The autologous mixed epidermal cell-T lymphocyte reaction is elevated in psoriasis: a crucial role for epidermal HLA-DR+/CD1a- antigen-presenting cells.

The objective of this study was to determine whether epidermal cells (EC) from psoriasis lesions and uninvolved skin could stimulate autologous T lymphocytes in the in vitro autologous mixed epidermal cell-T lymphocyte reaction (autologous MECLR). The functional role of antigen-presenting cell (APC) subsets was concurrently determined in this reaction. Mononuclear cells and purified T lymphocytes from peripheral blood of psoriasis patients showed a clear proliferative response to autologous unpurified epidermal cells from involved as well as uninvolved skin. The autologous mixed leukocyte reaction (MLR) was not elevated in psoriasis patients. In healthy controls and contact allergy patients, T-lymphocyte proliferation was not observed either in the autologous MECLR or in the autologous MLR. The level of proliferation in the autologous MECLR from psoriasis patients correlated to the number of epidermal cells that were added. To exclude the possibility that the observed proliferation in the autologous MECLR in psoriasis was due to the presence of epidermal T lymphocytes that were being stimulated and expanded in vitro, the stimulator EC were gamma irradiated (30 Gy) in some experiments. Preincubation of EC with cyclosporin A (CsA) significantly inhibited the autologous MECLR. The CsA-induced inhibition could be neutralized by the addition of fresh untreated EC to these cultures. This indicated that one of the modes of action of CsA in resolving psoriasis is, as some investigators have already shown, via inhibition of epidermal accessory cell function. In the autologous MECLR, APC from psoriasis skin could initiate this reaction, whereas APC from peripheral blood could not. This occurred in an MHC class II restricted fashion. Depletion experiments showed that Langerhans cells (HLA-DR+/CD1a+) were not the principal stimulators of autologous T lymphocytes in the MECLR. These results indicated that mainly HLA-DR+/CD1a- epidermal cells from psoriasis patients could stimulate autologous peripheral blood T lymphocytes in an MHC class II-restricted fashion.     

Distribution of naive and memory T-cells in photoprovoked and spontaneous skin lesions of discoid lupus erythematosus and polymorphous light eruption

Immune response to ultraviolet radiation-modified skin antigens has been suggested as a pathomechanism of skin lesions in discoid lupus erythematosus and polymorphous light eruption. In order to elucidate the role of T-lymphocyte subsets in this response, we studied the distribution of CD45RO+, CD45RA+ and CD31+ cells and the endothelial expression of adhesion molecules E-selectin/P-selectin, intercellular adhesion molecule-1 and CD31 antigen in photoprovoked and spontaneous skin lesions. Typically, CD45RA+ cells were the prevailing inflammatory cell population of discoid lupus erythematosus, whereas CD45RO+ cells prevailed in both diseases and in healthy controls. Epidermotrophism of any T-cell subsets was more typical of discoid lupus erythematosus, whereas no major differences in endothelial adhesion molecule expression was found between the 2 diseases. Strong keratinocyte ICAM-1 expression was associated with adjacent CD45RO+ cell infiltrates, not with CD45RA+ or CD31+ cell infiltrates. We conclude that the cellular immune response to UV radiation is dissimilar in discoid lupus erythematosus and polymorphous light eruption.     

Mixed skin cell lymphocyte culture reaction (MSLR) in psoriasis

The Mixed Skin Cell Lymphocyte Culture Reaction (MSLR) was studied as an in vitro approach of lympho-epidermal interactions in psoriasis. The ability of peripheral blood lymphocytes from patients with psoriasis to proliferate in response to stimulation by epidermal cells and the capacity of psoriatic epidermal cells to stimulate T cells were investigated and compared to results with cells from controls. While stimulation of control lymphocytes by autologous epidermal cells was observed, although weaker than the proliferation in response to allogeneic control epidermal cells, no stimulation was observed in autologous MSLR using psoriatic cells. The ability of epidermal cells from psoriatic skin, either uninvolved or involved skin, to induce proliferation of control lymphocytes in allogeneic MSLR did not differ from that of control epidermal cells. In contrast with results obtained with control lymphocytes and epidermal cells in allogeneic MSLR, peripheral blood cells from psoriatic subjects failed to react to stimulation by control allogeneic epidermal cells. These results indicate a normal capacity of psoriatic epidermal cells to stimulate in MSLR and a functional inability of peripheral blood lymphocytes from patients with psoriasis to react in MSLR which is in agreement with previous reports of abnormal T cell functions in the disease.     

