the number and severity of certain tumours and/or infections in humans. We report herein the data provided by a project that was funded by the European Union (Programme Environment), and that was aimed at the estimation of the risk associated with increased UVB exposure due to ozone depletion regarding the deleterious effects on the immune system and related resistance to tumours and infections in humans. The data, obtained by the different research groups involved, were assembled and used to calculate for the first time a risk assessment for increased environmental exposure to UVB in human subjects.

Animals↗
PubMed1998

Differential effect of phototherapy on the activities of human natural killer cells and cytotoxic T cells.

Exposure to ultraviolet B (UV-B) light is recognized to induce suppression of certain immune responses, particularly delayed hypersensitivity. However, its effect on cytotoxic T lymphocyte (CTL) activity, of major importance in the resistance to viruses and tumours, has not been assessed to the same extent. In this study five normal subjects, seropositive for herpes simplex virus (HSV), underwent a standard course of broadband UV-B therapy, as used in the treatment of psoriasis. They received whole-body irradiation thrice weekly for four weeks with incremental doses dependent on skin type. Blood samples were taken immediately before, at two time points during, and at the end of the therapy. An HSV-specific CTL assay was performed using autologous B cells transformed with Epstein-Barr virus as targets. No consistent modulation in CTL activity was obtained as a result of the therapy. The CTLs were separated into CD4 and CD8 subsets by positive selection and, again, no effect of irradiation on CTL activity within each of these two populations was observed. In contrast, the natural killer (NK) cell activity, assessed by the lysis of K562 cells, was significantly reduced at the first time point after the initiation of the phototherapy in all five subjects, and it continued to decline as the treatment progressed. Thus a differential effect of UV-B exposure on cytotoxic activity has been demonstrated: the HSV-specific CTL response is unchanged, while the NK response is suppressed.

Adult↗
PubMed1998

Contrasting effects of ultraviolet A1 and ultraviolet B exposure on the induction of tumour necrosis factor-alpha in human skin.

Ultraviolet B (UVB) irradiation of the skin causes immunosuppression which is relevant to the induction of skin cancer. The mechanism of this immunomodulation is unclear but various regulatory molecules have been implicated, including cis-urocanic acid (cis-UCA) and the cytokines tumour necrosis factor-alpha (TNF-alpha) and interleukin 10 (IL-10). Whether ultraviolet A (UVA) induces similar changes has not been investigated fully. We studied the effect of in vivo UVB and long-wave UVA (UVA1) exposure on the induction of TNF-alpha, IL-10 and cis-UCA in human skin. Volunteers were irradiated with three minimal erythema doses (MED) of UVB or UVA1. At different times after irradiation, suction blisters were raised from irradiated and from non-irradiated (control) skin. The TNF-alpha and IL-10 protein concentration, and the percentage of cis-UCA in the blister fluid, were then determined. UVB irradiation of human skin led to a rapid and significant increase in TNF-alpha concentration in suction-blister fluid, with maximal values 6 h after irradiation (n = 6, P < 0.05). In contrast, UVA1 irradiation led to a decrease in TNF-alpha concentration in the suction-blister fluid compared with non-irradiated skin, with the lowest values 6 h after irradiation (n = 6, P < 0.05). Both UVB and UVA1 exposure of the skin induced a slight increase in IL-10 concentration. However, the increase in IL-10 was only significant after UVB irradiation (UVB, n = 6, P < 0.05; UVA, n = 7, P < 0.1). As previously shown, both UVB and UVA1 result in the photo-isomerization of trans-UCA and an increased percentage of cis-UCA was found in the suction-blister fluid. Thus the results show differential effects of UVB and UVA1 irradiation on the induction of immunoregulatory molecules, which may help to explain the variation in immune responses after UVB and UVA1 exposure of human skin.

Adult↗
PubMed1998

Urocanic acid isomers in patients with basal cell carcinoma and cutaneous malignant melanoma.

Urocanic acid (UCA) is a major chromophore for ultraviolet (UV) radiation in the skin. On UV exposure, the naturally occurring trans-isomer converts to the cis-isomer in a dose-dependent manner. Accumulating evidence indicates that cis-UCA acts as an initiator of the UV-induced suppression of certain skin immune functions. This immunomodulation is recognized as an important factor in the development of skin cancer. In this study, pigmentation and UCA isomers were measured in 29 patients with previous basal cell carcinoma (BCC), 23 patients with previous cutaneous malignant melanoma (MM), and 32 healthy controls. Measurements were performed on UV-exposed (forehead, upper back) and UV non-exposed (buttock) skin. No significant differences in pigmentation percentage, total UCA concentration, relative (%) or absolute (nmol/cm2) cis-UCA concentration were observed between the groups in any of the body sites studied. The net production of cis-UCA after irradiation with a single test UV dose was evaluated. The relative production of cis-UCA following irradiation was significantly higher in both cancer groups when compared with the control group, while no significant difference was found between the BCC and the MM patients.

