Michele A. Grimbaldeston

Sunlight, Immunosuppression And Skin Cancer: Role Of Histamine And Mast Cells

1. The development into tumours of skin cells transformed by ultraviolet (UV) B radiation of wavelengths 290–320 nm is enhanced by the ability of UVB to suppress an immune response that would otherwise destroy them. Ultraviolet B‐induced immunomodulation may be by multiple mechanisms, but generally manifests in an antigen‐presenting cell defect and an altered cytokine environment in the draining lymph nodes.

Mast cells, neuropeptides, histamine, and prostaglandins in UV-induced systemic immunosuppression.

There is a direct correlation between dermal mast cell prevalence in dorsal skin of different mouse strains and susceptibility to UVB-induced systemic immunosuppression; highly UV-susceptible C57BL/6 mice have a high dermal mast cell prevalence while BALB/c mice, which require considerable UV radiation for 50% immunosuppression, have a low mast cell prevalence. There is also a functional link between the prevalence of dermal mast cells and susceptibility to UVB- and cis-urocanic acid (UCA)-induced systemic immunosuppression. Mast cell-depleted mice are unresponsive to UVB or cis-UCA for systemic immunosuppression unless they are previously reconstituted at the irradiated or cis-UCA-administered site with bone marrow-derived mast cell precursors. cis-UCA does not stimulate mast cell degranulation directly. Instead, in support of studies showing that neither UVB nor cis-UCA was immunosuppressive in capsaicin-treated, neuropeptide-depleted mice, cis-UCA-stimulated neuropeptide release from sensory c-fibers which, in turn, could efficiently degranulate mast cells. Studies in mice suggested that histamine, and not tumor necrosis factor alpha (TNF-alpha), was the product from mast cells that stimulated downstream immunosuppression. Histamine receptor antagonists reduced by approximately 60% UVB and cis-UCA-induced systemic immunosuppression. Indomethacin administration to mice had a similar effect which was not cumulative with the histamine receptor antagonists. Histamine can stimulate keratinocyte prostanoid production. We propose that both histamine and prostaglandin E(2) are important in downstream immunosuppression; both are regulatory molecules supporting the development of T helper 2 cells and reduced expression of type 1 immune responses such as a contact hypersensitivity reaction.

Tea tree oil reduces the swelling associated with the efferent phase of a contact hypersensitivity response.

Abstract. Objective: To examine the anti-inflammatory activities of tea tree oil (TTO) in vivo.¶Methods: Mice were sensitized to a chemical hapten, trinitrochlorobenzene, on their ventral skin and 7 days later challenged (or re-exposed) on their dorsal skin with the same hapten.¶Results: TTO applied 30 min before or up to 7 h after to the same dorsal site as hapten challenge caused a significant reduction in skin swelling after 24 h. TTO reduced oedema but not the influx of inflammatory cells. This finding was supported by the inability of TTO to suppress TNFa-induced E-selectin expression by human umbilical vein endothelial cells. TTO did not suppress irritant- or ultraviolet B-induced oedema.¶Conclusion: Topical TTO, specifically the TTO components, terpinen-4-ol and α-terpineol can regulate the oedema associated with the efferent phase of a contact hypersensitivity response.

A Critical Role for Dermal Mast Cells in Cis-Urocanic Acid-induced Systemic Suppression of Contact Hypersensitivity Responses in Mice

