Effect of ultraviolet radiation on Ia expression by keratinocytes.

Many skin diseases, such as graft-versus-host disease (GVHD), are marked by lymphocyte infiltrates in the skin. Severity of these diseases is often correlated with the induced expression of class II antigens (human, HLA-DR,; murine, Ia) by the keratinocytes. This suggests that HLA-DR-expressing keratinocytes may be involved in the pathogenesis of these diseases. Since some of these diseases are effectively treated with ultraviolet radiation (UVR), this study was conducted to determine whether UVR alters the keratinocyte expression of class II antigens. To test this hypothesis, 2 models of experimentally induced keratinocyte Ia expression were employed. First, athymic nude mice with one ear protected by electrical tape were exposed to UVR (450 J/m2/day on 4 consecutive days). They were then given an i.v. injection of normal mouse serum (NMS) to induce keratinocyte Ia expression. Keratinocytes in the UVR-exposed skin of these animals were not induced to express Ia; however, Ia-expressing keratinocytes were observed in the epidermis of shielded skin sites. Likewise, it was determined that UVR was capable of downregulating keratinocyte expression of Ia when administered to nude mice 7 d after receiving an injection of NMS. Second, employing a clinically relevant model, we found that Ia expression by keratinocytes in mice undergoing experimentally induced GVHD was abrogated by UVR treatment. This appeared to be a direct effect of the UVR, since keratinocytes in shielded skin sites and mucosal cells in the intestinal epithelium of animals with GVHD were shown to express Ia. These data provide compelling evidence for our hypothesis that decreased HLA-DR expression by keratinocytes in diseased skin treated with UVR is a mechanism by which UVR exerts its therapeutic effect.

Differential expression of Ia by murine keratinocytes and gut epithelium in response to recombinant gamma-interferon.

Keratinocyte expression of class II antigens (HLA-DR, human; Ia, murine) is associated with certain cutaneous diseases, especially those marked by the infiltration of immune and inflammatory cells into the skin. It has been shown that interferon-gamma (IFN-gamma) is capable of inducing human keratinocytes to express HLA-DR. Similar results, however, have not been duplicated in murine systems. The purpose of this study was to determine whether IFN-gamma was capable of inducing murine keratinocyte expression of Ia in vivo in an experimental model in which epithelial cells in a variety of organs were shown to express Ia after the i.v. injection of IFN-gamma. Recombinant murine IFN-gamma was injected into BALB/c mice. Biopsies of skin and intestine were analyzed by indirect immunoperoxidase to identify Ia-expressing keratinocytes and mucosal cells, respectively. Interferon-gamma was administered as either: 1) a single s.c. injection, 2) multiple i.v. injections of increasing doses (10(3)-10(5) U/d) on 3 consecutive d, or 3) i.p. injections of 5 X 10(4) U/d or 5 X 10(5) U/d on 6 consecutive d. At all i.v. and i.p. injection doses, the intestinal villi mucosal cells were induced to express Ia. Keratinocyte expression of Ia, however, was observed only in animals that received the two higher i.p. doses. Procedures to augment Ia expression, e.g., combined treatment with pertussis toxin, dinitrofluorobenzene, tumor necrosis factor, and indomethacin, did not enhance the ability of IFN-gamma to induce keratinocyte expression of Ia. We conclude that: 1) high doses of IFN-gamma are required to induce murine keratinocyte Ia expression in vivo and 2) low doses of IFN-gamma, although capable of inducing intestinal mucosal cells to express Ia, do not induce keratinocyte Ia expression.

Splenic contribution to the recovery of ATPase/Ia+ epidermal cells in the skin of mice after exposure to ultraviolet radiation.

