Stimulation of T cells by autologous mononuclear leukocytes and epidermal cells in psoriasis

Summary Based on reports suggesting aberrant cell-mediated immunity and altered infiltration of immunocompetent cells into the skin in psoriasis, we studied the stimulation of T cells by autologous non-T mononuclear leukocytes (autologous mixed lymphocyte reaction, AMLR) and by epidermal cells isolated from lesional and clinically uninvolved skin in psoriasis (autologous mixed epidermal cell lymphocyte reaction, AMECLR). Age- and sex-matched individuals served as controls. We found that the AMLR in psoriasis (n=11) was similar to that in healthy controls (n=16); furthermore, cell proliferation was alike in the presence of either 5% AB-serum or autologous serum. By contrast, while the AMECLR in healthy controls (n=9) resembled that in psoriatics employing epidermal cells from univolved skin, epidermal cells from lesional sites (n=10) induced a significantly higher proliferation of autologous T cells in the AMECLR (P<0.01). We conclude that the in vitro stimulation of T cells by non-T mononuclear leukocytes is normal in psoriasis and is not regulated by autologous serum. Lesional psoriatic epidermal cells, however, are more active in stimulating autologous T cell proliferation than cells from univolved psoriatic or normal epidermis.     

Adhesion molecules in lesions of American cutaneous leishmaniasis

Abstract Accessory signals, which include adhesion molecules, MHC-II molecules and cytokines. are necessary to foster the interaction between memory T cells and epidermal cells, that is required to promote cutaneous inflammatory responses. American cutaneous leishmaniasis (ACL) is characterized by a spectrum of immunological manifestations, and is a prototype disease for the study of regulatory mechanisms involved in immune protection against protozoal infection. In the present study, we show that diffuse cutaneous leishmaniasis (DCL) epidermis contains keratinocytes that do not express ICAM-I and HLA-DR molecules. Langerhans cells (LC) are within normal values or somewhat lower, and a very few cells expressing the HB15 molecule a new described member of the Ig superfamily are found in such lesions. Mucocutaneous leishmaniasis (MCL) epithelium shows an increased expression of ICAM-1 and HLA-DR molecules, few HBI5⁺ cells, and an absence of epithelial LC. Localized cutaneous leishmaniasis (LCL) epidermis displays ICAM-⁺ keratinocytes organized in patches, a uniform expression of HLA-DR, hyper-plasia of LC, and numerous HBI5⁺ cells. In all forms of the disease, infiltrating T cells express more LFA-1β than LFA-1α, but LFA-1β⁺ cells are more abundant in LCL granulomas. In contrast, there are more LFA-lα⁺ cells in DCL and MCL than in LCL granulomas. LCL lesions also show the highest numbers of HB15⁺ cells within the granu-loma. These results indicate the importance of adhesion molecules in ACL lesions, and open new possibilities for therapeutic schemes oriented towards the control of cell migration.     

银屑病发病机制中T细胞作用的进展

银屑病是一种Th1细胞介导的自身免疫性皮肤病,近来的研究表明,其他细胞也参与其发病过程,尤其是树突细胞、内皮细胞、Th17细胞及调节性T细胞等,其中T细胞的活化、增殖及分化是发病的主要环节,银屑病特征性的角质形成细胞增殖和异常分化及炎性细胞浸润是继发于T细胞活化后释放的细胞因子.一些黏附分子(E/P选择素等)及皮肤淋巴细胞相关抗原-P选择素糖蛋白配体-1复合体和皮肤淋巴细胞相关抗原-CD43复合体在银屑病发病中也起着一定的作用.     