Many studies have implicated cu‐urocanic acid (cu‐UCA) in UVB‐induced immunomodulation. The strongest evidence came from studies in mice whereby a cis‐UCA antibody blocked UVB‐induced suppression of de‐layed‐type hypersensitivity responses. Furthermore, in several studies, the cis‐UCA antibody at least partially reversed UVB suppression of contact hypersensitivity responses. Previous reports suggested that cis‐UCA was immunomodulatory through its effects on keratinocytes, Langerhans cells, fibroblasts, T lymphocytes, natural killer cells and monocytes/macrophages. As dermal mast cells were recently demonstrated to be critical to UVB‐induced systemic suppression of certain delayed‐type and contact hypersensitivity responses, we investigated whether they were involved in the processes by which cu‐UCA was immunomodulatory. Not only was there a correlation between dermal mast cell prevalence and the degree of susceptibility of different strains of mice to the immunomodulatory effects of cis‐UCA, there was also a functional link. Mast cell‐depleted Wf/Wf mice were rendered susceptible to immunomodulation by cis‐UCA injected subcutaneously only after their dorsal skin had been reconstituted with bone marrow‐derived mast cell precursors. These studies suggest that mast cells are critical to the processes by which cis‐UCA suppresses systemic contact hypersensitivity responses to the hapten, trinitrochlorobenzene, in mice.

AGE-RELATED CHANGES IN DERMAL MAST CELL PREVALENCE IN BALB/C MICE : FUNCTIONAL IMPORTANCE AND CORRELATION WITH DERMAL MAST CELL EXPRESSION OF KIT

Differences in dermal mast cell prevalence for adult mice of different strains have been reported previously. In this study, the dermal mast cell prevalence for BALB/c and C57BL/6 mice at 6 weeks of age was similar but as BALB/c mice matured from 6 to 10 weeks of age, their dermal mast cell prevalence halved. In contrast, there was no significant difference in the dermal mast cell prevalence of 6‐ and 10‐week‐old C57BL/6 mice. These differences determined the degree of susceptibility of BALB/c and C57BL/6 mice of different ages to UVB (UV radiation of wavelength 280–320 nm)‐induced systemic immunosuppression. Expression of the receptor for stem cell factor, Kit protein, was examined on mast cells under conditions in which the dermal mast cell prevalence varied. A significant correlation was observed between Kit expression by mast cells from adult BALB/c, DBA/2 and C57BL/6 mice and dermal mast cell prevalence. In BALB/c mice, mast cell Kit expression decreased as the mice matured from 6 to 10 weeks of age and correlated with the reduction in dermal mast cell numbers. Kit levels on dermal mast cells from C57BL/6 mice were consistently higher than on mast cells from BALB/c mice although significant reductions in Kit were also measured with ageing from 6 to 10 weeks. We hypothesize that regardless of the extent of Kit expression, the dermal mast cell populations were maximally expanded in C57BL/6 mice. We suggest that BALB/c mice of 6 and 10 weeks of age are useful hosts in which to quantitatively evaluate mast cell involvement in a range of functional assays involving skin.

The effect of ultraviolet radiation exposure on the prevalence of mast cells in human skin

Summary Background Dermal mast cells have been implicated as important effector cells in innate immunity, hypersensitivity responses and ultraviolet (UV)B‐induced suppression of cell‐mediated immune responses to contact allergens. Humans, like mouse strains, display variations in dermal mast cell prevalence. The factors determining these differences are yet to be fully elucidated. In mice, expression of the receptor for stem cell factor, c‐kit, on dermal mast cells correlates with prevalence.

TNF modulates susceptibility to UVB‐induced systemic immunomodulation in mice by effects on dermal mast cell prevalence

The mechanisms by which UV radiation is immunosuppressive are controversial, but there is growing evidence that processes of UVB‐induced suppression of the immune response towards a sensitizing antigen are different if this antigen is applied to irradiated compared with non‐irradiated sites. Consistent with this is our recent observation (Hart et al., J. Exp. Med. 1998. 187: 2045 – 2053) that the prevalence of dermal mast cells determines the extent of susceptibility of different mouse strains to UVB‐induced systemic, but not local, immunosuppression. Using C57BL/6 and BALB/c mice exposed to low and high doses of UVB, respectively, in the presence of a polyclonal anti‐TNF antibody, we found that TNF is directly involved as a mediator in the suppression by UVB of local immune responses. To determine whether TNF indirectly regulates UVB‐induced systemic immunomodulation by altering the prevalence of dermal mast cells, dermal mast cell numbers in gene‐targeted mice deficient in TNF or TNF receptors (p55/p75  −/‐ mice) were quantified by video image analysis. A reduced dermal mast cell prevalence in these mice correlated with decreased susceptibility for systemic immunosuppression caused by UVB. We hypothesize that TNF is one molecule that controls dermal mast cell prevalence by as yet unknown mechanisms. However, it is the mediators released from mast cells upon UVB‐induced degranulation, which do not include TNF, that directly signal suppressive events relevant to systemic immunosuppression.

