UVB-Dependent Modulation of Epidermal Cytokine Network: Roles in UVB-Induced Depletion of Langerhans Cells and Dendritic Epidermal T Cells

The epidermis of mice consists of three cellular components, i.e., keratinocytes, Langerhans cells (LC), and dendritic epidermal T cells (DETC). Each epidermal subpopulation produces a different set of cytokines, thereby forming a unique cytokine milieu. These cytokines, in turn, support the survival and growth of LC and DETC and regulate their immunological functions. LC and DETC play important, but distinct, effector roles in protective immunity against antigens that are generated in or penetrate into the epidermis. Acute or chronic exposure of mice to ultraviolet B (UVB) radiation is known to impair this cutaneous immunity, as evidenced by the failure to induce T cell-mediated immune reactions, by the generation of antigen-specific immunological unresponsiveness, and by the development of skin cancers. Importantly, these changes are associated with reduced densities of LC and DETC in UVB-exposed skin, suggesting that the deficiency in these epidermal leukocytes may account for some of the deleterious influences of UVB radiation on skin. Here I will review the recent advance in our understanding of the mechanisms by which UVB radiation may deplete LC and DETC from epidermis. More specifically, I will discuss the following possibilities: a) UVB-mediated suppression of the production of relevant growth factors for LC and DETC, b) UVB-induced abrogation of surface expression of growth factor receptors, and c) UVB-triggered apoptotic cell death in epidermal leukocytes.     

性激素对豚鼠表皮郎格罕细胞及变应性接触性皮炎的影响

观察了性激素对豚鼠表皮郎格罕细胞及变应性接触性皮炎(ACD)的影响。五组豚鼠分别皮下注射麻油、雌二醇、黄体酮、丙酸睾丸酮及外用丙酸睾丸酮。二周后作表皮LC计数。用两酸睾丸酮的两组豚鼠表皮LC数较前三组明显减少(P<0.01).同时各组动物用DNCB致敏。激发前一周各组仍继续使用上述药物。二周后激发ACD,丙酸睾丸酮的两组皮肤反应以及真皮内单一核细胞浸润较另三组明显轻微(P<0.01),提示丙酸睾丸酮可抑制豚鼠的ACD.     

Gamma-Interferon Therapy for Severe Cases of Atopic Dermatitis of the Adult Type

Recombinant gamma interferon (IFN-γ) was employed to treat adult-type atopic dermatitis. Eight cases received subcutaneous injections of 500,000 JRU of IFN-γ for 8 weeks. They responded relatively well to this treatment; however, the overall response to the treatment was not significantly better than that to conventional therapy in the control group. There was no significant suppression of itch or erythema. Swelling was reduced at the 8th week in the treatment group. Frequency of flushing attacks on the face was reduced and disappeared within four weeks in 6 of these patients; however, a similar reduction of frequency was observed in the control group. Papular and lichenified lesions on the trunk and extremities responded significantly to the treatment later than 5 weeks after its initiation. Serum IgE level was not affected by the treatment. Seven had the same level of serum IgE before and after the treatment. The serum cytokine level in the treated patients was also unaltered. Therefore, although IFN-γ treatment has some benefit in the treatment of severe cases of atopic dermatitis, it should be applied to limited cases because of its high cost.     

Role of Tight Junctions and Their Protein Expression in Atopic Dermatitis

Atopic dermatitis (AD) is a chronic inflammatory skin disease with xerosis, itchiness, as well as interconnection with immunoglobulin E (Ig E), mediated foods i...     

