Raf kinase inhibitor protein expression correlates with differentiation but not with ERK phosphorylation in cutaneous squamous cell carcinoma

BackgroundThe acute skin lesions of atopic dermatitis (AD) are associated with Th2 cells; however, the chronic skin lesions of AD are associated with Th1 cells via the action of IL-12.ObjectiveWe evaluated the associations of single nucleotide polymorphisms (SNPs) and haplotype in the IL-12 and IL-12 receptor genes, and determined the gene–gene interactions between the SNPs of these genes and the SNPs of the IL-18 gene that we previously reported.MethodWe genotyped 24 SNPs from 4 IL-12/IL-12R genes for 1089 case–control samples (631 AD patients and 458 normal controls). We measured the serum IL-12 concentrations in 89 individuals (79 AD patients and 10 controls) by ELISA. We analyzed the SNPs and haplotypes in each gene and also searched for the gene–gene interactions.ResultThe rs582504 (IVS ? 798A/T) SNP and the haplotype TA (rs582054 and rs2243151) in the IL-12A gene, and the rs438421 (IVS12 + 1266T/C) SNP and the haplotype CCA (rs375947, rs438421, and rs1870063) in the IL-12RB1 gene were significantly associated with the AD phenotype. We showed that the rs438421 polymorphism in the IL-12RB1 (TT) gene and the rs2066446 polymorphism in the IL-12RB2 (AA) gene had a significant interaction to develop the ADe phenotype (allergic type of AD), and those individuals with the risk alleles, TT/AA/CC (IL-12RB1/IL-12RB2/IL-18), have more than a 10-fold increased risk to develop ADe.ConclusionThis study provides evidence for a significant interaction between the IL-12RB1 and IL-12RB2 genes that contribute to a 4-fold increased risk for developing ADe. In addition to the IL-12R interaction, we suggest that the IL-18 gene can significantly interact with the IL-12R gene to develop ADe. In addition to the interaction, the SNPs and haplotypes in the IL-12A and IL-12RB1 genes are independently and significantly associated with the AD phenotype, and especially with the ADe phenotype. This data may contribute to our understanding of AD genetic interactions and account for the additional risk of certain patients to develop AD.     

Topical aminolaevulinic acid-photodynamic therapy produces an inflammatory infiltrate but reduces Langerhans cells in healthy human skin in vivo

Background Topical photodynamic therapy (PDT) elicits a therapeutic response in both skin cancer and immune‐mediated skin disorders. While PDT induces direct cell death, host inflammatory and immune responses to PDT may contribute to the therapeutic effects. Objectives To examine the impact of topical PDT on leucocyte trafficking and mediators of chemotaxis in healthy human skin. Methods Aminolaevulinic acid (ALA)‐PDT was performed on the buttock skin of seven healthy volunteers. Biopsies for immunohistochemical assessment were taken 1, 4 and 24 h post‐PDT and from untreated contralateral buttock skin (baseline). Results A significant dermal neutrophilic infiltrate appeared early, peaking at 4 h (P < 0·01) and returning to near baseline by 24 h. Expression of E‐selectin was significantly higher at 4 h (P < 0·05) and correlated strongly with neutrophil numbers (r = 0·93). Expression of intercellular adhesion molecule 1 was significantly elevated after 24 h (P < 0·05) with an apparent gradual increase in CD4+ T cells up to this time point. Notably, epidermal Langerhans cells were significantly reduced 24 h post‐PDT compared with baseline (P < 0·01) and comprised a significantly larger proportion of cells with migratory rather than dendritic morphology (P < 0·05). The number of epidermal cells expressing tumour necrosis factor‐α significantly increased at 4 h (P < 0·05) and remained elevated 24 h post‐PDT, whereas no significant change in expression of interleukin (IL)‐1β or IL‐8 was seen. Conclusions Reduction of Langerhans cells by topical PDT of human skin may play a significant role in PDT‐induced local immunosuppression, potentially benefiting the treatment of immune‐mediated skin disorders but negatively impacting on antitumour responses. Further exploration according to disease indication/treatment protocol is warranted.     

Immunohistochemical study of Langerhans cells in skin tumors

The behavior of Langerhans cells in skin tumors was investigated by immunohistochemical techniques using OKT6. OKT6-positive cells were numerous in squamous cell carcinomas, seborrheic keratoses and keratoacanthomas. They were rare in basal cell carcinomas, Bowen's disease, eccrine poromas, extramammary Paget's disease and warts. In solar keratosis, the number of OKT6-positive cells was almost equal or slightly larger compared to the normal epidermis. These results indicate that the density of Langerhans cells may not correlate with the degree of malignancy but, to a certain extent, with the nature of the membrane of tumor cells occurring e.g. during keratinization.     

