Gone but not forgotten: lesional memory in psoriatic skin

One of the most frustrating aspects of treating psoriasis is the tendency of psoriatic skin lesions to recur after therapy has been discontinued. Not only do lesions recur, but they often recur in the same anatomical locations, expanding to the size they were before therapy. This engenders feelings of frustration and futility in both patients and the dermatologists who care for them. In this issue, Suárez-Fari?as and colleagues identified a gene set-the residual disease genomic profile-of psoriasis, suggesting the presence of both immunologic and structural abnormalities within healed psoriatic lesions. By understanding this "invisible lesion," we may be one step closer to curing psoriasis.     

LTA4 hydrolase in human skin: decreased activity,but normal concentration in lesional psoriatic skin

Leukotriene A₄ (LTA₄) hydrolase which transforms LTA₄ into the proinflammatory compound LTB₄ has been identified in human epidermis. The purpose of this study was to investigate the potential role of this enzyme in psoriasis, in which LTB₄ is present in biologically active concentrations. The concentration and activity of LTA₄ hydrolase was determined in normal skin and in matched samples of involved and uninvolved psoriatic skin. The enzyme content was determined using an affinity-purified antibody. This antibody was also used for immunohistochemical staining of skin biopsies. Immunohistochemically LTA₄ hydrolase was localized predominantly in the basal and spinous layers in normal skin and in involved and uninvolved psoriatic skin. The LTA₄ hydrolase content varied between 2.8 and 3.1 μg enzyme/mg protein and was found to be similar in normal and psoriatic skin, involved as well as uninvolved. In contrast, the activity of the enzyme was decreased significantly in involved psoriatic skin (9.9±2.1 μg LTB₄/mg enzyme per min) compared with matched uninvolved psoriatic skin (16.4±3.5 μg LTB₄/mg enzyme per min), but was decreased only insignificantly compared with normal skin (12.4±1.8 μg LTB₄/mg enzyme per min). It was found that the conversion of LTA₄ to LTB₄ results in inactivation of LTA₄ hydrolase activity. This finding is compatible with the idea that the decreased LTA₄ hydrolase activity in involved psoriatic skin reflects transcellular LTB₄ formation in vivo. In peripheral lymphocytes the enzyme content was 1.3±0.3 μg enzyme/mg protein in normal lymphocytes and 1.4±0.3 μg enzyme/mg protein in psoriatic lymphocytes, which was significantly lower than in the skin. In contrast, the specific LTA₄ hydrolase activities in normal and psoriatic lymphocytes (23.4±1.3 and 21.3±1.7 μg LTB₄/mg enzyme per min) were significantly higher than in normal skin. These findings may indicate the existence of LTA₄ hydrolase isoforms in human lymphocytes and human skin.     

Immunoglobulin A (IgA) deposits in lesional skin of a patient with blepharochalasis

Summary We describe a 21-year-old male patient with blepharochalasis, a form of localized acquired cutis laxa. He had a 13-year history of recurrent swelling attacks of the eyelids of unknown origin leading to periocular localized cutis laxa. Histology of lesional skin confirmed almost complete loss of elastic fibres in the reticular and papillary dermis. Immunofluorescence and immunoelectron microscopy studies showed abundant immunoglobulin A (IgA) deposits around the remaining elastic fibres. Control skin of the forearm was negative. These findings support the hypothesis that immunopathogenetic mechanisms may contribute to the elastolytic process of blepharochalasis.     

Graft-versus-host disease-like eruption in a patient with non-Hodgkin's lymphoma

Graft-versus-host disease (GVHD) is most commonly seen as a complication of bone marrow transplantation, although it can occur whenever tissue or blood products are given whereby immunologically competent donor lymphocytes react against host tissues. A 65-year-old man with non-Hodgkin's lymphoma developed a severe widespread erosive eruption of the skin and mucosal surfaces. Clinically and histologically it was identical to cutaneous GVHD even though the patient had never received tissue or blood products. He failed to respond to conventional therapy for GVHD, but his skin improved significantly on treating his underlying lymphoma, which eventually proved fatal. There are two previous reports of GVHD associated with malignancy but we believe this to be the first case secondary to a lymphoma.     

T-cell activation is potentiated by cytokines released by lesional psoriatic, but not normal, epidermis.