Adult↗
PubMed1998

Urocanic acid isomers and photosensitivity in healthy children.

Episodes of intense sun exposure, particularly in childhood, seem to carry a risk for the development of malignant melanoma in later life. However, little is known about photosensitivity and natural photoprotection in children. In adult subjects, photoprotection is provided mainly by the epidermal content of melanin and the thickness of the stratum corneum, while the amount of urocanic acid (UCA), a major ultraviolet-absorbing component of the stratum corneum, is not thought to contribute significantly to photoprotection. The minimal erythema dose (MED) was determined in 22 healthy children aged 6-13 years and in 36 healthy adults (mean age 28.1 years). Pigmentation was measured at six body sites by use of reflectance spectroscopy and the concentration of UCA isomers was measured in a sun-exposed area (upper back) and in unexposed buttock skin. No significant differences between children and adults were found, either in pigmentation at exposed and unexposed body sites, or in MED. The concentration of total UCA was significantly higher in the children than in the adults on the buttock (median 22.2 vs. 13.6 nmol/cm2), but not on the back. On exposed back skin, the children had a significantly higher percentage of cis-UCA than the adults (median 60.1 vs. 28.3%), while no difference was found on the buttock. In both groups, a significant correlation was found between pigmentation and MED (children: Spearman correlation coefficient 0. 58, P = 0.006; adults: Spearman correlation coefficient 0.69, P < 0. 0001), indicating that pigmentation is of major importance in determining photosensitivity in children as well as in adults. The concentration of total UCA did not correlate with the MED in either group.

Adolescent↗
PubMed1998

The effect of UVB irradiation on antibody responses during herpes simplex virus type 1 (HSV-1) infections of mice.

Ultraviolet B (UVB) exposure suppresses cell-mediated immunity and may alter the cytokine profile, reducing T helper 1 (Th1) cytokines and promoting Th2 cytokines. Th1 cytokines enhance the production of immunoglobulin (Ig) G2a, IgG2b and IgG3 antibodies, while Th2 cytokines enhance the production of IgG1 and IgE antibodies. The effect of suberythemal UVB irradiation on antibody isotypes following infection of C3H/HeN mice with herpes simplex virus (HSV) was investigated using two protocols. First, mice were irradiated prior to two subcutaneous infections with HSV. Second, mice were immunised with inactivated HSV before being irradiated and challenged epidermally with HSV, which led to an increase in the size of the clinical lesions compared with unirradiated animals. In both models, the HSV-specific IgG titre was not affected by the UVB exposure but, generally, the irradiated animals showed a small reduction in both Th1- and Th2-associated HSV antibody isotypes. IL-4 knockout (IL-4-/-) mice were used to investigate the role of IL-4 in UVB-induced isotype switching. Here IL-4-/- and IL-4+/+ strains were irradiated prior to primary and secondary epidermal infections with HSV, followed by measurement of antibody titres and lesion size. In both the mutant and parent mice, UV irradiation led to an increase in lesion severity. In IL-4+/+ mice, UV exposure did not affect the HSV titre of any of the individual isotypes tested but did suppress the total IgG to HSV This suppression may be due to UV-induced IL-4 release because, in the IL-4-/- mice, HSV IgG was elevated by the UVB irradiation. If UV modulates the immune response solely via the action of cytokines, then the downregulation of Th1 cytokines and upregulation of Th2 cytokines should be accompanied by antibody isotype switching from IgG2a and IgG3 towards IgG1 and IgE. This result was not obtained in the models tested, perhaps because HSV infection promotes such a complex array of innate and acquired immune responses that a clear effect on virus-specific isotype production may not be apparent.

Animals↗
PubMed1998

Lack of association between interleukin-6 production by contact allergen-activated draining lymph node cells and lymphoproliferative activity.

