Gw Dandie

Ultraviolet light induced injury: Immunological and inflammatory effects

This article reviews many of the complex events that occur after cutaneous ultraviolet (UV) exposure. The inflammatory changes of acute exposure of the skin include erythema (sunburn), the production of inflammatory mediators, alteration of vascular responses and an inflammatory cell infiltrate. Damage to proteins and DNA accumulates within skin cells and characteristic morphological changes occur in keratinocytes and other skin cells. When a cell becomes damaged irreparably by UV exposure, cell death follows via apoptotic mechanisms. Alterations in cutaneous and systemic immunity occur as a result of the UV‐induced inflammation and damage, including changes in the production of cytokines by keratinocytes and other skin‐associated cells, alteration of adhesion molecule expression and the loss of APC function within the skin. These changes lead to the generation of suppressor T cells, the induction of antigen‐specific immunosuppression and a lowering of cell‐mediated immunity. These events impair the immune systems capacity to reject highly antigenic skin cancers. This review gives an overview of the acute inflammatory and immunological events associated with cutaneous UV exposure, which are important to consider before dealing with the complex interactions that occur with chronic UV exposure, leading to photocarcinogenesis.

The migration of Langerhans' cells into and out of lymph nodes draining normal, carcinogen and antigen-treated sheep skin.

Epidermal Langerhans’ cell (LC) migration to the regional lymph node and beyond into central lymph was examined in sheep following topical application of the complete chemical carcinogen 7,12‐dimethylbenz(a)anthracene(DMBA)or the contact sensitizing antigen 2,4,6‐trinitrochlorobenzene (TNCB). This was facilitated by cannulating previously constructed pseudoafferent lymphatic vessels draining the skin treated with these agents or alternatively, the efferent lymphatic vessel of the regional lymph node.

Effects of UV on the migration and function of epidermal antigen presenting cells

Depletion of epidermal Langerhans cells (LC) and the concomitant depression of the skin immune system after excessive exposure to ultraviolet B light (UVB) has been established in the international literature for some time. Our investigations were intended to determine whether or not these phenomena occurred as a direct result of increased LC migration being triggered by the UVB exposure. To test this hypothesis, a sheep model was established in which the lymphatic vessels draining a defined region of skin were cannulated and the cells migrating towards the regional lymph node continuously collected. Cell populations in these collections were identified and enumerated by indirect immunofluorescence and flow cytometry. These experiments showed there was a significant, dose-dependent increase in the rate of LC migration from sheep skin after exposure to doses of UVB light exceeding 1 minimal erythemal dose (MED). In a series of parallel experiments, the functional characteristics of dendritic cells (DC) migrating from normal or UVB irradiated sheep were studied. To assay them, enriched preparations of DC were collected via cannulated afferent lymphatic vessels and pulsed with antigen prior to incubation with autologous peripheral blood lymphocytes. The relative efficiency of antigen presentation was determined by the ability of DC to induce T cell proliferation. Our data clearly demonstrate that there is a profound loss of normal antigen-presenting cell function after exposure to UVB light. Various experiments were undertaken to determine the mechanism(s) associated with these changes in migration kinetics and cellular function. Electron microscopic examinations of LC migrating from normal or UVB irradiated skin have demonstrated a profound loss of dendritic processes after UVB exposure. This provides a possible explanation for the changes in skin immunity after UVB exposure.

Migration of Langerhans cells and γδ + dendritic cells from UV-B-irradiated sheep skin

Depletion of dendritic cells from UV‐B‐irradiated sheep skin was investigated by monitoring migration of these cells towards regional lymph nodes. By creating and cannulating pseudoafferent lymphatic vessels draining a defined region of skin, migrating cells were collected and enumerated throughout the response to UV‐B irradiation. In the present study, the effects of exposing sheep flank skin to UV‐B radiation clearly demonstrated a dose‐dependent increase in the migration of Langerhans cells (LC) from the UV‐B‐exposed area to the draining lymph node. The range of UV‐B doses assessed in this study included 2.7 kJ/m2, a suberythemal dose; 8 kJ/m2, 1 minimal erythemal dose (MED); 20.1 kJ/m2; 40.2 kJ/m2; and 80.4 kJ/m2, 10 MED. The LC were the cells most sensitive to UV‐B treatment, with exposure to 8 kJ/m2 or greater reproducibly causing a significant increase in migration. Migration of γδ+ dendritic cells (γδ+ DC) from irradiated skin was also triggered by exposure to UV‐B radiation, but dose dependency was not evident within the range of UV‐B doses examined. This, in conjunction with the lack of any consistent correlation between either the timing or magnitude of migration peaks of these two cell types, suggests that different mechanisms govern the egress of LC and γδ+ DC from the skin. It is concluded that the depression of normal immune function in the skin after exposure to erythemal doses of UV‐B radiation is associated with changes in the migration patterns of epidermal dendritic cells to local lymph nodes.

