Systemic lupus erythematosus developing immediately after necrotizing fasciitis.

Necrotizing fasciitis (NF) is a medical-surgical emergency characterized by severe bacterial infection that affects the subcutaneous tissue and spreads to the underlying fascia; usually it is caused by penetrating trauma, sometimes by surgical therapy, very rarely by minor insults such as insect bites. Systemic lupus erythematosus (SLE) is a potentially fatal autoimmune disease involving virtually all the key components of the immune system. Although cases of post-infection autoimmunity were already described, a literature search using Pub Med and Medline revealed that SLE was never reported to occur in patients affected, immediately before, with NF. We observed and herein report, however, a case of a woman showing an insect-bite-induced NF, which was immediately followed by the development of a SLE. In conclusion, this case of postinfection autoimmunity provides early evidence of a patient developing SLE immediately after NF, and suggests that caution in the follow-up of NF is necessary, because NF might favor the development of a severe autoimmunity.

Aromatase inhibitor-induced skin adverse reactions: exemestane-related cutaneous vasculitis.

BACKGROUND: Three aromatase inhibitors, namely anastrozole, letrozole and exemestane, which reduce circulating oestrogen, are used to treat breast cancer patients; the therapeutic use of such aromatase inhibitors is quickly increasing. OBJECTIVE: We intended (i) to review aromatase inhibitor-induced cutaneous adverse effects and (ii) to describe a recently observed case of cutaneous vasculitis triggered by exemestane. PATIENTS/METHODS: The so-far reported literature cases of aromatase inhibitor-induced cutaneous adverse effects were analysed retrospectively. Especially, the clinical case of exemestane-induced cutaneous vasculitis herein reported is unique, because such an observation has not yet been published in the literature. RESULTS: Merely 12 cases of cutaneous adverse reactions induced by aromatase inhibitors, namely erythema nodosum (6), subacute cutaneous lupus erythematosus (1), cutaneous rashes (2), vasculitis (3, including the one described in this study), are reported in the literature. In fact, in the present case, cutaneous vasculitis was strictly related to exemestane. CONCLUSION: As aromatase inhibitors (e.g. exemestane) are increasingly incorporated into the treatment strategy of breast cancer patients, it is important to recognize possible cutaneous adverse effects. Specifically, with regard to cutaneous vasculitis, some patients might progress to severe vasculitis manifestations if the offending drug (e.g. exemestane) is not quickly stopped.

Cytoplasmic beta-catenin is lacking in a subset of melanoma-associated naevi, but is detectable in naevus-associated melanomas: potential implications for melanoma tumorigenesis?

BACKGROUND: An excess of intracellular beta-catenin protein is triggered by various genetic alterations in melanoma cell lines, and has been suggested to play a role in melanoma tumorigenesis. OBJECTIVES: To investigate the role played in vivo by beta-catenin in melanoma tumorigenesis, we compared the cytoplasmic detection of beta-catenin in benign melanocytic cells vs. malignant melanoma cells presumably generated from these benign melanocytic cells. For this purpose, melanocytic naevi occurring in association with melanoma, which were suggested to be melanoma precursors, were compared with their associated melanoma for beta-catenin cytoplasmic immunoreactivity. METHODS: Fifty-seven consecutive cases of primary cutaneous melanoma were considered, and 15 of them were found to be associated with a melanocytic naevus portion. The naevus portion showed features of acquired melanocytic naevus (total 12 cases: five dysplastic, seven intradermal) or congenital growth pattern naevus (total three cases: one superficial, two deep). All specimens were immunohistochemically investigated for beta-catenin. RESULTS: Virtually all primary cutaneous melanomas, including those associated with a naevus portion, showed cytoplasmic beta-catenin positivity. However, the intradermal naevus portion was consistently cytoplasmic beta-catenin negative, while both the dysplastic and the congenital naevus portions were cytoplasmic beta-catenin positive. CONCLUSIONS: Beta-catenin excess may play a role in melanoma tumorigenesis, because beta-catenin cytoplasmic reactivity was found in primary cutaneous melanoma but not in its associated intradermal naevus precursor. As, however, beta-catenin cytoplasmic reactivity was detected not only in primary cutaneous melanoma but also in its associated dysplastic/congenital naevus precursors, beta-catenin stabilization alone is not sufficient to play a decisive role for melanoma onset.

Familial Uncombable Hair Syndrome: Ultrastructural Hair Study and Response to Biotin.