Antigen presentation and T-cell activation in epidermodysplasia verruciformis

Aberrant immune responses may play a role in the susceptibility of patients with epidermodysplasia verruciformis to human papilloma virus (HPV). We examined the stimulatory capacity of antigen-presenting cells from HPV-infected skin and peripheral blood T-cell responses of patients with epidermodysplasia verruciformis. The percentage of Langerhans cells in relation to total epidermal cells in suspension was slightly reduced in HPV-infected lesions, relative to apparently clinically uninfected epidermis. In addition, the morphologic appearance of Langerhans cells was altered in lesional epidermal sheets. Despite these abnormalities, Langerhans cells were functionally intact in their capacity to present alloantigens to T cells and, in fact, the epidermis of HPV-infected lesions demonstrated enhanced antigen-presenting activity in three of four patients tested. The antigen-presenting activity was entirely abrogated by removal of Langerhans cells and was not associated with increased activity of cytokines with stimulatory activity for the thymocyte co-stimulation assay. Although epidermodysplasia verruciformis T cells were unresponsive to autologous HPV-infected epidermis, they responded well to mitogens, allogeneic mononuclear leukocytes, and allogeneic epidermal cells. Epidermodysplasia verruciformis T cells were inhibited in their capacity to respond to allogeneic epidermal cells when they were simultaneously exposed to autologous epidermal cells from HPV-infected lesional epidermis, but not to normal-appearing epidermis. Thus, although Langerhans cell activity is intact in epidermodysplasia verruciformis, these individuals fail to respond to autologous papillomas, which may, at least in part, be explained by an interaction between papillomal epidermal cells and autologous T cells that results in an inhibited response.     

Severe sun sensitivity and the presence of antinuclear antibodies in patients with polymorphous light eruption-like lesions. A form fruste of photosensitive lupus erythematosus?

BACKGROUND: Initial lesions seen in some cases of lupus erythematosus may simulate the clinical features of polymorphous light eruption. OBJECTIVE: To evaluate the significance of antinuclear antibody screening in patients with polymorphous light eruption or to find better methods to define patients at risk to have lupus erythematosus, we analyzed the data of 198 patients with polymorphous light eruption. METHODS: History, type, and persistence of skin lesions were reviewed, and serologic variables, the minimal erythema dose, and the ultraviolet action spectrum for inducing skin lesions were determined. RESULTS: The morphologic features of skin lesions and results of phototesting were consistent with previously published characteristics of patients with polymorphous light eruption. Twenty-eight (14%) had high titers of antinuclear antibody (greater than or equal to 1:80). We found a highly significant correlation between severe sun sensitivity and the presence of high antinuclear antibody titers. Of these patients with severe sun sensitivity and high titers of antinuclear antibody, in three the diagnosis of systemic lupus erythematosus could be established according to American Rheumatism Association criteria. CONCLUSION: These results suggest that a combination of severe sun sensitivity and high titers of antinuclear antibody may characterize a subset of sun-sensitive patients with some features of lupus erythematosus.     

Jessner's lymphocytic infiltration of the skin: a CD8+ polyclonal reactive skin condition

BACKGROUND: Jessner's lymphocytic infiltration of the skin (JLIS) is a clinically and histologically distinct disease entity. Conflicting results have been reported concerning its differentiation from cutaneous lupus erythematosus and polymorphous light eruption, its relationship to palpable migratory arciform erythema and its classification as a B-cell or a CD4+ T-cell lymphoproliferative disease. OBJECTIVE: Our study was performed in order to re-evaluate JLIS clinically and by immunohistochemical and molecular analyses. METHODS: Stringent inclusion/exclusion criteria were used to collect a cohort of 34 patients with JLIS that did not overlap with lupus erythematosus or polymorphous light eruption. Clinical data were analysed, and immunohistochemical and molecular studies were performed including TCR-gamma PCR GeneScan software analysis of tissue and peripheral blood samples. RESULTS: In the majority of the patients, the lesions consisted only of papules and plaques while in 12% annular lesions were also seen. The lesions were found on the face (38%), on the trunk and arms (50%) or at both sites (12%). Immunohistochemical analyses revealed a clear predominance of T cells in all patients, and of CD8+ T cells in 77% of the patients. As judged by TCR-gamma PCR GeneScan analysis, 98 and 79% of the tissue and peripheral blood samples, respectively, showed a polyclonal T-cell population; identical T-cell clones were not detected concomitantly in both the skin and the peripheral blood of the same patient. CONCLUSIONS: JLIS occurs at 2 major predilection sites, that is the face and trunk. Therefore introduction of palpable migratory arciform erythema as a separate entity is not justified. The lymphoid infiltrates are dominated immunohistochemically by CD8+ T cells that do not show clonality on molecular analysis. Thus, JLIS represents a characteristic CD8+ polyclonal reactive skin condition.     