银屑病患者皮肤中原位记忆T淋巴细胞的检测

目的 研究皮肤组织原位记忆T淋巴细胞在银屑病发病过程中的作用。 方法 收集32例进行期斑块状银屑病患者的临床资料,采集每例患者的皮损和非皮损组织、9例患者皮损消退后皮肤标本;10例健康人皮肤为对照。采用免疫组化法检测组织原位记忆T淋巴细胞的特征性表面标志CD69和CD103,分析组织原位记忆T淋巴细胞在银屑病发病不同时期的情况。两组免疫组化结果进行t检验。 结果 32例进行期银屑病患者皮损和非皮损每高倍视野中CD69+CD103+ T淋巴细胞数量分别为11.34 ± 7.60和2.72 ± 4.20,皮损区明显高于非皮损区（t = 8.46,P ＜ 0.01）;其中9例患者皮损消退前后每高倍视野中CD69+CD103+ T淋巴细胞数量分别为14.33 ± 2.21和12.00 ± 4.58,皮损消退前后比较差异无统计学意义（t = 1.98,P = 0.08）;健康对照组为1.70 ± 2.98,与银屑病患者非皮损区比较,差异无统计学意义（t = 0.71,P > 0.05）。 结论 银屑病患者皮肤中原位记忆T淋巴细胞可能在皮损的形成和复发过程中起作用。     

Psoriatic skin reveals the in vivo presence of an epidermal IL-1 inhibitor

Summary Production of inhibitor(s) of IL-1 activity can be induced in keratinocytes by exposure to UVB. We describe in this study the characterization of an endogenous constitutively expressed IL-1 inhibitor which is present in extracts of human psoriatic epidermal keratome biopsies. Size-fractionated extracts of normal human epidermis did not reveal IL-1 inhibitory factor(s) activity in normal epidermis. Psoriatic epidermal extracts, however, contained virtually no IL-1 bioactivity and inhibited the activity of recombinant human IL-1. This IL-1 inhibitor has a molecular weight of approximately 30 kDa and a pI of 5.3, as revealed by fast protein liquid chromatography size fractionation and chromatofocusing of psoriatic epidermal extracts. IL-1 inhibitory activity was not blocked by neutralizing anti-TGF monoclonal antibody. It did not have any inhibitory effect upon normal cellular proliferation but could block the IL-1 induction of IL-2 production by LBRM.33 cells as late as 4 h after exposure of LBRM.33 cells to IL-1. Thus, in vivo human psoriatic epidermis expresses an IL-1 inhibitor that specifically inhibits IL-1 activity but which appears distinct from previously described UV-induced epidermal IL-1 inhibitory activity or TGF.     

PUVA suppresses the expression of cell adhesion molecules of lymphocytes

Abstract To determine the therapeutic mechanism of PUVA in psoriasis vulgaris, the effects of PUVA on activated T lymphocytes were investigated in vitro. Peripheral blood mononuclear cells (PBMC) obtained from healthy volunteers were activated with Con A stimulation (Con A blasts). Both untreated PBMC and Con A blasts were irradiated with UVA light in the presence of 8-methoxypsoralen (8-MOP). The expressions of CD4, CDS, VLA-4 and LFA-1 of PBMC and Con A blasts were stained with each monoclonal antibody and the intensity of fluorescence was analyzed by FACScan. PUVA-treated PBMC showed decreased response to both Con A and PHA stimulation. PUVA treatment also suppressed the IL-2 production of Con A blasts and IL-2 response of PBMC with increasing UVA fluence. The expressions of LFA-I, VLA-4, CD4, CDS and CD25 (IL-2R) molecules were decreased in PUVA-treated Con A blasts. Con A blasts were more sensitive than untreated PBMC to PUVA treatment. These results suggest that the therapeutic effects of PUVA on psoriasis vulgaris can be induced by suppression of the expression of cell surface molecules of activated T lymphocytes.     

Skin-homing T lymphocytes: detection of cutaneous lymphocyteassociated antigen (CLA) by HECA-452 in normal human skin

The immigration of circulating T cells into specific tissues is directed by the interaction between adhesion molecules on lymphocyte subpopulations and their ligands on vascular endothelium. Of these, endothelial leucocyte adhesion molecule (ELAM-1), weakly expressed in normal human skin (NHS), seems to be the counter-structure for cutaneous lymphocyte-associated antigen (CLA). CLA is a 200 kDa cell-surface glycoprotein of which the sugar moieties sialyl Le(a) and sialyl Le(x) are the possible epitopes recognized by the monoclonal antibody HECA-452. HECA-452 was originally described as a marker for lymphoid organ high endothelial cells, but 16% of peripheral-blood-derived T cells react with this antibody. We studied the expression of CLA on the cellular constituents of the skin immune system (SIS). By applying immunohistochemical double staining, 41% of CD3+ T cells, 44% of CD4+ T cells and 31% of CD8+ T cells were found to express CLA. Keratinocytes, CD1a+ Langerhans cells (LC) and endothelial cells did not express HECA-452 in significant numbers in NHS. Monocytes were found to express HECA-452 in 14% of CD68+ cells. CLA expression was present on a relatively low percentage of T cells and subsets localized distant from NHS vessels, suggesting loss of the molecule during further migration after transendothelial passage. However, intraepidermal T cells expressed CLA in similar percentages to T cells localized directly perivascularly. Our findings support the notion that CLA expression by T cells is associated with their homing into cutaneous structures.     

