Effect of tumour necrosis factor alpha in vivo on human granulocyte oxidative metabolism

Summary Tumour necrosis factor alpha (TNF) effectively stimulates the oxidative metabolism of human PMN in vitro. Moreover, preincubation of PMN with TNF has been shown to result in an altered response of the target cells to subsequent stimulation. In the present study the response of PMN to stimulation in vitro was investigated in patients with metastasizing malignant melanoma receiving bolus injections of recombinant human TNF as therapy. TNF was given daily for 5 days. Blood samples were taken prior to TNF administration on days 1 to 4 and on day 8. Lucigenin-enhanced chemiluminescence (CL) was used as a sensitive measure of granulocyte oxidative metabolism. PMN were stimulated with TNF, TNF, GM-CSF, PMA, opsonized zymosan and f-met-leu-phe. A significant increase in CL responses was detected upon stimulation with TNF, TNF and PMA from day 1 to day 3, whereas no significant changes were observed for the background activity or when GM-CSF or opsonized zymosan were used as stimuli. On day 4 all CL responses returned to the day 1 starting level. A further significant decrease was observed on day 8 upon stimulation with TNF, TNF and GM-CSF. In contrast, the effect induced by f-met-leu-phe reached a maximum on day 4, but the CL response was found to be at the starting level on day 8. The results indicate that TNF induces significant changes in PMN response to distinct stimuli in vivo. Moreover, it may be possible that continous daily infusions with TNF induce a hyposensitization of PMN oxidative metabolism.     

Effects of tumor necrosis factor-α on connective tissue metabolism in normal and scleroderma fibroblast cultures

Recent studies have demonstrated that tumor necrosis factor-(TNF-) selectively decreases production of collagens I and III, the major types of collagen in the dermis, and increases production of collagenase in cultured dermal fibroblasts. The effects of TNF- on collagens I, III and VI, fibronectin and collagenase gene expression by fibroblasts derived from normal individuals and patients with systemic sclerosis (SSc) were studied. SSc is characterized by excessive accumulation of collagen in the skin and in certain organs. TNF- inhibited collagen production and mRNA levels of collagens I and III and of fibronectin, and stimulated collagenase activity and collagenase mRNA levels in SSs fibroblasts. Levels of mRNA for 1(VI) and 3(VI) collagen and for -actin were unaltered in SSc fibroblasts incubated with TNF-. Similar results were observed for mRNA levels in normal fibroblasts incubated with TNF-. These results suggest that TNF- could be expected to be beneficial in the treatment of SSc. In addition, our results indicated that collagen-VI expression is regulated independently from expression of collagens I and III, and expression of fibronectin and collagens I and III are regulated in parallel in fibroblasts treated with TNF-.     

High affinity IgE receptor (FcεRI) expression on eosinophils infiltrating the lesions and mite patch tested sites in atopic dermatitis

Expression of the high affinity IgE receptor (FcRI) on eosinophils has recently been reported. This led us to evaluate FcRI expression on eosinophils in atopic dermatitis (AD). Double immunofluorescence stainings with an anti-FcRI monoclonal antibody (mAb) and a polyclonal antieosinophil cationic protein (ECP) antibody were performed on lesional biopsy specimens from patients with AD and from patients with bullous pemphigoid (BP) as controls. In AD and BP lesions, 77% and 70% of eosinophils expressed FcRI, respectively. However, the intensity of FcRI staining in AD was much stronger than in BP, suggesting upregulation of FcRI expression on eosinophils in AD. In addition, the eosinophils infiltrating AD lesions were stained strongly with anti-CD23 mAb and anti-IgE antibody. At the sites of mite patch testing in AD, FcRI-, CD23- and IgE-positive eosinophils were observed to the same degree as in the lesions, and a considerable number of mite antigen-bearing eosinophils were detected. FcRI and CD23 were both upregulated on the skin-infiltrating eosinophils in AD and bound IgE molecules.     