All-trans retinoic acid induces functional maturation of epidermal Langerhans cells and protects their accessory function from ultraviolet radiation

Abstract Retinoids provide some protection against ultraviolet radiation-induced skin damage. We have previously shown that topical all-trans retinoic acid prevents ultraviolet light from reducing the density of epidermal Langerhans cells in the epidermis but does not inhibit the development of immunosuppression to a locally applied contact sensitizer. We therefore investigated the ability of all-trans retinoic acid to modulate Langerhans cell induction of allogeneic T-cell proliferation in the mixed epidermal cell lymphocyte reaction. Langerhans cells isolated from all-trans retinoic acid-treated mice induced an enhanced mixed epidermal cell lymphocyte reaction. This is similar to Langerhans cells cultured with granulocyte-macrophage colony stimulating factor. Retinoic acid treatment also enhanced the allogeneic cell-stimulating capability of Langerhans cells isolated from ultraviolet-irradiated mice. Langerhans cells from all-trans relinoic acid-treated, ultraviolet-irradiated mice which were “matured” by 3 days in culture induced a larger mixed epidermal cell lymphocyte reaction than mice treated with solvent and ultraviolet irradiation. Thus all-trans retinoic acid treatment of mice causes Langerhans cell maturation and inhibits ultraviolet light from reducing their density or impairing their allogeneic cell-stimulating capacity. However, these mice remained immuno-suppresscd upon application of a contact sensitizer to irradiated or unirradiated skin. It is thus likely that, whereas all-trans relinoic acid protects local Langerhans cell numbers and function, it does not inhibit the production of an ultraviolet radiation-induced photoproduct which causes immunosuppression.     

Antigen-independent expansion of T cells from psoriatic skin lesions: phenotypic characterization and antigen reactivity

The pathogenesis of psoriasis appears to depend on T cells, which have been proposed to mediate the disease through an autoimmune process. To test this hypothesis we have propagated four T-cell lines from biopsies of psoriatic skin lesions by antigen-independent methods. Flow cytometric immunophenotyping showed the lines to be composed mainly of CD4-positive, αβ-cell receptor (TCR)-positive cells, which secreted a cytokine profile suggestive of predominant T-helper type 1 (Th1) status. Analysis of TCR variable region (Vβ) usage revealed two- to eight-fold increases in the expression of certain Vβ species in lesional lines as compared with autologous peripheral blood mononuclear cells (PBMC), with the increased Vβ species being expressed on more than 5% of cells in two of the lines. Lines were also used to test for responses to a range of epidermal antigen preparations in the presence of irradiated autologous PBMC as antigen-presenting cells. The lines failed to proliferate in response to psoriatic lesional stratum corneum extracts, dispase-separated normal human epidermal extracts, and an epidermal keratin preparation before and after trypsinization, in spite of good proliferative responses to anti-CD3 which indicated that the lines were not anergic. In addition, the lines and PBMC from normal volunteers and the patients with psoriasis gave little or no response to recombinant streptococcal M protein. Thus, in spite of accumulating evidence for selective expansion of certain Vβ-expressing T cells in psoriatic lesions, epidermal autoantigens have not been identified by using a bioassay which depended largely on the proliferation of lesional CD4-positive cells. The role of streptococcal M protein, which bears some homology with epidermal keratin is also open to question, at least in chronic plaque psoriasis. Further work is therefore required to obtain direct evidence that autoimmune processes are important in the pathogenesis of chronic plaque psoriasis.     

