Chronic actinic dermatitis is a group of chronic, persistent, spectral diseases with chronic dermatitis changes at exposed and non-exposed sites in middle-aged and elderly men, whose pathogenesis is not fully understood and is thought to be related to genetic, environmental, and immune factors. In recent years, we have conducted some studies on the immune mechanism of its pathogenesis, and this paper will present our findings in this area and the current status of research at home and abroad.
Photosensitive dermatoses are a group of diseases caused by various lesions on the skin after exposure to sunlight or other rays, and are a common and frequent disease in dermatology. In clinical practice, polymorphic sun rash (PLE) and chronic actinic dermatitis (CAD) are common.
Chronic actinic dermatitis (CAD) is a group of chronic, persistent, spectral diseases that occur in middle-aged and older men with chronic dermatitis changes at exposed and non-exposed sites, including: persistent light reactivity (PLR), photosensitive eczema, photosensitivity dermatitis (PLE), and chronic dermatitis. These include persistent light reactivity (PLR), photosensitive eczema, photosensitivity dermatitis (PD), and actinic reticuloid (AR).
The clinical manifestations are mainly erythema, papules and nodules with pruritus on the face, neck, hands and other areas exposed to light. These diseases are all related to certain known or unknown photosensitive substances, and the above diseases have certain similarities in both clinical manifestations and histology, and are considered to be different manifestations of the same disease or different stages of the disease process. The prevalence in the normal population in Yunnan Province is 0.18% and accounts for 0.17% of patients seen in hospitals.
The pathogenesis of CAD is not fully understood, and it is thought that genetic, environmental, and immune factors may be involved in its development. The presence of photosensitizers is definitely an important pathogenic factor. Exogenous photosensitizers are exposed to the skin or absorbed and reach the skin through the bloodstream, causing changes in some normal components of the skin to form new antigens under long-wave ultraviolet and medium-wave ultraviolet (UVA, UVB) irradiation. Allergy;
Due to the chronic inflammatory reaction and the continuous extravasation of lymphocytes from the blood vessels to the inflammatory site, the antigenic nature of the neoantigens is continuously generated, which causes delayed type hypersensitivity (DTH) by continuously stimulating the immune system. Most scholars in China and abroad accept that it is mainly a delayed hypersensitivity reaction. Therefore, the immune system and the immune mechanism play an important role in its development. In this paper, we will present our findings in this area and the current status of research at home and abroad.
Immune phenotype of CAD dermal infiltrated mononuclear cells and their secreted cytokines
In recent years, foreign scholars have generally accepted the hypothesis that the mechanism of CAD development may be a delayed hypersensitivity reaction of the skin at the site of exposure to light-induced products, pointing to the predominance of Tc cell infiltration in old lesions. The reason supporting CAD as DTH is the delayed onset after sun exposure and the similarity of the pathology and immunohistochemistry to persistent antigenic contact dermatitis.
Immunohistochemistry suggests a predominance of CD8+ cells over the course of the disease, as well as the proliferation of Langham’s giant cells and the presence of non-Langham’s giant cells, the epidermophilia of lymphocytes and the patient’s generally good response to T-cell immunomodulatory drugs, in addition to the role of interleukins 1, 6, and 8 in CAD [4] and the high expression of some adhesion molecules in the dermis support a DTH response in CAD and PLE.
Our study of infiltrated single nucleated cells in lesions at the site of exposure in CAD patients by immunohistochemistry showed that the infiltrated single nucleated cells in the epidermis and dermis of CAD patients were mainly T cells, and mainly Tc cells. Previously, different scholars have had different results on the subpopulations of T cells, and it is now believed that the reason for the different conclusions may be due to the different periods in which the lesions were taken. Morris et al. induced polymorphic heliotropic eruption (PLE) in the laboratory using suberythematic amounts of UV light and found that the lesions were predominantly infiltrated by CD8+ cells after 72 h. Studies on CAD now consider a similar situation [6], which is also consistent with our study.
Normal body Th/Tc cells maintain a dynamic balance, while their subpopulations Th1/Th2 and Tc1/Tc2 also maintain a dynamic balance, and Th1/Th2 imbalance is associated with the development of rheumatoid arthritis, contact dermatitis, systemic lupus erythematosus, scleroderma, and HIV [8], while Tc1/Tc2 imbalance is less studied and has only been reported to be associated with the development of atopic dermatitis. However, the relationship with the development of CAD has not been reported.