BACKGROUND: Previous investigations in BALB/c strain mice have revealed that, after skin sensitization, draining lymph node cells (LNC) produce high levels of interleukin 6 (IL-6) and that the secretion of this cytokine correlates closely with the proliferative activity of LNC. The main source of IL-6 within draining lymph nodes was found to be dendritic cells (DC), most of which derive from epidermal Langerhans cells. OBJECTIVE: To explore further the relationship between DC-derived IL-6 production in lymph nodes, LNC proliferative activity, and the development of contact sensitization, comparisons between BALB/c and C3H/HeN strains of mice have been conducted. METHODS: Contact sensitizing potential was measured in both strains of mice as a function of lymphocyte proliferative responses (assessed by the incorporation of radiolabelled thymidine) and challenge-induced increases in ear thickness. The concentration of IL-6 in skin homogenates and the production of IL-6 by allergen-activated LNC were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: In both strains of mouse, topical exposure to oxazolone, a potent contact allergen, induced a vigorous proliferative response by draining LNC and the development of skin sensitization. However, under these conditions of exposure, activated LNC prepared from mice of C3H/HeN strain failed to secrete substantial amounts of IL-6, the levels of this cytokine being on average some 20- to 40-fold less than those measured in BALB/c mice. The failure of LNC from C3H/HeN mice to secrete comparable levels of IL-6 was not attributable to a reduced ability of DC to accumulate in draining lymph nodes after skin sensitization. Nor did reduced IL-6 secretion by C3H/HeN LNC reflect a systemic inability to elaborate this cytokine. Epicutaneous exposure of C3H/HeN mice to oxazolone resulted in the induction of cutaneous IL-6 at levels similar to, or greater than, those observed after identical treatment of BALB/c strain mice. CONCLUSIONS: The conclusion drawn is that there does not exist a universal association between IL-6 production in draining lymph nodes and the vigor of proliferative responses by LNC. Further, cutaneous immune responses and skin sensitization may proceed apparently normally in the absence of high levels of IL-6 production by lymph node cells.

Allergens↗
PubMed1997

Urocanic acid isomers: relation to body site, pigmentation, stratum corneum thickness and photosensitivity.

Urocanic acid (UCA), present in the stratum corneum as trans-UCA, absorbs ultraviolet (UV) radiation and isomerizes to cis-UCA. Cis-UCA has been demonstrated to initiate suppression of selected immune responses in several experimental systems. Topical application of UCA-containing products reduces UV-induced erythema, but a role for endogenous UCA in photoprotection has not been reported. In this study the relationship between UCA isomers, pigmentation, minimal erythema dose (MED), and stratum corneum thickness was investigated. Pigmentation, concentration of total UCA, and the percentage present as the cis-isomer was measured in 36 healthy subjects, skin type I-IV, at six UV-exposed and nonexposed body sites: forehead, chest, back, outer upper arm, inner upper arm, and buttock. The MED was determined by phototesting on buttock skin, and a punch biopsy for measurement of stratum corneum thickness was taken adjacent to the site of the phototest. The percentage of cis-UCA was significantly higher in UV-exposed than on nonexposed areas. A small intraindividual variation in total UCA was found, being high on the buttock and the arm, lowest on the forehead. The subject to subject variation of total UCA was considerable at all body sites. No correlation was found between total UCA and MED, skin type, pigmentation, or stratum corneum thickness.

Adolescent↗
PubMed1997

Biological effects of narrow-band (311 nm TL01) UVB irradiation: a review.

The narrow-band UVB (TL01) lamp (311 nm emission) was developed for use in phototherapy, as an alternative to a broad-band UVB source and to photochemotherapy, both of which have significant side effects and carry a risk of carcinogenesis. This new lamp has proved to be particularly effective at clearing psoriasis. It is now acknowledged that the TL01 lamp is probably 2-3 times more carcinogenic per minimum erythema dose than broad-band UVB, but the cumulative dose required in therapy is considerably less than when using broad-band UVB sources. In terms of irradiation dose, the TL01 lamp is about 5-10-fold less potent than broad-band UVB for erythema induction, hyperplasia, oedema, sunburn cell formation and Langerhans cell depletion from skin. However, the broad-band UVB to TL01 potency ratio for cis-urocanic acid formation in the skin is approximately unity. In addition, the TL01 lamp, as used in phototherapy, has relatively more suppressive effects than broad-band UVB on systemic immune responses as judged by natural killer cell activity, lymphoproliferation and cytokine responses. However, the TL01 lamp is less effective at reducing epidermal antigen presentation, inducing dendritic cell migration to lymph nodes draining irradiated sites and suppressing contact hypersensitivity at the doses tested. Therefore the use of the TL01 lamp in phototherapy should be considered carefully after weighing up its diverse effects on the skin and immune system.

Animals↗