Expression of IL-18 in psoriasis

Abstract Interleukin-18 (IL-18) is a novel cytokine that plays an important role in the T-helper 1 (Th1) response, primarily via its ability to induce IFN-γ production in T cells and NK cells. Human keratinocytes produce IL-18, as do monocytes and macrophages, which are the two major sources of this molecule. It is thought that IL-18 derived from keratinocytes might be involved in the cutaneous Th1-type immune response. In the present study, we investigated the expression of IL-18 in psoriatic lesional skin and attempted to determine whether immunoreactive IL-18 in crude extracts of psoriatic scales is processed to the mature, active form. Immunohistochemical and RT-PCR analysis showed that the expression of IL-18 was increased in psoriatic lesional skin relative to that in normal skin. Western blotting and an ELISA for IL-18 in combination demonstrated that the immunoreactive IL-18 in extracts of psoriatic scales contained the mature form of IL-18, but most of the IL-18 was pro-IL-18. No bioactivity of IL-18 or IFN-γ inducibility in human PBMC could be detected in psoriatic scales. Taken together, these findings indicate that keratinocyte-derived IL-18 participates in the development of the Th1 response in psoriatic lesions, and that its bioactivity appears to be tightly regulated in cutaneous inflammation. Received: 18 October 2000 / Revised: 3 February 2001 / Accepted: 27 April 2001     

银屑病T细胞活化和信号转导的进展

银屑病发病与辅助性T细胞亚群分化失衡，活化T细胞信号转导失控及特定基因表达异常密切相关。T细胞可经抗原或非抗原刺激而活化，活化T细胞的信号转导途径有：Ca^2＋离子依赖的蛋白激酶C途径、Ras丝裂原活化的蛋白激酶途径和詹纳斯激酶一信号转导及转录活化因子途径等。其中詹纳斯激酶一信号转导及转录活化因子途径是细胞因子信号转导的主要途径。有效调控T细胞活化和信号转导途径对治疗银屑病有重要意义。     

T淋巴细胞及细胞因子与银屑病的发病关系

近年来一些新的研究发现，银屑病患者外周血的T细胞表面的CD80和天然杀伤细胞受体的表达明显上调，单核细胞的活性也有所改变，而T细胞还可以影响正常皮肤的表皮通过时间，皮损中调节性T淋巴细胞亚群也有变化，白介素-23、20、19以及α-干扰素对银屑病的发病均有促进作用。一些新的免疫学研究发现，CD11α单抗、LFA-3／IgGl融合蛋白、TNF—α已经成为银屑病免疫治疗中较为成熟的疗法，而粒细胞-巨噬细胞集落刺激因子单抗IgGl，CD4单抗及补体受体3抗体的治疗作用在动物实验中已得到初步验证，有望为银屑病的治疗提供新的突破点。     

调节性T淋巴细胞和Th17细胞与银屑病的研究进展

银屑病是一种与T淋巴细胞相关的自身免疫性疾病,新近研究发现,除了与Th1细胞有关外,调节性T淋巴细胞尤其叉头/翅膀状螺旋转录因子诱导表达的调节性T细胞和Th17细胞在银屑病的发病过程中起着非常重要的作用。其中,叉头/翅膀状螺旋转录因子（＋）调节性T细胞平衡免疫抑制和免疫激活的转换在银屑病加重方面起到关键作用,Th17细胞分泌的细胞因子IL-17A、IL-17F、IL-22、IL-23、IL-36及肿瘤坏死因子α等在皮肤疾病发生发展中起到重要的作用。银屑病是由调节性T细胞和Th17细胞等多种免疫细胞和细胞因子共同参与的疾病。     