We report a family affected to the fourth generation by uncombable hair syndrome. This syndrome is characterized by unruly, dry, blond hair with a tangled appearance. The family pedigree strongly supports the hypothesis of autosomal dominant inheritance; some members of the family had, apart from uncombable hair, minor signs of atopy and ectodermal dysplasia, such as abnormalities of the nails. The diagnosis was confirmed by means of extensive scanning electron microscopy. A trial with oral biotin 5 mg/day was started on two young patients with excellent results as regards the hair appearance, although scanning electron microscopy did not show structural changes in the hair. After a 2-year-period of follow-up, hair normality was maintained without biotin, while nail fragility still required biotin supplementation for control.

Primary cutaneous plasmacytoma: a role for a triggering stimulus?

Primary cutaneous plasmacytoma is a rare type of cutaneous B-cell lymphoma, characterized by clonal proliferation of plasma cells, that primarily develops in the skin. Five cases have been described to date in which a local triggering stimulus may be involved in development of this skin tumour. We describe the case of a primary cutaneous plasmacytoma localized to the lower lip. This site had been affected for 15 years with recurrent herpes simplex virus-1 infection. Neoplastic plasma cells were found to be bcl-2-positive. We hypothesize that chronic stimulation of keratinocytes by herpes simplex virus-1, possibly through toll-like receptors, may have favoured the release of cytokines (e.g. interleukin-6) able to induce plasma cell proliferation, transformation and survival.

Scleredema of Buschke: remission with factor XIII treatment.

We describe the case of a 55-year-old man with scleredema of Buschke of the torso complicated by insulin-dependent diabetes mellitus. Due to (i) the patient's poor general health status, (ii) the similarity between scleroderma and scleredema of Buschke, and (iii) the well known efficacy of factor XIII infusions in scleroderma, we attempted an intravenous treatment with factor XIII. This therapy resulted in marked increase of movements and in softening of the skin, together with ultrasonographic and histopathological improvements. In conclusion, to the best of our knowledge, this is the first case in which factor XIII has been successfully used for the treatment of scleredema of Buschke.

The tolerogenic molecule CD95-L is expressed on the plasma membrane of human activated, but not resting, Langerhans' cells.

Although dendritic cells (DC) are well known for their immunogenic capacities, they may even induce peripheral T-cell tolerance, and such a tolerogenic potential can be exerted in mouse through the expression on the DC plasma membrane of the CD95-ligand (CD95-L) molecule, which is able to trigger apoptosis of CD95-expressing antigen-specific T cells. We therefore asked whether epidermal DC, namely Langerhans' cells (LC), either resting (i.e. within the epidermis, 'in situ') or activated (i.e. suspended from the epidermis) or both, could express the CD95-L molecule on the plasma membrane. For such a purpose, two colloidal gold-immunoelectron microscopy (IEM) double-step procedures were carried out: an 'in situ' method, able to investigate resting LC, was performed on ultrathin frozen sections obtained by ultracryomicrotomy (UCMT) of normal skin biopsies; a pre-embedding (P-E) method, able to investigate suspended LC, was performed on epidermal cells (EC) suspended from normal skin specimens. In UCMT/IEM sections, resting LC showed gold particles within the cytoplasm but very rarely within organelles and never along the plasma membrane: resting LC are therefore capable of synthesizing CD95-L but not of expressing it in a functional location, thus autoreactive phenomena against CD95-expressing EC being avoided in normal epidermis. On the other hand, in P-E/IEM preparations, suspended LC showed several gold particles along the plasma membrane: activated LC are therefore capable of expressing CD95-L in a functional location, thus bearing the potential to exert tolerogenic capabilities against CD95-expressing T cells, e.g. to prevent inflammatory/autoimmune cutaneous disorders and/or favor the resolution thereof.

Keratinocytes constitutively express the CD95 ligand molecule on the plasma membrane: an in situ immunoelectron microscopy study on ultracryosections of normal human skin.