The density of Langerhans cells (LC) is significantly decreased in skin sites exposed to ultraviolet radiation (UVR). This results in reduced antigen-presenting cell (APC) activity in UVR-exposed skin. We have previously reported that the recovery in the density of ATPase/Ia+ epidermal cells (EC) parallels the restoration of APC function in the UVR-exposed skin of mice. The present study was designed to determine whether the spleen might serve as a source of ATPase/Ia+ cells to restore APC function to the skin after UVR exposure. ATPase/Ia+ EC densities were calculated from skin biopsies taken from BALB/c mice at various time points after low dose UVR treatment (2000 J/m2 protracted over 4 days). The recovery rate of ATPase/Ia+ EC in splenectomized mice after UVR exposure was similar, although delayed, compared to that of sham-operated mice. For example, 3 days after UVR exposure the density of ATPase/Ia+ EC in sham controls was 90% of normal and exceeded normal values by 5 days. In contrast, ATPase/Ia+ EC density in splenectomized mice was 60% of normal at 3 days and did not exceed normal values until 7 days after UVR exposure. Normal recovery of ATPase/Ia+ EC was restored to splenectomized mice given an adoptive transfer of syngeneic spleen cells immediately after UVR exposure. Fluorescein-labeled spleen cells used for adoptive transfer were observed within the epidermis of splenectomized mice 1 and 3 days after UVR exposure. Indirect immunofluorescent staining employing phycoerythrin-labeled reagents revealed that the fluorescein-labeled splenic EC expressed Ia, MAC-1, CLA, and Fc-receptor molecules. These results indicate that a portion of the ATPase/Ia+ EC that recovery after UVR exposure originate from the spleen. These cells may be distinct from LC, but appear to restore APC function to the skin following LC depletion by UVR exposure.

Photoimmunology: the mechanisms involved in immune modulation by UV radiation.

Ultraviolet radiation (UVR) may be the most prevalent agent that man encounters in his environment. As a result, certain biological adaptations take advantage of the beneficial effects of UVR exposure, e.g. the photoactivation steps involved in vitamin D metabolism. In this regard, UVR plays an important role in maintaining our good health; however, it must be noted that UVR is potentially the most harmful naturally occurring agent in our environment. Thus, it appears that several mechanisms have evolved to protect us against the detrimental effects of UVR overexposure. Although epidermal melaninization or "tanning" may be the most obvious example of these processes, we would argue that adoptive mechanisms within the immune system also provide protection against UVR-induced skin damage. It is now known that UVR affects the distribution and functional activities of various immunocompetent cells within the skin, as well as modifying the production of inflammatory and hematopoietically active cytokines. This review will focus on the known mechanisms involved in the immune modulatory effects of UVR and how adoptive immune responses to UVR-induced skin damage contribute to specific pathological processes.

Parallel recovery of epidermal antigen-presenting cell activity and contact hypersensitivity responses in mice exposed to ultraviolet irradiation: the role of a prostaglandin-dependent mechanism.

Contact hypersensitivity (CH) responsiveness to 2-4-dinitro-1-fluorobenzene (DNFB) is depressed in mice that are sensitized through skin sites exposed to ultraviolet radiation (UVR). This is partially due to a reduction in antigen-presenting cell (APC) activity within UVR-exposed skin, a condition marked by a decrease in the density of ATPase/Ia-positive epidermal cells. The purpose of this study was to correlate the histological and functional recovery of APC activity in the skin of C3H mice exposed to low-dose (4 X 450 J/m2) or high-dose (1 X 15 kJ/m2) UVR with the normalization of CH responsiveness. Skin biopsy specimens taken at various intervals after UVR exposure revealed a rapid recovery in the density of ATPase/Ia positive cells: about 70% of normal by 3 days, and normal after 5 days. Functional analyses showed that lymph node cells obtained from donors that were sensitized with DNFB 3 days after UVR treatment transferred normal ear-swelling responsiveness to non-primed recipients, thus indicating that APC activity in UVR-exposed skin paralleled the recovery of ATPase/Ia-positive epidermal cells. This suggested that an alternative mechanism causes the persistent depression of CH in mice exposed to UVR. Mice pretreated with indomethacin prior to UVR exposure demonstrated a capacity to elicit CH responses to DNFB, which paralleled the histological and functional recovery of APC in the skin (i.e., normal CH responses were elicited 3 days after exposure to UVR). We conclude from this study that APC activity in the skin recovers rapidly after exposure to UVR, and that a PG-dependent mechanism is responsible for many of the persistent and systemic effects that cause a depression in the CH responsiveness of mice treated with UVR.