Migration of Langerhans cells and gammadelta dendritic cells from UV-B-irradiated sheep skin.

Depletion of dendritic cells from UV‐B‐irradiated sheep skin was investigated by monitoring migration of these cells towards regional lymph nodes. By creating and cannulating pseudoafferent lymphatic vessels draining a defined region of skin, migrating cells were collected and enumerated throughout the response to UV‐B irradiation. In the present study, the effects of exposing sheep flank skin to UV‐B radiation clearly demonstrated a dose‐dependent increase in the migration of Langerhans cells (LC) from the UV‐B‐exposed area to the draining lymph node. The range of UV‐B doses assessed in this study included 2.7 kJ/m2, a suberythemal dose; 8 kJ/m2, 1 minimal erythemal dose (MED); 20.1 kJ/m2; 40.2 kJ/m2; and 80.4 kJ/m2, 10 MED. The LC were the cells most sensitive to UV‐B treatment, with exposure to 8 kJ/m2 or greater reproducibly causing a significant increase in migration. Migration of γδ+ dendritic cells (γδ+ DC) from irradiated skin was also triggered by exposure to UV‐B radiation, but dose dependency was not evident within the range of UV‐B doses examined. This, in conjunction with the lack of any consistent correlation between either the timing or magnitude of migration peaks of these two cell types, suggests that different mechanisms govern the egress of LC and γδ+ DC from the skin. It is concluded that the depression of normal immune function in the skin after exposure to erythemal doses of UV‐B radiation is associated with changes in the migration patterns of epidermal dendritic cells to local lymph nodes.

Dendritic Cells Migrating from Carcinogen-Treated Skin Have Reduced Antigen-Presenting Function

Chemical carcinogens have a recognised ability to reduce the status of cutaneous immunity. Antigen presentation through carcinogen-treated skin results in immune suppression rather than activation of effector mechanisms (reviewed by 1). Topical application of the complete chemical carcinogen 7,12-dimethylbenz[a]anthracene (DMBA) leads not only to the development of skin tumours but also induces a rapid depletion of Langeihans cells (LC) from the epidermis - up to 50% of the LC are depleted from the epidermis in the 3–4 days following DMBA application2.

Down-regulation of an Established Immune Response via Chemical Carcinogen or UVB-Altered Skin

The ability to produce antigen‐specific down‐regulation of an established immune response was investigated in 2,4,6‐trinitrochlorobenzene (TNCB)‐immune mice by delivery of antigen through chemical carcinogen‐ or ultraviolet B (UVB)‐treated skin. When TNCB‐immune mice were treated on the dorsal trunk skin with 7,12‐dimethylbenz(a)anthracene (DMBA) followed by TNCB there was an antigen‐specific reduction in both contact sensitivity and antibody production. Further, immune mice that received spleen cells from naive syngeneic donors treated with DMBA followed by TNCB also exhibited a reduction in both contact sensitivity and antibody production. In contrast, mice treated with UVB irradiation followed by TNCB had a reduction in contact sensitivity but not antibody production. These results provide evidence that an ongoing immune response can be manipulated by immunization through a modified skin immune system. This may provide a beneficial approach for the treatment of autoimmune disease.

Migration of Langerhans cells and |[ggr]||[dgr]||[plus]| dendritic cells from UV-B-irradiated sheep skin

Depletion of dendritic cells from UV‐B‐irradiated sheep skin was investigated by monitoring migration of these cells towards regional lymph nodes. By creating and cannulating pseudoafferent lymphatic vessels draining a defined region of skin, migrating cells were collected and enumerated throughout the response to UV‐B irradiation. In the present study, the effects of exposing sheep flank skin to UV‐B radiation clearly demonstrated a dose‐dependent increase in the migration of Langerhans cells (LC) from the UV‐B‐exposed area to the draining lymph node. The range of UV‐B doses assessed in this study included 2.7 kJ/m2, a suberythemal dose; 8 kJ/m2, 1 minimal erythemal dose (MED); 20.1 kJ/m2; 40.2 kJ/m2; and 80.4 kJ/m2, 10 MED. The LC were the cells most sensitive to UV‐B treatment, with exposure to 8 kJ/m2 or greater reproducibly causing a significant increase in migration. Migration of γδ+ dendritic cells (γδ+ DC) from irradiated skin was also triggered by exposure to UV‐B radiation, but dose dependency was not evident within the range of UV‐B doses examined. This, in conjunction with the lack of any consistent correlation between either the timing or magnitude of migration peaks of these two cell types, suggests that different mechanisms govern the egress of LC and γδ+ DC from the skin. It is concluded that the depression of normal immune function in the skin after exposure to erythemal doses of UV‐B radiation is associated with changes in the migration patterns of epidermal dendritic cells to local lymph nodes.