银屑病患者皮损及非皮损部位粘附分子免疫组化研究

目的　为了更好地了解浸润 T淋巴细胞和内皮细胞粘附分子的原位表达在银屑病皮损中的相互关系。方法　采用免疫组化染色方法研究银屑病皮损部位和非皮损部位的浸润 T淋巴细胞亚群和内皮细胞粘附分子 (ICAM- 1,EL AM- 1,VCAM- 1)的原位表达情况。结果　银屑病患者皮损部位 T细胞亚群和内皮细胞粘附分子的原位表达均显著高于非皮损部位 ,而且浸润 T淋巴细胞亚群的细胞密度和内皮细胞粘附分子的原位表达程度呈显著正相关。与正常人相比 ,银屑病非皮损部位和经外用皮质类固醇激素治疗后外观正常的皮肤内皮粘附分子仍呈上调表达。结论　银屑病患者皮肤真皮血管内皮细胞粘附分子的异常上调表达是造成银屑病复发的原因之一。     

IL-1 and IL-1 receptor antagonist regulation during keratinocyte cell cycle and differentiation in normal and psoriatic epidermis

Abstract Changes in the levels of IL-1 (IL-1α, IL-1β, and its receptor antagonist, IL-1RA) occur upon keratinocyte differentiation in vitro and are associated in vivo with abnormal differentiated and hyperproliferative states of psoriatic keratinocytes. A flow cytometric procedure, capable of detecting changes in the intracellular levels of IL-1, was used to determine whether intracellular IL-1/IL-1RA levels in psoriatic and normal keratinocytes alter during in vivo differentiation and the cell cycle. Increases in the IL-1RA levels and IL-1α levels were observed as both normal and psoriatic keratinocytes differentiated from basal stem cells (β₁ integrin⁺, small size) into transient amplifying cells (TAC; β₁ integrin⁺, large size). Upon further differentiation (β₁ integrin^–, large size) both IL-1RA and IL-1α levels dropped. However, while psoriatic IL-1β levels increased as cells differentiated into TACs, little change occurred in the IL-1β levels of normal keratinocytes during differentiation. Changes in IL-1/IL-1RA levels were also detected as keratinocytes progressed through the cell cycle. Within the basal stem cell population of both normal and psoriatic keratinocytes, the IL-1α and IL-1RA levels increased between G0/G1 and S but not between S and G2/M. However, psoriatic basal keratinocyte IL-1β levels differed from those of normal keratinocytes by showing no increase between S and G2/M. The IL-1/IL-1RA levels of normal TAC increased throughout the cell cycle. However, in psoriatic TAC, a slight decrease in IL-1α and IL-1RA levels was observed between G0/G1 and S followed by a delayed increase between S and G2/M. IL-1β levels in psoriatic TAC varied little throughout the cell cycle. Thus, we were able to detect precisely the regulation of IL-1/IL-1RA intracellular levels during the keratinocyte cell cycle and differentiation, showing notably decreased IL-1β upregulation in psoriatic keratinocytes progressing through the cell cycle. Received: 15 July 1996     

Pathogenic role of IL-17 in psoriasis and psoriatic arthritis

Psoriasis is a chronic inflammatory skin disorder resulting from a complex network of cytokines and chemokines produced by various immune cell types and tissue cells. Emerging evidence suggests a central role of IL-17 and IL-23/T17 axis in the pathogenesis of psoriasis, giving a rationale for using IL-17-blocking agents as therapeutics.Three agents targeting IL-17 signaling are being studied in Phase III clinical trials: secukinumab and ixekizumab (IL-17 neutralizing agents), and brodalumab (IL-17 receptor antagonist). Preliminary results are highly promising for all anti-IL17 agents, creating fair expectations on this class of agents as the new effective therapeutic approach for the treatment of psoriasis.     