T Cell Receptor Expression by Dendritic Epidermal T Cells

Dendritic epidermal T cells (DETC) in murine epidermis express the γδ T cell receptor (TCR). The major population of DETC utilize Vγ5 and Vδ1 without any junctional diversity, corresponding to the earliest fetal thymocytes which express TCRγδ. Using PCR, we recently found another population of DETC which express VγI-Vδ6 with junctional diversity in addition to Vγ5-Vδ1, although they exist in small numbers in normal mice. In athymic nude mice, Vγ1+ cells also exist. Therefore, this subset of γδ T cells is the product of an extrathymic pathway. These Vγ1 + cells may recognize mycobacterium antigen or heat shock protein (HSP), thus playing an important role in the first defense of the skin. In contrast to normal mice, in nude mice, we could not detect any DETC using anti CD3ε antibody (2C11). In order to solve this puzzle, we examined the components of TCR complex utilizing immunoprecipitation and northern blot analysis. TCR is composed of either αβ or γδ chains associated with CD3γ, δ, ε and ζ-ζ chains. By immunoprecipitation of ¹²⁵I labelled DETC cell lines using anti-CD3ε antibody, we detected γδ chains and CD3γ and CD3ε chains, but not CD3δ or CD3ζ chains. Northern blot analysis showed that these cells express CD3γ, ε, and ζ chains, but not the CD3δ chain. We concluded that the lack of the CD3δ chain and/or CD3ζ protein may change the configuration of the TCR complex, leading to the lack of staining by anti-CD3ε antibody in the DETC of nude mice. This defect of TCR in nude DETC may explain functional abnormalities such as poor response to mitogens and diminished killing activity. Moreover, in ζ-chain deficient mice, full expression of TCR was observed. This fact suggested that DETC may utilize the FcεRIγ chain instead of the ζ chain for cell surface expression or signal transduction of TCR.     

Levels of serum IgE, serum soluble-Fc epsilon RII, and Fc epsilon RII(+) peripheral blood lymphocytes in atopic dermatitis.

Levels of serum IgE, serum soluble-Fc epsilon RII (S-Fc epsilon RII), and Fc epsilon RII(+) peripheral blood lymphocytes (PBL) were examined in 73 patients with atopic dermatitis (AD) and 17 control subjects with no atopic disease, in order to investigate the correlation of these parameters with AD. AD patients showed increases in IgE, S-Fc epsilon RII and Fc epsilon RII(+)PBL as compared with control subjects. In AD patients, levels of serum IgE and Fc epsilon RII(+)PBL increased as the extent of dermatitis became more severe, while levels of serum S-Fc epsilon RII showed no correlation with the extent of dermatitis. In 8 of the 73 AD patients who showed an improvement in their symptoms with treatment with topical corticosteroids or antihistamine, IgE, Fc epsilon RII(+)PBL, and S-Fc epsilon RII were measured before and after treatment. Fc epsilon RII(+)PBL correlated with disease activity; IgE and S-Fc epsilon RII did not show any such correlation. Patients with elevated IgE levels (IgE greater than 5,000 U/ml) showed low levels of S-Fc epsilon RII. Severely affected cases with a history of respiratory atopy also showed decreased S-Fc epsilon RII levels. It is believed that S-Fc epsilon RII binds to IgE in serum and may neutralize or down-regulate IgE mediated allergic reactions. A low level of S-Fc epsilon RII may cause an elevation of IgE and an exacerbation of the disease.     

Secretion of IL-2, IL-4, and IFN-γ for Dust Mite Antigens in a Patient with Atopic Dermatitis

In a 21-year-old female with severe atopic dermatitis, the secretion of interleukin-2 (IL-2), interleukin-4 (IL-4), and interferon-γ (IFN-γ) by her peripheral blood mononuclear cells (PBMC) was measured after incubation with/without antigens extracted from Dermatophagoides pteronyssinus (Dp), to which the patient had developed a positive patch-test reaction. Incubation with Dp antigen produced marked secretion of IL-2 and IFN-γ, but not IL-4. This may suggest that Dp-specific T lymphocytes present in the circulating blood cells are capable of producing IL-2 and IFN-γ, which may be relevant to the delayed-type allergic reaction occurring in the skin lesion.     

长波紫外线对小鼠朗格汉斯细胞生物学活性的影响

目的　研究体外长波紫外线 (UVA)对小鼠表皮朗格汉斯细胞 (LC)生物学活性的影响。方法　观察不同剂量的UVA对BALB/c小鼠表皮LC存活率、膜相关抗原 (Ia、B7 1、B7 2、CD40 )的表达及其抗原提呈功能的影响。结果　生理剂量的UVA (<80kJ/m2 )照射 ,对LC的存活率影响不明显 ,却能增加LC膜抗原的表达 ,促进其抗原提呈功能。超生理剂量的UVA则反之。结论　生理与非生理剂量的UVA对LC会产生不同的生物学效应 ,这可能是UVA调节机体免疫功能的分子基础。     

Macrophage Colony-Stimulating Factor (M-CSF) Inhibits the Decrease in the Amount of rRNA and IAβ mRNA in Cultured Epidermal Langerhans Cells of the Mouse