重症药疹患者外周血药物特异性T细胞扩增及干扰素γ产生的研究

目的 检测重症药疹患者外周血中药物特异性T细胞扩增及干扰素γ(IFN-γ)产生情况.方法 共收集10例重症药疹门诊患者,分离患者外周血单一核细胞(PBMC),经相应的致敏药物刺激后培养出T细胞株,用体外ELISpot和培养ELISpot方法检测患者PBMC及药物特异性T细胞株分泌IFN-γ的情况.对10例患者同时设立与致敏药物分子结构不同的无关药物对照组.结果 重症药疹组中的10例患者PBMC、药物特异性T细胞株经致敏药物刺激后,IFN-γ的分泌明显高于正常对照组(P<0.01),且T细胞株经药物刺激后IFN-γ的分泌显著高于PBMC组(P<0.01).与致敏药物分子结构不同的无关对照药物不能够使药疹患者PBMC产生IFN-γ,不能培养出相应的T细胞.3例重症药疹患者治愈1～3年后,PBMC中仍存在药物特异性T细胞.结论 重症药疹患者体内存在药物特异性T细胞.体外ELISpot联合培养ELISpot方法在体外检测可能有助于致敏药物的鉴定.药疹患者治愈后体内持续存在药物特异性T细胞.     

多形性日光疹皮损中板层小体分布、神经酰胺酶表达与皮肤屏障功能

目的 探讨多形性日光疹（PLE）表皮中板层小体的分布、神经酰胺酶的表达与皮肤屏障受损的相关性。方法 选取PLE患者47例及正常人对照40例,通过电镜观察两组皮损处颗粒层、棘层板层小体的数量及分布情况,运用免疫组化测定皮损处神经酰胺酶的表达,采用无创性皮肤测试仪测量皮损处经皮水分丢失（TEWL）、角质层含水量及皮脂含量。结果 透射电镜结果显示：与对照组相比,PLE患者颗粒层、棘层板层小体数量明显少于正常人对照组,分布较正常人对照组紊乱。免疫组化结果显示：PLE患者皮损处神经酰胺酶表达20例阳性、21例弱阳性、6例阴性;正常人对照组中36例阳性、4例弱阳性,差异有统计学意义（P < 0.01）;皮损处TEWL（34.2191 ± 12.70）较正常人对照组（16.8350 ± 6.50）高,角质层含水量（22.7319 ± 8.71）较正常人对照组（29.4250 ± 5.08）低,差异有统计学意义（P < 0.01）;皮脂含量两者之间差异无统计学意义。结论 PLE患者存在神经酰胺合成障碍,可能是皮肤屏障受损的原因之一。     

Psoriasis is mediated by a cutaneous defect triggered by activated immunocytes: induction of psoriasis by cells with natural killer receptors

This study was performed to ask whether psoriasis is a unique pathologic response of epidermis of psoriatic patients, or cells with natural killer receptors can induce psoriatic changes in skin from nonpsoriatic donors. Human nonlesional skin from five psoriatics, as well as from seven nonpsoriatics was grafted on to beige-SCID mice. Lymphocyte lines with natural killer activity, and mixed natural killer, natural killer T cell phenotype, were generated by culture of peripheral blood mononuclear cells from both psoriatic, and normal donors, in 100 U interleukin-2 per ml for 14 d. Natural killer cells were injected into the human skin grafts, and the grafts were harvested after 4 wk. Injection of natural killer cells from psoriatic donors into autologous nonlesional psoriatic skin resulted in classic psoriasis histology with a significant increase in epidermal thickness, and proliferation, as well as expression of epidermal human leukocyte antigen DR, intercellular adhesion molecule-1, CD1d, and K-16. Superantigen stimulation was not necessary. In contrast, injection of natural killer cells from normal donors into autologous normal skin did not induce the histology of psoriasis, but that of psoriasiform dermatitis. This is a nonspecific reaction pattern. These grafts also exhibited a significant increase in epidermal thickness, and proliferation. Differences from psoriasis included mild epidermal edema (spongiosis), hypergranulosis, irregular elongation of rete ridges, and lack of thinning of the suprapapillary plate. Injection of allogeneic natural killer cells into grafts also resulted in psoriasiform dermatitis, regardless of the source of natural killer cells, or skin. Psoriasis induction by cells with natural killer receptors appears to be dependent upon the source of skin. This suggests that psoriasis results from a cutaneous defect that is triggered by an autoimmune activation.     