BACKGROUND: Tissue homeostasis is mainly preserved by cytolytic functions. Cytolytic cells, when expressing the CD95 ligand (Fas-L) molecule on the cell membrane, are able to kill CD95 (Fas)-expressing target cells. Although cultured epidermal keratinocytes (KC) have been shown to express Fas-L, and normal skin has been shown to bear Fas-L mRNA, efforts so far to find possible constitutive Fas-L expression on the cell membrane by resting KC in normal human epidermis (i.e. in a functionally active location) have been inconclusive. OBJECTIVES: The aim of the present study was therefore to show the constitutive expression of Fas-L on the plasma membrane of KC. METHODS: Gold immunoelectronmicroscopy, a highly specific and sensitive immunodetection system, was performed in situ on skin sections obtained by ultracryomicrotomy, without previous embedding (i.e. in conditions strictly similar to the in vivo situation). RESULTS: Relatively few (51.55 +/- 28.61), 10-nm colloidal gold particles were observed at the cell surface of KC in the basal layer of the epidermis and an even smaller (P < 0.005) number of gold granules was detected in the KC of the spinous layer. CONCLUSIONS: Although scanty, the constitutive Fas-L expressed on the surface of KC can bind Fas expressed by possible occasional inflammatory cells entering the epidermis, and kill them, so preventing inflammation. Fas-L-expressing KC could moreover induce apoptosis of epidermal cells bearing viral or neoplastic antigens. Thus, the expression of Fas-L by KC may contribute to the preservation of epidermal homeostasis in vivo.

A partially humanized monoclonal antibody to human IFN-gamma inhibits cytokine effects both in vitro and in vivo.

The mouse monoclonal antibody (MoAb) IGMB17 (muIGMB17) is a high-affinity antibody- neutralizing human interferon (IFN)-gamma and, accordingly, is a potential therapeutic agent for patients suffering from various diseases in which the cytokine is abnormally expressed. The clinical usefulness of mouse antibodies is limited, however, owing to their immunogenicity in humans. MuIGMB17 antibody was partially humanized by engrafting a small portion of mouse light chain (LC) in a human framework and by engineering its heavy chain (HC) in a chimeric version. The engineered IGMB17 (huIGMB17) was able to replicate a range of functional properties of the original muIGMB17, namely, specific binding to IFN-gamma, inhibition of histocompatibility complex (HLA-DR) expression in response to IFN-gamma induction, reversion of IFN-gamma antiproliferative activity on sensitive cell lines. We have hypothesized that as huIGMB17 was able to block IFN-gamma binding to its receptor as well as its murine counterpart, huIGMB17 could neutralize all cytokine activity, also in vivo. Indeed huIGMB17 was capable of interfering with delayed-type hypersensitivity reaction in humans, thus demonstrating its effectiveness in neutralizing IFN-gamma-mediated reactions in vivo.

"High-dose" UVA1 therapy of widespread plaque-type, nodular, and erythrodermic mycosis fungoides.

BACKGROUND: UVA1 (340 to 400 nm) was found to be effective in the treatment of early-stage mycosis fungoides (MF). OBJECTIVE: The purpose of this study was to assess the efficacy of UVA1 phototherapy for widespread plaque-type, nodular, and erythrodermic MF. METHODS: Thirteen patients (8 with stage IB, 4 with IIB, and 1 with III MF) received 100 J/cm(2) UVA1 daily until remission. Four patients also had lesions inaccessible by UVA1 that were considered control lesions. Immunocytologic studies of skin infiltrates and circulating T cells were done before and after the therapy. RESULTS: Eleven patients showed complete clinical and histologic responses. Two patients had a partial improvement. Unirradiated control lesions never improved. Serious short-term side effects were not recorded. Circulating CD4(+)/CD45RO(+) and CD4(+)/CD95(+) lymphocytes were significantly reduced by the therapy. CONCLUSION: UVA1 therapy is an effective and well-tolerated treatment for advanced MF. The therapeutic relevance of the effects on circulating lymphocytes remains to be established because lesions in nonexposed cutaneous areas did not respond.

Identification of Fas-L-expressing apoptotic T lymphocytes in normal human peripheral blood : in vivo suicide.

Fas-L molecules expressed by in vitro stimulated T cells may be critically involved in suicidal activation-induced cell death (AICD) of such cells through engagement of their Fas receptors. A similar suicide of T cells was postulated to occur even in vivo, to eliminate dangerous activated lymphocytes; however, the demonstration of suicidal AICD of T cells in healthy humans in vivo is still lacking. We therefore investigated the possible occurrence of Fas-L-linked suicidal apoptosis of T cells in normal human peripheral blood. For this purpose, we took advantage of immunoelectron microscopy, which allows simultaneous visualization of the morphological apoptotic cellular changes together with surface expression of Fas-L molecules. Very few T lymphocytes were observed showing the ultrastructural features of apoptotic lymphocytes; these occasional apoptotic T cells, together with the majority of the normal T cell population, expressed the Fas molecule on the plasma membrane, as expected. Interestingly, the apoptotic cells were also Fas-L-positive, whereas normal T cells were Fas-L-negative. Such Fas-L-associated T cell suicide operating in vivo in healthy individuals is presumably able to suppress immune responses and prevent autoreactivity, thus maintaining the homeostasis of human blood.