Steroid hormone receptors in human melanoma

Summary Human epidermis uncontaminated by fibroblasts was isolated by a suction blister method. DNA synthesis in short-time organ cultures of isolated epidermis was strongly inhibited by aphidicolin, suggesting that DNA polymerase is involved in DNA replication in human epidermis. On the basis of their responses to inhibitors, primer-template requirements, and chromatographic properties, DNA polymerases , , and were all identified in epidermal extracts.Supported by the Erna and Olav Aakres Foundation for Cancer Research     

Immunoelektrophoretische Untersuchungen an Hautkranken

Zusammenfassung Immunoelektrophoretische Serumanalysen bei 113 Patienten mit verschiedenen Hauterkrankungen ergaben bei Purpura hyperglobulinaemica Waldenström, Antikörpermangel-Syndrom und Xanthomatosen der Haut krankheitsspezifische Serumeiweißbilder.Die Waldenströmsche Purpura zeigt ein charakteristisches Makroglobulin im ₂-Bereich. Beim Antikörpermangel-Syndrom fehlt das -Globulinsystem ganz oder teilweise. Bei den Xanthomatosen der Haut findet sich eine massive Vermehrung von -und ₂-Lipoproteinen und eine Verstärkung des ₂-Makroglobulins. Das ₁-Lipoprotein erscheint unverändert. Es finden sich keine Unterschiede zwischen hyperlipidämischen und hypercholesterinämischen Formen.Entzündliche Erkrankungen der Haut und der HautgefÄße zeigen häufig eine Vermehrung von Proteinen aus der Gruppe der -Glykoproteine und des -Globulinsystems, und zwar vorwiegend des ₂-Makroglobulins und des ₂-Makroglobulins.     

γδ T-cell receptor-positive cells of human skin. II. Appearance in delayed-type hypersensitivity reaction

In order to investigate the distribution and involvement of human T-cell receptor-positive (TCR⁺) cells in delayed-type hypersensitivity reactions of the skin, we examined the occurrence and kinetics of TCR⁺ cells during skin reactions of allergic contact dermatitis. In normal human skin sections, TCR⁺ cells were scarce. In allergic contact dermatitis from DNCB, increased TCR⁺ cells were observed both in the epidermis and in the dermis from 48 h after the challenge. Most of the TCR⁺ cells were TCR1⁺ TCS1^– BB3⁺ TiA⁺ (V1^– V2⁺ V9⁺). The percentage of TCR⁺ cells in the peripheral blood remained unchanged and a few TCR⁺ cells in the skin lesions proliferated in situ. It is suggested that the TCR⁺ cells in skin lesions of allergic contact dermatitis may not be involved in initiation of delayed-type hypersensitivity but may have some other roles responding to factors induced in the reaction.     

Nipple and Areolar Eczema in the Breastfeeding Woman

Sommaire Leczéma du mamelon et de Laréole peut parfois apparaître chez des patientes qui allaitent et en conjonction avec des douleurs et des brûlures. La gestion de Leczéma comprend Lélimination de tout allergène et irritant à effet indésirable ainsi que Lusage judicieux de préparations corticoïdes appropriées. Les patientes doivent également recevoir un Lappui adéquat et des moyens efficaces de maîtriser la douleur. Le diagnostic et la gestion appropriés de Leczéma du mamelon et de Laréole durant la période dallaitement contribueront à éviter le sevrage prématuré et iatrogène.     

Der Einfluß von Δ 1-Dehydro-Hydrocortison auf das Verhalten proteingebundener Kohlenhydrate im Blutserum bei Neurodermitis diffusa

Zusammenfassung Bei 14 Patienten mit Neurodermitis diffusa wurde das Verhalten der Serumeiweißzucker nach Applikation von ₁-Dehydro-Hydrocortison untersucht. Deutlich war den Befunden eine Verminderung von Glucosamin an Albumin, -und -Globulin. Die proteingebundenen Hexosen stiegen unter der Therapie an und zeigten sich zumeist an Albumin, -und -Globulin vermehrt.     

Beitrag zur Ätiologie und Therapie der Onychogryposis

Ohne ZusammenfassungMit 4 Textabbildungen.Gryposis von =krümmen, also nicht mit ph.     

Pro-inflammatory cytokines upregulate the skin immunoreactivity for NGF,NT-3, NT-4 and their receptor,p75NTR in vivo: a preliminary report

Skin and hair follicles are both source and target of various cytokines and neurotrophins (NTs). While several pro-inflammatory cytokines are recognized to alter the expression of NTs and their receptors (NTRs), for example, on brain cells and fibroblasts in vitro, it is unknown whether this also occurs in normal mammalian skin in vivo. As a first step toward exploring this, we studied in murine back skin (C57BL/6) whether intradermally injected interleukin-1 (IL-1), tumor necrosis factor- (TNF-), and interferon- (IFN-) altered the cutaneous immunoreactivity patterns of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4 (NT-4), Trk-A, Trk-B, Trk-C and p75NTR and their receptors (TrkA, TrkB, TrkC, p75NTR) on the protein level in situ. By immunohistology, IFN, IL-1, and TNF- as well as a cocktail of all three cytokines increased NGF immunoreactivity (IR) in the proximal outer root sheath and hair matrix of anagen VI pelage hair follicles. The cytokine cocktail upregulated NT-3 and NT-4 IR in the epidermis, increased NT-4 IR in selected cells of the proximal outer root sheath, and also enhanced IR of p75NTR, in the follicular dermal papilla. Therefore, this pilot study provides the first preliminary indications that proinflammatory cytokines upregulate the cutaneous immunoreactivity of NGF, NT-3, NT-4 and their receptor p75NTR in vivo. This raises the question to which extent several of the recognized cutaneous effects of IFN, IL-1 and TNF- are mediated indirectly via modulating the expression of selected NTs and/or NTRs.Holger Bläsing and Sven Hendrix have contributed equally     