Increased dermal mast cell prevalence and susceptibility to development of basal cell carcinoma in humans.

Exposure to ultraviolet B (UVB) radiation (280-320 nm) is the primary etiologic factor associated with the development of basal cell carcinoma (BCC). The outgrowth of these keratinocyte-derived skin lesions is enhanced by the ability of UVB to impair an immune response that would otherwise eliminate them. Studies in a range of inbred mouse strains as well as mast cell-depleted mice reconstituted with mast cell precursors support a functional link between histamine-staining dermal mast cells and the extent of susceptibility to UVB-induced systemic immunomodulation. Humans, like mouse strains, display variations in dermal mast cell prevalence. In a study of Danish and South Australian BCC patients and control subjects, one 4-mm punch biopsy of non-sun-exposed buttock skin was sampled from each participant. This skin site was investigated to avoid any changes in mast cell prevalence caused by sun exposure. Two sections (4 microm) per biopsy were immunohistochemically stained for detection of histamine-containing dermal mast cells. Computer-generated image analysis evaluated dermal mast cell prevalence in both sections by quantifying the total number of mast cells according to the total dermal area (expressed as mast cells per square millimeter). This technique enabled us to detect heterogeneity of dermal mast cell prevalence in buttock skin between individuals and provided evidence of an association between high dermal mast cell prevalence and BCC development in two diverse populations. We hypothesize that mast cells function in humans, as in mouse strains, by initiating immunosuppression following UV irradiation and, thereby, allowing a permissive environment for the development of BCC. Thus, a high dermal mast cell prevalence as demonstrable in buttock skin is a significant predisposing factor for development of BCC in humans.

Susceptibility to Basal Cell Carcinoma is Associated with High Dermal Mast Cell Prevalence in Non–sun-exposed Skin for an Australian Population¶

Abstract In a Danish population, basal cell carcinoma (BCC) patients have a higher dermal mast cell prevalence in buttock skin than controls. This finding was supported by a functional link in mice between histamine-staining dermal mast cells and the extent of susceptibility to UV-B–induced systemic immunomodulation. It was important to confirm that this association was maintained in an Australian population with very different ancestry and sun exposure patterns. Australian BCC patients (n = 26) had significantly higher densities of mast cells in the dermis of buttock skin than control subjects (n = 25) (P = 0.0003, Mann–Whitney U-test). However, this correlation was lost at the sun-exposed site of the hand (P = 0.547, Mann–Whitney U-test). To further evaluate whether a relationship exists between dermal mast cell prevalence in sun-exposed skin and incidence of BCC in a larger study, biopsies of dorsal hand skin were obtained from an age-stratified random sample of 166 Queensland subjects, together with the 51 South Australian subjects, and dermal mast cell prevalence was quantified. Older subjects (over the median age of 42 years) had a greater incidence of BCC development (P = 0.0001, chi-square test) and significantly higher mast cell densities in hand skin (P = 0.0001, chi-square test) than younger subjects. However, mast cell density in sun-exposed hand skin was not significantly associated with BCC incidence. Finally, cellular expression of c-kit correlated with mast cell prevalence in non–sun-exposed skin, thereby implicating the stem cell factor–c-kit axis in the intrinsic mechanisms that regulate prevalence. These results show that high prevalence of dermal mast cells in buttock skin but not hand is associated with BCC development in an Australian population.