Alterations in molecular killing mechanisms: implications in skin disease.

Cytolytic T lymphocytes exert two main specific molecular killing mechanisms against target cells, namely (i) they can synthesize and release soluble cytolytic factors, and (ii) they can express effector molecules that act as ligands of receptors expressed by target cells on the cell surface; by these two pathways cytolytic T lymphocytes kill several targets, e.g. cells infected with intracellular pathogens, cells transformed by malignancy and cells producing autoantibodies. This review investigates the contribution from alterations in these molecular killing mechanisms to the pathogenesis of cutaneous diseases. In fact, molecular components involved in such killing mechanisms are often altered or distorted in skin pathology, e.g. cutaneous viral infections, skin cancer, contact hypersensitivity and autoimmune diseases with cutaneous involvement. Treatments capable of repairing the molecular components operating in such killing mechanisms could presumably favour the resolution of these skin diseases.

Clinical, histological and immunopathological features of 58 patients with subacute cutaneous lupus erythematosus. A review by the Italian group of immunodermatology.

BACKGROUND: Subacute cutaneous lupus erythematosus (SCLE) is a distinct subset of cutaneous lupus erythematosus clinically characterized by psoriasiform and/or annular lesions and by a mild or absent systemic involvement. OBJECTIVE: The Italian Group of Immunodermatology of the Italian Society of Dermatology and Venereology reviewed the cases of SCLE seen in 10 years (1987-1996). PATIENTS: Forty-six women and 12 men have been retrospectively studied, 42% had annular lesions, 39% psoriasiform ones and 16% both. RESULTS: Lesions were mainly localized on the neck and face and relapsed in spring and autumn. Seventeen patients had 4 or more American College of Rheumatology criteria and could be classified as having systemic lupus erythematosus. The most frequent histopathological alterations were epidermal atrophy, hydropic degeneration of the basal layer and perivascular lymphocytic infiltrate. Deposits of immunoglobulins and C3 at the dermo-epidermal junction on the clinically involved skin were present in 86% of the patients. Dust-like particles in the epidermis were only found in 3% of cases. Anti-Ro/SSA antibodies were found in 71% of the cases and anti-dsDNA only in 5% of cases. CONCLUSIONS: SCLE is a particular subset of cutaneous lupus erythematosus with peculiar clinical and immunopathological features.

Dexamethasone-induced healing of chronic leg ulcers in a patient with defective organization of the extracellular matrix of fibronectin.

Previous investigations have shown that skin fibroblasts derived from patients affected by Ehlers-Danlos syndrome (EDS) lack an organized extracellular matrix (ECM) of fibronectin (FN). As retarded wound healing is a sign of EDS, we hypothesized that a young healthy man suffering from chronic recalcitrant leg ulcers might be affected by a defect of FN-ECM organization similar to that observed in EDS. Immunofluorescence of cultured skin fibroblasts obtained from skin biopsies from the patient and a control demonstrated that the patient's fibroblasts lacked FN-ECM organization, in contrast with those of the control; this was restored by 10-7 mol/L dexamethasone (DEX) in vitro. DEX treatment of the patient was associated with healing of his leg ulcers. In conclusion, DEX may be effective in reversing impaired wound healing associated with a lack of FN-ECM organization

Reduced production of both Th1 and Tc1 lymphocyte subsets in atopic dermatitis (AD).

An imbalance of interferon-gamma (IFN-gamma)-bearing CD4+ T (Th1) cells in the pathogenesis of AD is well recognized; however, a possible role in AD for CD8+ T cells secreting Th1-like cytokines (Tc1) has not been properly addressed. In this study, two- and three-colour FACS analysis allowed us to discriminate the Th1 from the Tc1 subset. AD patients had half the number of IFN-gamma-producing circulating T cells (P < 0.005; 13.6 +/- 1.9% (mean +/- s.d.)) compared with normal donors (25.0 +/- 2.4%). Specifically, both Th1 (4.8 +/- 0.7%) and Tc1 (8.1 +/- 1.1%) cells in AD were decreased compared with Th1 (8.8 +/- 0.8%) and Tc1 (15.0 +/- 1.5%) cells in controls. Moreover, at the mRNA level, the ratios of IFN-gamma/IL-4 and IFN-gamma/IL-10 were lower in cells from AD patients compared with controls. In conclusion, the decrease of IFN-gamma-producing T lymphocytes in AD is due to a reduction in both Th1 and Tc1 IFN-gamma-secreting cells; this may not only contribute to the over-production of IgE, but also explain the high incidence of cutaneous infections observed in AD patients.