Macrophage colony-stimulating factor (M-CSF) is a keratinocyte-derived cytokine whose function in skin is not completely clarified. We investigated its effects on Langerhans cells by examining the amount of IA_β mRNA, β-actin mRNA and rRNA per cell, and compared them with the effects of other cytokines such as granulocyte/macrophage colony-stimulating factor (GM-CSF) and tumor necrosis factor-α (TNF-α). After culture for 24 h in the absence of exogenous cytokines, rRNA in Langerhans cells decreased steeply while β-actin mRNA increased. IA_β mRNA also decreased sharply. These decreases in the amount of rRNA and IA_β mRNA were limited when cytokines were added to the culture medium (in order of efficiency M-CSF>GM-CSF>TNF-α), but M-CSF was less potent than GM-CSF in up-regulating β-actin mRNA (GM-CSF>M-CSF, TNF-α). The effect of M-CSF, but not that of GM-CSF, was restricted by simultaneous treatment of cells with TNF-α. None of these effects engendered a change in the viability of the Langerhans cells in a 24-hr culture. Reverse-transcribed polymerase chain reaction analysis demonstrated that c-fms, the gene of the M-CSF receptor, was expressed in Langerhans cells, implying the physiological importance of M-CSF in vivo. A protein kinase C activator, TPA, up-regulated the amount of IA_β mRNA, while a protein kinase C inhibitor, H-7, suppressed the effects of all three cytokines. These results suggest that M-CSF, in conjugation with TNF-α and GM-CSF, plays an important role in controlling the physiological state of Langerhans cells, probably through the activation of protein kinase C.     

趋化性细胞因子受体CCR4和CXCR3在特应性皮炎患者外周血的表达

目的为研究特应性皮炎患者外周血趋化性细胞因子受体CCR4和CXCR3在特应性皮炎的发病过程中的作用。方法采用三色流式细胞仪测定20例特应性皮炎患者和30例健康对照者外周血趋化性细胞因子受体CCR4和CXCR3的表达水平。结果特应性皮炎患者外周血CCR4+CD4+T细胞的水平明显高于对照组(P<0.01);特应性皮炎患者外周血CCR4/CXCR3比率明显高于对照组P<0.01);特应性皮炎患者外周血CXCR3+CD4+T细胞的水平与对照组差异无统计学意义。结论趋化性细胞因子受体CCR4可能促进了Th2细胞从血液进入特应性皮炎患者炎症皮损。     

异位性皮炎超微病理、免疫病理改变及临床意义

目的 通过探讨异位性皮炎(AD)皮损超微病理结构和免疫球蛋白在皮损中的沉积种类，为临床治疗提供理论依据。方法 对10例AD患者皮损进行了常规病理、电镜和免疫病理的观察。结果 AD皮损常规病理表现为皮肤的亚急性和慢性炎症改变；电镜下存在免疫反应细胞相互接触现象；免疫球蛋白亚类的沉积以IgG1为主，沉积部位主要为真皮乳头区域。结论 细胞间的相互接触现象可能为皮肤免疫应答反应的细胞形态学基础，而皮损中IgG1的沉积可能与皮肤的感染有关。     

血清维生素D水平与儿童特应性皮炎的相关性分析

目的研究儿童血清中维生素D与特应性皮炎(AD)积分指数评分(SCORAD)之间的关系,同时分析血常规的嗜酸粒细胞百分比及嗜酸粒细胞绝对值、血清总IgE、血清钙离子及身高、体质量、身体质量指数与SCORAD之间的关系。方法选取2016年6月—2016年12月于我院诊治的44例AD患儿的临床资料作为观察组,并收集同时期相同数量健康儿童的资料作为对照组。观察组用SCORAD进行评分,观察组及对照组均测定其血常规、血清总IgE、血清钙离子和血清维生素D,并根据体质量、身高计算出身体质量指数(BMI),由同1名医师对患儿进行SCORAD计算。结果观察组中血清维生素D与SCORAD呈负相关(r=-0.305,P=0.044),与钙离子浓度呈正相关(r=0.366,P=0.015)。另外,SCORAD与嗜酸粒细胞百分比、绝对值及总IgE值呈正相关(r1=0.355,r2=0.398,r3=0.397;P1=0.018,P2=0.008,P3=0.008)。观察组的25(OH)D浓度低于对照组(Z=-2.028,P=0.043),嗜酸粒细胞百分比及绝对值、总IgE和钙离子浓度高于对照组(Z1=-3.965,Z2=-4.112,Z3=-2.479;P1<0.001,P2<0.001,P3=0.013)。结论儿童25(OH)维生素D可能与SCORAD有负相关。     