BACKGROUND AND DESIGN--T-cell activation appears to be critical for the maintenance of psoriatic lesions. In this study, we determined whether cytokines released by epidermal cells from psoriatic lesions are providing signals that result in propagation of intralesional T-cell activation. Supernatants were obtained from epidermal cell cultures derived from skin biopsy specimens of psoriatic patients and normal subjects. These supernatants were added to purified normal CD4+ T cells activated via T-cell receptor (immobilized anti-CD3 and fibronectin) or via other activating pathways (anti-CDw60 or UM4D4). RESULTS--Psoriatic supernatants (n = 9), but not normal supernatants (n = 7, P < .0006), potentiated T-cell stimulation with anti-CD3 and fibronectin to 172% +/- 41% over control stimulation levels. The degree of lesional psoriatic epidermal cell potentiation correlated with the clinical severity of the lesion (r = .82, P = .007). Psoriatic epidermal cytokine potentiation of T-cell activation was not limited to T-cell receptor mediated stimulation; potentiation of anti-CDw60-stimulated CD4+ T cells was also observed. Neutralizing antisera to interleukin 1 and interleukin 8, but not interleukin 6, were found to reduce only partly the observed potentiation of T-cell activation. To determine whether cyclosporine is down modulating T-cell-potentiating cytokine activity in psoriasis, we compared samples obtained during a double-blind clinical trial of intralesional cyclosporine. T-cell-potentiating activity from psoriatic lesional sites treated with cyclosporine was not significantly modulated relative to the activity derived from vehicle-treated or untreated sites. CONCLUSION--These data demonstrate that lesional psoriatic epidermal cells release a balance of cytokines that potentiate T-cell activation. Because normal epidermal cells do not potentiate T-cell activation in this system, these findings demonstrate a mechanism by which the epidermis may non-specifically potentiate and perpetuate T-cell activation in psoriatic lesions.     

Cimetidine treatment for viral warts enhances IL-2 and IFN-gamma expression but not IL-18 expression in lesional skin

Cimetidine has been shown to improve various types of human neoplasms and more recently it has been shown to be effective in treating recalcitrant or multiple viral warts in some reports. However, it is not well understood why cimetidine is effective on those kinds of viral warts. We investigated 55 patients with multiple viral warts treated only with oral cimetidine for up to 4 months to examine the efficacy of treatment. The patients were divided into two groups: group A received oral cimetidine (<20 mg/kg/day) and group B received the drug (30 to 40 mg/kg/day). In addition, using real time PCR, we measured mRNA levels of the cytokines interleukin-2 (IL-2), IL-18, and interferon (IFN)-gamma taken from selected punch biopsy specimens before and during treatment. As a result, 34.5% (19/55) of the patients had a dramatic clinical improvement or complete remission (CR) of their viral warts and 23.6% (13/55) of the patients had partial responses (PR) within 4 months of cimetidine therapy. IL-2 and IFN-gamma mRNA levels were significantly increased and IL-18 mRNA levels were decreased in tissues of effectively treated viral warts. Our results show that the higher dose of oral cimetidine was more effective in treating multiple viral warts, that cimetidine activates Th1 cells to produce IL-2 and IFN-c and that their expression correlates with wart remission. These results suggest that cimetidine is an effective treatment for viral warts. In addition, based on the decrease in IL-18 mRNA elicited by the drug, IL-18 might be expressed by keratinocytes infected with HPV.     

Intraepidermal expression of basement membrane components in the lesional skin of a patient with dystrophic epidermolysis bullosa

The patient was a 15-year-old male. Since birth, he had developed blistering and erosion of the skin. Biopsy skin specimen of the bullous lesions showed subepidermal blister formation. Electron microscopic examination revealed that tissue separation had occurred at the sublamina densa level. By indirect immunofluorescence using antibodies specific for alpha 6 integrin, laminin 5, type IV collagen, and type VII collagen, all of these basement membrane components were detected as coarse granular intracytoplasmic deposits only in the basal and suprabasal cells of the blister roof. In the non-blistered regions, these basement membrane components showed a linear pattern similar to that seen in normal skin. These findings suggest that intraepidermal expression of basement membrane components was closely related to the blister formation. The biological meaning of intraepidermal expression of basement membrane components were also discussed.     

Graft-versus-host disease-like syndrome following blood transfusion in a patient with duodenal ulcer

Graft-versus-host disease (GVDH)-like syndrome occurred in a 45 year-old man with duodenal ulcer who had received a transfusion of 8 units of packed red blood cells. Clinical features included high fever, macropapular rash, hepatic dysfunction, pancytopenia and, finally, fatal septicemia. A skin biopsy obtained from the chest revealed satellite cell necrosis of epidermal cells, mononuclear cell infiltrate of the upper dermis and epidermis, and vacuolar degeneration of basal cells. Autopsy bone marrow was aplastic. The occurrence of GVHD in immunologically normal individuals following blood transfusion is extremely rare.     

Immunohistologic studies in Schamberg's disease. Evidence for cellular immune reaction in lesional skin

We studied eight cases of Schamberg's disease immunohistologically by using monoclonal antibodies. The dermal infiltrate was composed of Leu-1-reactive T cells, OKT6-reactive Langerhans' cells, and Leu-M5-reactive (Leu-M5+) macrophages. Among them, the major population consisted of T cells with the predominance of Leu-3a-reactive (Leu-3a+) T cells over Leu-2a-reactive (Leu-2a+) T cells. On the other hand, the epidermotropic mononuclear cells consisted of Leu-2a+ and Leu-3a+ T cells without any predominant pattern, and Leu-M5+ macrophages. Furthermore, note that a pemphiguslike intercellular staining pattern was observed in the epidermis in most of the cases, when the sections were stained either with anti-HLA-DR antibody or with OKT6, suggesting the HLA-DR antigen expression on the keratinocyte surface and possibly an enlargement of Langerhans' cells. Based on these immunohistologic findings, we think that Langerhans' cells play an important role in the pathomechanism of Schamberg's disease, and that cellular immune reactions are taking place in the lesional skin.     