The effects of ultraviolet B treatment on the expression of adhesion molecules by circulating T lymphocytes in psoriasis

BACKGROUND: T lymphocytes are believed to play a role in the pathogenesis of psoriasis; > 80% of T lymphocytes that infiltrate psoriatic lesions express the surface glycoprotein cutaneous lymphocyte-associated antigen (CLA), compared with < 20% in the blood. Exposure to ultraviolet (UV) B is an effective treatment for psoriasis. OBJECTIVES: To compare the effects of UVB treatment of psoriasis on the expression of CLA and several other surface markers expressed by circulating T lymphocytes. METHODS: Peripheral blood mononuclear cells from psoriatic patients were stained for adhesion molecules and stimulated with streptococcal antigens before and once weekly during 3 weeks of UVB treatment. RESULTS: A marked and progressive decrease was observed during the treatment in expression of the CLA and the very late antigen-4alpha by T cells; this decrease correlated closely with clinical improvement (Psoriasis Area and Severity Index). T-cell expression of intercellular adhesion molecule-1 was not significantly affected during the treatment and no change was observed in the activation markers CD25 and CD69 or lymphocyte proliferation after stimulation with streptococcal antigens or superantigens. CONCLUSIONS: UVB treatment is associated with a marked reduction in the expression of skin-homing molecules by circulating T cells. This may be relevant to the therapeutic effect of UVB in psoriasis.     

Th17细胞相关因子与寻常性进行期银屑病的相关性研究

目的探讨Th17细胞相关因子白细胞介素(IL)-17A、IL-17F、IL-21、IL-22与寻常性进行期银屑病发病的相关性。方法通过实时定量反转录聚合酶链式反应(RT-PCR)分别检测30例患者和20名正常人外周血单个核细胞(PBMC)、12例患者皮损、12名正常皮肤组织中上述4种细胞因子的mRNA表达水平。结果患者组PBMC中IL-17A、IL-17F、IL-21和IL-22的mRNA表达水平较正常组显著升高(P均0.05),患者组皮损中4种细胞因子的mRNA表达明显高于正常组(P均0.05)。结论 Th17细胞因子IL-17A、IL-17F、IL-21和IL-22的mRNA水平在患者组PBMC及皮肤组织中明显升高,提示Th17细胞因子可能与寻常性银屑病的发病有一定相关性。     

组织常驻记忆性T细胞与银屑病

银屑病为免疫介导的慢性炎症性皮肤病,复发是其特点之一,且复发一般位于原皮损部位［1?3］。白细胞介素23（IL?23）/IL?17轴在银屑病的发病中具有重要作用［4］。γδT细胞为银屑病产生关键致病性细胞因子IL?17最主要的细胞［5］,应用咪喹莫特诱导的银屑病样鼠模型中,γδT细胞Vγ4+T细胞亚群具有记忆功能并长期存在于小鼠皮肤,再次经咪喹莫特刺激后能够产生比初次反应更强更快的反应［6］。Vγ4+ T细胞的特征与组织常驻记忆性T细胞（TRM）的特征相似,可能也是银屑病在相同部位复发的关键性细胞。我们综述银屑病与TRM之间的联系……     

An important role of tumor necrosis factor-α in the induction of adhesion molecules in psoriasis

Abstract Recent studies have suggested that cell adhesion plays an important role in the development and regulation of inflammation. To elucidate the mechanisms of regulation of adhesion molecule expression by cytokines in psoriatic lesions, we compared the expression of intercellular adhesion molecule-1, vascular cell adhesion molecule-1, E-selectin, and P-selectin immunohistochemically in involved and uninvolved psoriatic skin with the expression of these molecules in normal skin, and measured the amounts of tumor necrosis factor-α, interferon-γ, interleukin-1α, and interleukin-1β in the supernatant of freeze-thawed skin specimens using an enzyme-linked immunosorbent assay. There was strong staining for P-selectin on endothelial cells from involved skin. There was also strong staining for intercellular adhesion molecule-1 on keratinocytes, dermal infiltrates, and endothelial cells from involved skin and on endothelial cells from uninvolved skin, and strong staining for vascular cell adhesion molecule-1 on dermal dendritic cells and fibroblasts and for E-selectin on endothelial cells from involved skin. Large amounts of tumor necrosis factor-α were detected in six out of ten specimens of involved skin, but not in uninvolved or normal skin, although interferon-γ was detected in both involved and uninvolved skin to the same extent. Neither interleukin-1α nor interleukin-1β was detected in involved skin. There was strong staining for tumor necrosis factor-α on keratinocytes and endothelial cells from involved skin. These findings suggest that tumor necrosis factor-αmight play an important role in the induction of vascular adhesion molecules in psoriatic lesions. Received: 17 June 1997