Suppressor cell activation and enhanced skin allograft survival after tumor promotor but not initiator induced depletion of cutaneous Langerhans cells

During chemical carcinogenesis Langerhans cells (LC) are depleted from the epidermis, disrupting the normal immunological functions of the skin. Tumor promotors but not initiators, have been shown to deplete adenosine triphosphatase (ATPase)-positive LC from the skin and therefore the cutaneous immune system may be impaired during tumor promotion but not initiation. The present study shows that the tumor promotor 12-O-tetradecanoylphorbol 13-acetate (TPA) but not the initiator urethane depletes Ia-positive LC from BALB/c murine ear epidermis, and beta-glucuronidase-positive LC from C57BL mouse tail skin. Sensitization with 2,4-dinitrofluorobenzene (DNFB) through urethane-treated skin resulted in a normal contact sensitivity response when the mice were challenged 5 days later. In contrast, tolerance resulted from sensitization through TPA-treated skin as a result of the generation of suppressor cells. In addition, TPA but not urethane-treated C57BL mouse tail skin survived for an extended time when grafted onto histoincompatible BALB/c mice. Therefore, impairment of the normal immunological functions of skin resulted from treatment with the tumor promotor TPA but not the tumor initiator urethane, which suggests that a loss of LC during tumor promotion may impair immunological protection against skin tumors.     

Sensitive skin is highly frequent in extrinsic atopic dermatitis and correlates with disease severity markers but not necessarily with skin barrier impairment

Background

Sensitive skin is a condition of cutaneous hypersensitivity to environmental factors. Lactic acid stinging test (LAST) is commonly used to assess sensitive skin and composed of four distinct sensations (pain, burning sensation, itch, and crawly feeling). A link between sensitive skin and barrier dysfunction has been proposed in atopic dermatitis (AD) patients. However, clinical and laboratory factors that are associated with sensitive skin remain unelucidated.

Increased densities of Langerhans cells in the epidermis of skin tumors

Using OKT6 monoclonal antibody (MCA) and β-specific anti-S-100 protein (S-100β) MCA, the numbers of Langerhans cells (LC) in the epidermis overlying squamous cell carcinoma (SCC), basal cell epithelioma (BCE), dermatofibroma (DF), and in the lesional epidermis of seborrheic keratosis (SK) were investigated. The numbers of LC were significantly increased in the epidermis overlying SCC and in SK. Moreover, significantly more LC were observed in the epidermis overlying SCC than in SK. The increased density of LC in the epidermis overlying SCC may suggest participation and activation of the mononuclear phagocyte system in this neoplasm. In 8 cases of SCC, the subpopulations of infiltrating lymphocytes around the tumor cell nests were analyzed. The ratio of Leu 3a-positive cells/Leu 2a-positive cells ranged from 0.63 to 1.99. This diversity may reflect complicated immunological interaction between the tumors and the hosts.     

Presence of clusters of Langerhans cells and lymphoid cells in the peritumoral infiltrate of a case of basal cell naevus syndrome. Ultrastructural study (author's transl)]

A case of naevoid basal cell carcinoma syndrome with clusters of Langerhans' and lymphoid cells in the inflammatory peritumoral infiltrate, is reported. Electron microscopy shows intercellular contacts between eight to ten lymphoid cells and a single Langerhans' cell. These contacts occur over limited areas of the cell membranes by means of zones of high electron density on the outer edge of the cytoplasm. The functional significance of this finding is discussed, bearing in mind that recent observations have established certain analogies between Langerhans' and interdigitating reticulum cells. The latter might, within the thymus-dependent region of the lymph nodes, contribute to the formation of a micro-environment favourable to certain immunological activities of T-lymphocyte populations.     

Adult Langerhans cell histiocytosis limited to the skin

BACKGROUND: The incidence of Langerhans cell histiocytosis (LCH) is 4-5 per million in children with only 30% of this number having an adult onset. While dermatological manifestations occur in as many as 50% of cases, disease limited to the skin is uncommon among reported cases of adult LCH. OBJECTIVES AND METHODS: To present 3 new cases of adult LCH and a review of the literature of isolated cutaneous LCH in adults. RESULTS: Three adults with scalp, vulvar and generalized LCH lesions had refractory responses to treatment. CONCLUSIONS: LCH may present with unusual cutaneous manifestations limited to the skin in adults. Optimal treatment has not yet been determined.     