Jessner's lymphocytic infiltration of the skin. A clinical study of 100 patients

Jessner's lymphocytic infiltration of the skin is a well-known but poorly understood disorder. Some doubt still exists about whether it is a single entity or a heterogeneous group that can pass into polymorphous light eruption, discoid lupus erythematosus, or even malignant lymphoma. Therefore, a large number of patients with lymphocytic infiltration of the skin (N = 100; 46 male, 54 female) were examined to elucidate these questions. We conclude that lymphocytic infiltration of the skin is a single entity. Progression into polymorphous light eruption, discoid lupus erythematosus, or lymphoma was not observed. However, this study shows that lymphocytic infiltration of the skin and polymorphous light eruption cases occur simultaneously in 1 patient. In this study the cases of 10 patients with this combination are reported. An effective but harmless therapy is yet unknown. Intermittent use of topical steroids can be useful but is not effective in many patients.     

Histopathologic findings in papulovesicular light eruption

Papulovesicular light eruption (PVLE) is a distinct clinical and histological subset of polymorphous light eruption. Biopsies from 16 patients with PVLE showed prominent epidermal and dermal changes consisting of intercellular edema, papillary dermal edema and a perivascular and interstitial infiltrate in the upper dermis.     

UVB-induced leucocyte trafficking in the epidermis of photosensitive lupus erythematosus patients: normal depletion of Langerhans cells

BACKGROUND: The pathogenic mechanisms of UV-induced skin lesions of lupus erythematosus (LE) are unknown. In a recent study of pathogenic mechanisms of polymorphic light eruption (PLE), significantly more Langerhans cells (LCs) persisted in the epidermis after UVB overexposure than in healthy individuals. Interestingly, the same phenomenon was observed in one subacute cutaneous lupus erythematosus (SCLE) patient. It could therefore be hypothesized that both photodermatoses share a common pathogenic mechanism of photosensitivity. In the present study, we tested this hypothesis by investigating leucocyte trafficking in the initial phase of cutaneous LE after intense UVB exposure. METHODS: In 22 photosensitive LE patients (12 chronic discoid lupus erythematosus, seven systemic lupus erythematosus and three SCLE) and nine age/sex-matched controls, uninvolved buttock skin was exposed to six minimal erythemal dose (MED) UVB radiation. Subsequently, biopsies were taken after 24, 48 and 72 h, and one control biopsy was taken from unirradiated skin. Skin sections were stained for the presence of LCs, neutrophils and macrophages. Areal percentages of positively stained cells within the epidermis were quantified and compared between the patients and controls. RESULTS: A gradual decrease of epidermal LCs and a gradual increase of epidermal neutrophils and macrophages at several timepoints after six MED irradiation was observed equally in both LE patients and controls. CONCLUSION: Immunohistopathology of irradiated uninvolved skin of photosensitive LE patients did not reveal the same pathologic trafficking of LCs and neutrophils as described for PLE patients. We conclude that different mechanisms are operative in the pathogenesis of PLE and photosensitive LE.     

Successful treatment of severe polymorphous light eruption with azathioprine

Two patients with severe, disabling polymorphous light eruption, who were unable to tolerate photochemotherapy and who were unresponsive to alternative recognized therapies, are described. In both cases short-term treatment with azathioprine achieved a marked clinical improvement, confirmed by testing with an irradiation monochromator. This response suggests an immunological basis for polymorphous light eruption. Patients with polymorphous light eruption vary considerably with regard to degree of photosensitivity, and while azathioprine therapy should not be considered in the majority of sufferers, we have shown that it can be very helpful in rare patients with exceptionally severe disease.     