IFN-γ is mainly secreted by Tc1 and T h 1, mediating cellular immunity, activating macrophages and inducing DTH, whereas IL-12 induces IFN production by resting and activated T cells and NK cells, thus promoting the development of DTH, while promoting Tc1 and Th1 differentiation among T0 cells and inhibiting Tc2 or Th1 differentiation and inhibit the secretion of Tc2 or Th 2 cytokines;
IL-4 is mainly secreted by Tc2 and Th2 to mediate humoral immunity, stimulate B lymphocyte proliferation and eosinophil activation, and induce IgG and IgE production; IL-10 has the ability to promote the differentiation of resting T cells (T0 cells) to Tc2 or Th 2 cells, and inhibit the proliferation of Tc1 and Th 1 cells and cytokine secretion.
Our experimental results using immunohistochemistry on cytokine receptors on the surface of infiltrated mononuclear cells in the patient’s lesions indicate that cytokine receptors on the cell surface are dominated by receptors for IFN-γ and IL-12, while measurement of cytokine levels in the peripheral blood of patients by ELISA revealed that IFN-γ and IL-12 were increased in the peripheral blood of CAD patients compared to normal subjects.
We hypothesize that the Tc1/Tc2 imbalance plays a role in the development of the disease, and that the development of the disease may be related to the overexpression of Tc1 cells and the release of excessive class I cytokines while the expression of Tc2 cells is suppressed. For the findings that IFN-γ and IL-12 were increased in peripheral blood of CAD patients compared with normal subjects, and that cytokine receptors on the surface of infiltrating mononuclear cells in lesions were increased in CAD patients, we speculate that the increase in IL-12 may be due to the fact that it was stimulated by the increase in IFN-γ after the increase in IFN-γ.
Apoptosis protein expression in keratinocytes
UV radiation has an important role in the pathogenesis of CAD. UV radiation can also cause damage to keratinocytes, formation of pyrimidine dimers and skin tumorigenesis. In contrast, apoptosis has an important role in maintaining the self-stability of cells and the normal function of the immune system. The abnormal expression of apoptotic proteins and tumorigenesis are closely related. Apoptosis is induced by exogenous and endogenous pathways, the former represented by Fas-mediated apoptosis and the latter controlled by the Bcl-2 family.
Normal keratinocytes basically do not express Fas antigen, while some skin diseases with pathological manifestations of non-specific inflammation such as: contact dermatitis and chronic eczema, whose rashes can strongly express Fas antigen, while Bcl-2 and Bcl-xl are associated with some inflammatory proliferative diseases, such as psoriasis. In our study, the expression of Fas and Bcl-2 in CAD epidermis was not significantly different from normal controls; the expression of Bcl-xl and Fasl, especially in the upper spine layer, granular layer and stratum corneum was significantly different from normal controls.
Fas/Fasl are membrane protein molecules that induce apoptosis, and the combination of Fas and Fasl induces apoptosis in cells where Fas protein is located. The expression of Fas and Fasl in normal keratinocytes were weakly positive and were mainly expressed in the upper spine layer, granular layer and stratum corneum, and our study showed that the expression of Fasl was higher than normal in both stratum corneum and stratum corneum, while the expression of Fas was not significantly different. Similar to previous studies. We speculate that in the early stage of the disease, the high expression of Fasl without significant changes in the expression of Fas caused the cells to fail to apoptosis normally and caused the overproliferation of keratinocytes.
In contrast, our previous study showed that the expression of Fas gradually increased with the prolongation of the disease, and the same situation was observed in the study of psoriasis, presumably preventing malignant proliferation of keratinocytes due to the expression of both Fas and Fasl by keratinocytes.
Bcl-2 and Bcl-xl are members of the Bcl-2 family of proteins, which are apoptosis-inhibiting proteins. Bcl-2 is most strongly expressed in normal skin keratin-forming cells in the basal layer of the epidermis and becomes progressively less expressed as the cells differentiate. It is barely detectable in the stratum corneum. In contrast, Bcl-xl was expressed with the highest intensity in the outermost layer of the epidermis and not in the basal layer, suggesting that Bcl-xl and Bcl-2 control cell growth and apoptosis, respectively, at different stages of differentiation during the proliferation and differentiation of keratinocytes.
Our study showed that the expression of Bcl-2 in CAD was not significantly different from normal control, while the expression of Bcl-xl, especially in the upper spiny layer, was significantly different from normal control, a situation also seen in some studies of inflammatory skin diseases such as psoriasis, presumably the overexpression of Bcl-xl inhibited the apoptosis of keratin-forming cells and prolonged the life span of keratin-forming cells, resulting in the overproliferation of keratinocytes. The overexpression of Bcl-xl could also increase the expression of a class of cytokines in T cells such as IFN-γ.
From the reported literature combined with our study, we found that there is a relationship between the imbalance of T cell subpopulation expression and the occurrence and development of CAD, and the overexpression of Tc1 cells predominates. The association between abnormal expression of apoptotic proteins and the pathogenesis of CAD warrants further investigation.