Reduction in murine Langerhans cell ATPase staining following topical but not systemic treatment with steroid and non-steroid immunosuppressants

The effects on murine Langerhans cells (LC) of steroid and non-steroid immunosuppressive drugs which are commonly used for long-term immunotherapy of human patients were investigated. Hydrocortisone, prednisolone, cyclosporin A or azathioprine was administered daily for 7 consecutive days either topically by application to the skin, or systemically by intraperitoneal injection. LC densities were determined on the day following cessation of treatment by staining for the plasma membrane-bound enzyme adenosine triphosphatase (ATPase). All immunosuppressants caused a significant reduction in ATPase-positive LC when administered topically, but not systemically. The systemically administered drugs, although given in high concentration, may not have penetrated the epidermis in sufficient concentrations to disrupt the LC membrane. These observations are consistent with long term immunosuppressants depleting cutaneous LC by bone marrow suppression rather than by a direct effect on LC.     

朗格汉斯细胞组织细胞增生症皮肤损害临床分析

目的:分析朗格汉斯细胞组织细胞增生症(LCH)的临床特点.方法:回顾性分析近10余年国内文献报道的918例诊断LCH的临床资料.结果:918例LCH中皮肤受累510例,占55.5%,以皮疹为首发症状的106例,占11.55%.临床上以湿疹样、脂溢性皮炎样或紫癜样皮疹多见.所有病例均合并其他系统损害,以发热(52.07%),肝肿大(52.29%)、脾肿大(48.26%)、骨损害(38.78%)、肺部损害(36.16%)最为常见.在918例LCH中,男593例,女317例,性别不详8例,最小出生4h,最大65岁,1岁以下占19.17%.皮肤活检151例.结论:皮肤是LCH常累及器官,对于1岁以下的小儿出现不典型湿疹样、脂溢性皮炎样或紫癜样皮疹应警惕LCH的可能,应进一步完善各项检查以明确诊断.     

Langerhans cell migration into ultraviolet light-induced squamous skin tumors is unrelated to anti-tumor immunity.

There has been much speculation as to the role of Langerhans cells (LC) in the induction of anti-tumor immunity. Whereas there is considerable circumstantial evidence that disruptions in the density and function of these cells during the early stages of ultraviolet (UV) light- and chemical carcinogen-induced carcinogenesis may be important for enabling developing neoplasms to escape immune destruction, the role of the large number of these cells found infiltrating developed skin tumors is less clear. To investigate this we have compared the LC density infiltrating transplanted non-immunogenic and immunogenic UV-induced murine tumors as well as LC in the epidermis overlying the tumors. Whereas two non-immunogenic tumor lines attracted large numbers of Ia+ dendritic cells, an immunogenic tumor line did not. Similar results were obtained whether the tumors were transplanted into syngeneic immunocompetent or athymic immunodeficient mice. Hence, there was no relationship between tumor immunogenicity or host immunocompetence and Ia+ dendritic cell density. Furthermore, there was no correlation with the pattern of T-cell infiltration of the tumors or CD4/CD8 cell ratio. Our results also indicate that whereas UV light decreased Ia+ cell density, both in the epidermis and the tumors, it did not inhibit the tumors from attracting Ia+ dendritic cells. Thus, the Ia+ dendritic cells infiltrating skin tumors are unlikely to indicate a host immune response to the tumor, but are more likely to be attracted by tumor-derived cytokines.     

Membrane‐bound stem cell factor is the major but not only driver of fibroblast‐induced murine skin mast cell differentiation

The maintenance and modulation of cutaneous mast cell (MC) numbers is held to be important for skin immune responses to allergens and pathogens. The increase in MC numbers in the skin is achieved by proliferation and the differentiation of precursor to mature MCs. Fibroblast‐derived SCF is thought to be the major skin MC growth factor and it potently induces MC proliferation. The mechanisms of fibroblast‐induced skin MC differentiation, including the role of SCF, however, remain insufficiently characterized and understood. Using cocultures of immature murine MCs and fibroblasts, we found that the adhesion of immature MCs to fibroblasts via VCAM‐1 and α₄β₇ integrin is very important for subsequent differentiation, which is driven by fibroblast membrane‐bound SCF and additional fibroblast‐derived membrane‐bound signals. Thus, our results show that fibroblast‐induced MC differentiation is induced by direct cell–cell contact and involves both Kit‐dependent and Kit‐independent pathways. Our findings add to the understanding of how immature mast cells mature in murine skin and encourage further analyses of the underlying mechanisms, which may result in novel targets for the modulation of skin mast cell driven diseases.     

免疫组化在上皮性皮肤肿瘤诊断中的应用进展

上皮性皮肤肿瘤是指来源于皮肤角质形成细胞或皮肤附属器的肿瘤.上皮源性皮肤肿瘤诊断主要依靠形态学特征,在某些诊断困难情况下,免疫组化是一个有价值的辅助诊断指标.包括鉴别肿瘤起源,肿瘤良恶性及原发或者转移性上皮源肿瘤.有时候,需要组合数个抗体来进行明确诊断.在临床实践中对组化结果需要小心解释并结合组织学特征,才能出正确诊断.