Flexural erythematous eruption following autologous peripheral blood stem cell transplantation: a study of four cases

Autologous bone marrow transplantation and autologous peripheral blood stem cell transplantation (APBSCT) are alternative therapeutic options in the treatment of various malignancies. We describe four patients undergoing APBSCT for malignancies; they developed a cutaneous eruption characterized by confluent erythematous and hyperpigmented patches within the flexural areas during the first month after transplantation. The lesions were poorly circumscribed without epidermal changes such as scaling, xerosis, erosions or atrophy. The skin patches were treated with topical corticosteroids and resolved within a few days with discoloration. Histopathological findings were characterized by focal vacuolar degeneration of the basal layer with epidermal dysmaturation. We believe that these cutaneous eruptions are consistent with an interplay of high-dose chemotherapy and local factors such as friction, local skin temperature and eccrine gland distribution, which could explain the constant location of this eruption in the axillae and genital area.     

Alopecia areata. Autoreactive T cells are variably enriched in scalp lesions relative to peripheral blood.

BACKGROUND AND DESIGN--Alopecia areata is a condition characterized by hair loss in association with perifollicular infiltration of T cells and antigen-presenting cells. Autoreactive T cells are postulated to amplify this abnormality by interacting with DR+ follicular epithelium. These cells may recognize either autologous major histocompatibility complex class II antigen or an autoantigen restricted by major histocompatibility complex class II. Limiting dilution analysis was used to determine the frequency of autoreactive lymphocytes in scalp biopsy specimens and peripheral blood from seven adult patients with alopecia areata. Autoreactive T cells are defined for this study as those that proliferate in response to autologous irradiated peripheral blood mononuclear cells. RESULTS--Autoreactive lymphocytes were enriched in scalp biopsy specimens relative to peripheral blood in five of seven patients. This enrichment was statistically significant in four of five patients. Five autoreactive T-cell clones derived from lesional scalp were characterized. Four of these clones were CD3+CD4+CD8- and one clone was CD3+CD4-CD8+. CONCLUSIONS--Enrichment of autoreactive cells in lesions of alopecia areata supports a role for these cells in the pathogenesis of this condition. Enrichment of autoreactive lymphocytes is also found in allergic contact dermatitis. Thus, these autoreactive lymphocytes may have a general role in inflammation.     

Repeated exposure to ultraviolet A in polymorphous light eruption patients and normal subjects: a clinical and histopathological study

The clinical and histopathological responses to repeated exposures of ultraviolet A were studied in patients with polymorphous light eruption and in normal controls. Variable degrees of perivascular and diffuse infiltrates (lymphocytic and neutrophilic) were detected in both groups. These findings indicate that more specific parameters should be used to distinguish reactive from pathological responses.     

The role of histopathology in polymorphous light eruption light testing

Provocative light testing was performed in ten patients with polymorphous light eruption (Pmle) and in ten normal subjects to determine whether the histopathology of irradiated test sites could be used as an end point for a positive response. Three separate test sites on the lower back were irradiated (UV-B) with a single exposure to i minimal erythema dose (MED), a single exposure to 5 x MED, or three consecutive daily exposures to 3 x MED. Biopsies of all test sites were coded and examined without knowing if the biopsy was from a normal subject or a patient with Pmle. In no case was a rash reproduced by light testing. A spectrum of histologic features were observed at the three test sites in both normal subjects and patients with Pmle with no significant differences noted between the two groups. It was concluded that the histology at these UV-B irradiated test sites could not be used as an endpoint Pmle for testing. In establishing Pmle light testing techniques which rely on histology it is mandatory to include adequate numbers of normal controls.     

Ultraviolet A radiation-induced biological effects in human skin: relevance for photoaging and photodermatosis

There is increasing evidence that longwave ultraviolet (UV) radiation (UVA; 320-400 nm) plays an important role in the pathogenesis of photodermatoses such as polymorphous light eruption as well as photoaging. In order to fully understand these detrimental effects it is critical to analyze the photobiological and molecular mechanisms by which UVA radiation affects the function of human skin cells. In this review, our current knowledge about the signal transduction pathway involved in UVA radiation-induced expression of proinflammatory genes relevant to the pathogenesis of polymorphous light eruption will be summarized. In addition, recent studies on the role of mitochondrial DNA mutations in UVA radiation-induced photoaging of human skin will be discussed. For both biological endpoints the UVA radiation-induced generation of singlet oxygen within human skin appears to be of critical importance. These studies are of enormous clinical relevance because they indicate that prevention of the generation of singlet oxygen or inhibition of singlet oxygen-induced signaling pathways may prove to be critical for effective protection of human skin against UVA radiation-induced damage.