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. 2. Immune responses to microbial or self-antigens may be dysfunctional by similar mechanisms following UVB exposure. 3. Earliest-acting intermediates in the initiation of UVB-induced immunosuppression are the UVB absorbers (photoreceptors) of the skin, notably DNA resulting in immunoregulatory cytokine production, and trans-urocanic acid (UCA), which, upon isomerization to its cis isomer, signals downstream immunosuppressive events. 4. In mice, dermal mast cells are critical to UVB-induced systemic immunomodulation. In mice, there is a functional link as well as a linear relationship between the prevalence of histamine-staining dermal mast cells and the log of the dose of UVB required for 50% immunosuppression. Studies with histamine receptor antagonists support histamine as the main' product of mast cells involved. Histamine acts in large part via a prostanoid-dependent pathway. 5. Approximately 50% of humans and greater than 90% of patients with non-melanoma skin cancer are UVB susceptible for suppression of a contact hypersensitivity response. Neither cytokine polymorphisms nor UVB-induced levels of cis-UCA in irradiated skin have been linked to UVB susceptibility. Patients with basal cell carcinomas (BCC) have an increased dermal mast cell prevalence in non-sun-exposed buttock skin. We propose that mast cells function in humans, as in mice, by initiating immunosuppression and, thereby, allowing a permissive environment for BCC development.
Hart
P H
PH
Department of Microbiology and Infectious Diseases, School of Medicine, Flinders University, Adelaide, South Australia, Australia. prue.hart@flinders.edu.au
Grimbaldeston
M A
MA
Finlay-Jones
J J
JJ
D000818:Animals; D002280:Basal Cell Carcinoma / Q000276:immunology* / Q000378:metabolism; D003877:Dermatitis, Contact / Q000276:immunology* / Q000378:metabolism; D006632:Histamine / Q000276:immunology / Q000378:metabolism / Q000528:radiation effects*; D006801:Humans; D007165:Immunosuppression Therapy; D008407:Mast Cells / Q000276:immunology / Q000378:metabolism / Q000528:radiation effects*; D051379:Mice; D009381:Neoplasms, Radiation-Induced / Q000276:immunology* / Q000378:metabolism; D012878:Skin Neoplasms / Q000276:immunology* / Q000378:metabolism; D014466:Ultraviolet Rays / Q000009:adverse effects*
D006632:Histamine