Lymphocytes and macrophages of the epidermis and dermis in lesional psoriatic skin,but not epidermal Langerhans cells,are depleted by treatment with cyclosporin A

Summary Since cyclosporin A (CsA) is an immuno-suppressive agent, its beneficial effect in psoriasis suggests that immune cells may play a role in the pathogenesis and resolution of psoriasis. To determine early effects of CsA in psoriasis, we quantitated immune cells using double immunofluorescence microscopy on biopsy specimens obtained prior to therapy and after 3,7, and 14 days of CsA therapy. CsA therapy resulted in significant reductions in the absolute number of immune cells (including T cells, monocytes/macrophages, and antigen presenting cells) contained within psoriatic skin. The effect was rapid, with over one-half of the reduction in the density of HLe1⁺ (human leukocyte antigen-1 positive or bone marrow derived) cells, including T cells, activated T cells, monocytes, and Langerhans cells (LCs), occurring within 3 days. Despite the overall reduction in the numbers of immunocytes in the skin, the proportion of T cells, Langerhans cells, and monocytes in relation to the total number of immune cells was unchanged with therapy, reflecting equally proportional losses of each subtype. Dermal CD1⁺DR⁺ cells (putative Langerhans cells), which are not found in normal skin but are present in lesional psoriasis skin, were virtually cleared from the papillary dermis after CsA therapy. Although absolute numbers of epidermal Langerhans cells, defined as cells expressing both CD1 (T6) and DR molecules (CD1⁺DR⁺), were also reduced after CsA, epidermal non-Langerhans CD1^-DR⁺ cells (macrophages, activated T cells, DR^- keratinocytes) demonstrated a proportionally greater decrease, with the ratio of CD1⁺DR⁺ Langerhans cells/non-Langerhans CD1^-DR⁺ epidermal cells changing from a mean of 0.82 at baseline to 1.92 at day 14. Thus, early in the course of therapy, CsA appears to be effective at clearing CD1^-DR⁺ cells while leaving LC relatively intact in the epidermis.This work was supported in part by the Babcock Foundation     

T lymphocytes in lesional skin of patients with dermatitis herpetiformis

Ten patients with dermatitis herpetiformis had biopsies taken from involved skin.Monoclonal antibodies and the avidin-biotin peroxidase staining technique were used to stain for T cells and Langerhans cells in skin sections. A significant increase in the number of CD3-positive T cells was observed in the upper dermis of involved compared with uninvolved skin (P<0.0005). Most of the T cells in involved skin were CD45RO-positive memory cells; CD4-positive T cells exceeded the number of CD8-positive T cells by a ratio of 4:1. In addition, CD1a-positive dendritic cells were observed within the clumps of T cells in involved dermis in nine of the 10 patients, but were absent from the dermis of uninvolved skin. Double immunofluorescent staining demonstrated that approximately 20–40% of the CD3-positive T cells were activated, and expressed the HLA-DR antigen. These findings suggest that activated T cells are involved in the pathogenesis of dermatitis herpetiformis skin lesions.     

Increased lysophosphatidylcholine content in lesional psoriatic skin

Various cell stimuli occur via activation of phospholipase A₂, which hydrolyses polyunsaturated fatty acids from the sn-2 position of membrane phospholipids, resulting in the formation of polyunsaturated fatty acids and lysophospholipids. The level of lysophospholipids is determined by the balance between phospholipase A₂ activity and the rate of catabolism of the lysophospholipids. One of the lysophospholipid classes, lysophosphatidylcholine, has been shown to stimulate certain leucocyte activities which are of importance for the induction and maintenance of inflammation. In addition, it has been demonstrated that phospholipase A₂ activity is increased in psoriatic skin. In the present study, we analysed the levels of lysophosphatidylcholine, by thin layer chromatography, in lesional psoriatic skin, uninvolved psoriatic skin and normal skin. The lysophosphatidylcholine content, expressed as μmol lysophosphatidylcholine/μmol phosphatidylcholine, was 1.55, 0.21 and 0.12% in lesional psoriatic skin, uninvolved psoriatic skin and normal skin, respectively. The level of lysophosphatidylcholine was significantly elevated in lesional compared with uninvolved psoriatic skin (P= 0.004) and normal skin (P= 0.002). The increased lysophosphatidylcholine levels in psoriatic skin indicate that the phospholipase A₂ activation is not accompanied by a corresponding increase in the activity of enzymes catabolizing lysoPC. If present in biologically active concentrations, lysophosphatidylcholine may contribute to the induction and maintenance of the inflammatory and immunological processes occurring in lesional psoriatic skin.