Evaluation of Soluble Cell Adhesion Molecules in Atopic Dermatitis

Recent studies have indicated the importance of cell adhesion molecules (CAMs) between the vascular endothelium and activated leukocytes in various inflammatory skin diseases. Soluble forms of CAMs (sCAMs) have also been detected in sera from such diseases. In order to elucidate the role of the soluble forms in skin inflammation, we determined the serum levels of E-selectin, vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1) in patients with atopic dermatitis (AD). Using an enzyme-linked immunosorbent assay, we quantified sCAMs levels in 21 patients with atopic dermatitis and in 16 healthy controls. In severe AD patients, levels of these three types of sCAMs were markedly elevated. sE-selectin was significantly elevated in severe AD over the levels in mild AD. A positive correlation with individual clinical activity was found for changes in the sE-selectin and sVCAM-1 levels. sE-selectin levels were correlated with the serum IgE levels and the number of eosinophils. The sVCAM-1 level was also significantly correlated with the number of monocytes. Among these three molecules, sE-selectin appeared to be the most sensitive clinical parameter in monitoring the clinical course of AD patients.     

Critical Evaluation of Food and Mite Allergy in the Management of Atopic Dermatitis

The subject of allergic causation of atopic dermatitis (AD) has been a source of controversy for over sixty years. While there is general agreement of allergen-induced asthma and allergic rhinoconjunctivitis, AD lesions cannot be readily or consistently induced by foods and inhalants. The most consistent perturbators of atopic conditions are irritants, probably reflecting the consistent inflammatory cell hyper-reactivity due to elevated cyclic AMP-phosphodiesterase activity. The immunologic reactions are another manifestation of that general cellular dysregulation.     

中西医结合治疗特应性皮炎的临床研究

目的探讨中西医结合治疗脾虚湿盛型特应性皮炎(Atopic Dermatitis,AD)的疗效及作用机制.方法 61例AD患者分两组,采用西药和中西医结合治疗,并于治疗前后观察其血清总IgE水平、外周血T细胞亚群分布的变化.结果中西医结合治疗组疗效优于西药组,可降低血清总IgE水平,CD3 T细胞和CD8 T细胞百分计数,治疗后比治疗前显著升高(P分别＜0.05和0.01);CD4 细胞/CD8 细胞比值,治疗后显著低于治疗前(P＜0.05).结论中西结合治疗方法治疗AD,疗效肯定,其机制可能与调节外周血T细胞亚群并降低血清总IgE水平有关.     

Phenotypic Differences between Human Blood Monocyte Subpopulations in Psoriasis and Atopic Dermatitis

Peripheral blood monocytes seem to be of importance in the initiation and maintenance of cutaneous inflammatory disorders such as psoriasis and atopic dermatitis. Functional abnormalities of monocytes have been observed in both diseases. We sought to determine whether these abnormalities are reflected by an altered phenotypic expression of functionally active surface molecules. Peripheral blood monocyte subsets varying in cellular density and cell size from patients with psoriasis and atopic dermatitis were investigated using FACS analysis employing a panel of monoclonal antibodies (CD14, CD16, HLA-DR, HLA-DQ, Fc?RII, IL-2R, ICAM-1, CR3). Furthermore, the modulation of expression by interferon-γ in monocyte subsets from patients was compared to normal controls. The results show that HLA-DR and -DQ expression on monocyte subsets in psoriatic patients was significantly decreased; “large” monocytes expressed significantly less HLA-DR than “small” monocyte subpopulations. Decreased HLA-DR and -DQ expression could be upregulated by incubation of psoriatic monocytes with IFNγ. In atopic dermatitis, a different phenotype pattern of monocyte subsets was demonstrated: HLA-DR expression and HLA-DQ expression were both decreased in both “large” and “small” monocytes as compared to normal controls. However, there were no significant differences in HLA-DR and HLA-DQ expression between “large” and “small” monocyte subpopulations in atopic dermatitis. Moreover, the ICAM-1 and IL-2R expression of “large” and “small” monocyte subpopulations was significantly decreased in atopic patients from levels in normal controls and psoriatic patients. The altered expression of HLA-DR, -DQ, ICAM-1 and IL-2R could be upregulated by incubation of atopic monocytes with IFNγ. In addition, there was a significant increase in the percentage of monocytes in the differential count of patients with psoriasis or atopic dermatitis. We conclude that the differential phenotype pattern of surface molecules on monocytes in psoriasis and atopic dermatitis may reflect an abnormal monocyte maturation/differentiation state. This may explain the functional abnormalities of monocytes observed in patients with psoriasis and atopic dermatitis.     