CD8+ cytolytic T lymphocytes and the skin.

T lymphocytes show a special affinity for the skin. Although the roles played by the CD4+ population of T lymphocytes in immunodermatology were so far actively investigated, much less is known about the roles played in the skin by CD8+ cytolytic T lymphocytes (CTL). The activity of CD8+ CTL in the immunodermatological context, however, is likely to be most important; the immuno-biology itself of CD8+ CTL, moreover, although far from being fully understood, shows intriguing characteristics. Immunophenotype, function and cytokine profile of CD8+ CTL are overviewed in the first section of this review. Phenotypically, not only CD8+ CTL can be subdivided into CD8+ CD28+ CD11b- and CD8+ CD28- CD11b+ subsets, but also an up-to-now undetected CD8+ CD28- CD11b- subset does exist. Functionally, not only "cytotoxic" but even "suppressor" subpopulations have been shown to exert cytolytic capabilities indeed, and "suppression" itself may be due to such a lytic capacity. According to cytokine synthesis, CD8+ CTL can be split into Tc1 and Tc2 subsets, each able to influence specific patterns of immune responses. The impact of CD8+ CTL in immunodermatology, overviewed in the second section of the current review, is crucial. The pathophysiology of inflammatory dermatoses is deeply influenced by the activity of CD8+ CTL: e.g., CD8+ CTL within psoriatic epidermis are possibly associated to the persistence of psoriatic lesions not undergoing resolution; on the other hand, in late lesions of lichen planus CD8+ CTL predominate, thus explaining presumably both the cytolytic attack against keratinocytes and the modulation of the inflammatory reaction up to the final resolution of the lesions, Tc1 cells are decreased in atopic dermatitis, and such a decrease can account both for IgE overproduction and for development of infections. Finally, CD8+ CTL can sustain against cutaneous viruses/tumors cytolytic immune responses not only of secondary but even of primary type, i.e. induced by Langerhans cells/dendritic cells either transfected or pulsed with skin virus/tumor-associated antigens, thus allowing the production of vaccines against cutaneous viral/neoplastic diseases.

Bath-5-methoxypsoralen-UVA therapy for psoriasis.

BACKGROUND: After oral intake, 5-methoxypsoralen (5-MOP) is as effective as 8-MOP for PUVA therapy for psoriasis, with a lower incidence of acute cutaneous side effects. OBJECTIVE: We compared bath-water delivery of 5-MOP and 8-MOP for photochemotherapy of psoriasis. METHODS: Twenty-two patients underwent phototesting with 0.0003% 5-MOP or 8-MOP aqueous solutions. Twelve patients with palmar psoriasis were studied with a side-to-side comparison, and 10 patients with recurrent plaque-type psoriasis were treated with one therapy or the other. RESULTS: Minimal phototoxic dose (MPD) values were 2.8 +/- 1.2 J/cm2 with 8-MOP and 2.0 +/- 1.2 J/cm2 with 5-MOP (p < 0.01). Both therapies cleared palmar lesions but 8-MOP required more UVA irradiation (46.3 +/- 21.0 J/cm2 vs 30.2 +/- 21.5 J/cm2; p < 0.01) and more exposures (21.0 +/- 6.0 vs 17.0 +/- 5.0; p = 0.02). Bath-5-MOP-UVA was also more effective in the treatment of plaque-type psoriasis (cumulative UVA doses, 56.8 +/- 39.2 vs 59.1 +/- 27.9 J/cm2; number of exposures, 20.0 +/- 5.7 vs 21.6 +/- 4.7), but these differences were not significant (p = NS). Patients developed an intense tan significantly earlier with 5-MOP than with 8-MOP (3.5 +/- 0.5 weeks vs 4.4 +/- 0.5 weeks; p < 0.01). CONCLUSION: Bath-5-MOP-UVA was more phototoxic than bath-8-MOP-UVA. It was more effective in the treatment of palmar psoriasis, whereas its greater pigmentogenic activity appeared to have an adverse effect on therapeutic effectiveness in the treatment of plaque-type psoriasis.