Guidelines for Diagnosis and Treatment of Atopic Dermatitis in China (2020) #

Atopic dermatitis (AD) is a common disease clinically characterized by chronic recurrent eczematous lesions, dry skin, and pruritus. AD can negatively impact pa...     

特应性皮炎患者趋化因子及其受体的研究

目的 探讨几种重要的趋化因子及其受体的表达在特应性皮炎(AD)发病中的作用。方法 采用酶联免疫吸附试验检测39例AD患者及正常人血清中γ干扰素诱导蛋白-10(IP-10)、基质细胞衍生因子-1α(SDF-1α)、嗜酸粒细胞趋化因子、胸腺和活化调节的趋化因子(TARC)及巨噬细胞来源的趋化因子(MDC)等水平;同时用流式细胞仪分析外周血CD4⁺T细胞表面趋化因子受体CXCR3、CXCR4、CCR3、CCR4及CCR5的表达。结果 与正常人对照组相比,AD患者血清SDF-1α、TARC和MDC水平显著升高(P<0.001),IP-10及嗜酸粒细胞趋化因子水平则无明显改变(P>0.05),外周血CXCR3、CCR3、CCR4及CCR5在CD4⁺T细胞表达水平显著增加(P<0.001);血清TARC和MDC水平的变化与疾病严重程度相关(r分别为0.669及0.409,P分别为<0.001及<0.01)。结论 具有生物活性趋化因子及其受体介导的T细胞和嗜酸/嗜碱粒细胞的聚集、激活后释放的炎性介质在AD发病中起着重要作用。     

健脾渗湿法治疗特应性皮炎患者血清总IgE、IgG、IgG4变化及疗效评价

目的通过检测血清中总IgE(TIgE)、IgG、IgG4浓度在特应性皮炎(AD)发病过程中的变化,探讨健脾渗湿法治疗有效率与指标间的联系。方法选择38例AD患者为研究对象,于治疗前后观察其主要症状(包括瘙痒、睡眠、皮损面积、皮损严重程度),记录SCORAD积分,及检测血清中TIgE、IgG、IgG4水平。并将各项血清学指标与治疗有效率进行相关分析。结果治疗前的SCORAD评分为55.46±15.05,治疗后为49.41±12.33,两者有显著性差异(P<0.01);AD患者血清治疗前、后TIgE、IgG、IgG4均高于正常对照组(P<0.05)。但治疗后TIgE相对于治疗前明显下降,而IgG、IgG4水平明显升高。治疗有效率与TIgE、TIgE/IgG4治疗前后变化差值成中等正相关,相关系数分别为0.541,0.793。结论 TIgE、TIgE/IgG4水平变化是反映AD病情变化的重要指标,在一定程度上可用于评价病情是否好转。使用健脾渗湿法治疗AD后,TIgE、TIgE/IgG4随症状改善变化明显。     

Skin mast cells develop non‐synchronized changes in typical lineage characteristics upon culture

Despite their hematopoietic origin, mast cells (MCs) develop exclusively in tissues, hampering their ample use in research. To circumvent this problem, tissue‐derived MCs are typically first expanded in culture, but the changes MCs may undergo in the novel micromilieu are poorly defined. Here, we monitor skin MCs from a number of donors over time, revealing profound yet non‐synchronized modulations in culture. While tryptase and chymase, the most specific markers, strongly decline, FcεRI surface expression, and FcεRI‐mediated histamine release steeply increase (from ≈15.5% to ≈60%), replicated by similar increments in TNF‐α secretion. Interestingly, the modulations are independent of cell cycle progression, as they are comparable in the growth and postgrowth phase, implying they primarily result from microenvironmental conditioning. The data highlight a high degree of MC versatility, but also advise that results based on cultured MCs should be viewed with some caution, as they may not accurately reflect their counterparts in situ.