Inhibitory effects of 13-cis-retinoic acid on human sebaceous glands

Summary The effects of 13-cis-retinoic acid, which is clinically very effective in the treatment of severe acne, on sebaceous glands in humans was studied by means of histology, planimetry, and autoradiography. Histologically and planimetrically, one finds a marked decrease of size of sebaceous glands of up to 90% of the pretreatment values after 12 weeks of treatment. Additionally, the ratio of the so-called differentiating cell pool (DCP) vs. the so-called undifferentiating cell pool (UCP) changed from 21 to 17, probably indicating a disturbance of differentiation (lipid-production) of sebocytes. The labeling index of sebocytes also regressed significantly under therapy with 13-cis-retinoic acid.Supported by the Deutsche Forschungsgemeinschaft Pl 58/6     

Absence of tumor necrosis factor-α in suction blister fluids and stratum corneum from patients with psoriasis

Summary Tumor necrosis factor (TNF)- is a cytokine with multiple biological properties, particularly proinflammatory, apart from the induction of tumor necrosis. In order to elucidate the role of TNF- in the pathogenesis of psoriasis, we have carried out bioassay and enzyme-linked immunosorbent assay for TNF- in suction blister fluids and horny tissue extracts from psoriatic skin. Although bioassay showed some activities in the suction blister fluids and horny tissue extracts, there were no significant differences between the levels of activities from normal and psoriatic skin. They were at the background level and pretreatment of the samples with anti-TNF- antiserum failed to abrogate the activities. ELISA confirmed the absence of TNF-. Therefore, the present study could not verify that TNF- plays a major role in the pathogenesis of psoriasis.     

Transforming growth factor β1 inhibits IL-3- and IL-4-dependent mouse connective tissue-type mast cell proliferation

Transforming growth factor 1 (TGF1) is a regulator of cell proliferation and differentiation. Using a mouse peritoneal cell-derived mast cell culture system, we investigated the effects of TGF1 on mast cell proliferation. TGF1 inhibited IL-3- and IL-4-dependent connective tissue-type mast cell proliferation. The effect was concentration dependent: 50% inhibition was observed with 1.0 ng/ml TGF1 and the maximal inhibitory effect (no proliferation), was observed with 10 ng/ml. Flow cytometric analysis suggested that the inhibitory effect of TGF1 was due to blocking of both G₁ and G₂ phases. Both control and TGF1-treated mast cells showed similar histamine release induced by the calcium ionophore, A23187. TGF1 seems to be an important negative regulator of connective tissue-type mast cell proliferation with apparently no appreciable effect on mast cell function.     

Human interferon-γ induces expression of HLA-DR on keratinocytes and melanocytes

Summary Primary human epidermal cell cultures composed of keratinocytes and melanocytes were exposed to supernatants of phytohaemagglutinin (PHA)-stimulated T cells, various lymphokines and interferon-, and checked for the emergence of HLA-DR antigen using immunofluorescence and immunoelectron microscopy. HLA-DR expression was induced by the supernatants and human recombinant interferon- (rIFN-), whereas recombinant ₂, interleukin-2 and non-recombinant human interferon- had no such effect. The threshold concentration of rIFN- required to induce this phenomenon was 10 IU/ml; no further increase of reaction intensity was observed using doses of more than 100 IU/ml. Maximum reaction intensity was achieved after 72 h of incubation; a minimum of 3 h of incubation with rIFN- followed by 72 h incubation in rIFN--free medium proved sufficient to induce HLA-DR expression. The inductive effect of the supernatants and rIFN- could be completely abrogated by pretreatment with excess doses of the monoclonal antibody GZ4 specific for human IFN-. Keratinocytes and melanocytes reacted in an identical fashion both qualitatively and quantitatively in all experiments. These data indicate that IFN- possesses specific signal functions in the induction of HLA-DR expression on epidermal cells.Abbreviations IFN- interferon- - rIFN- recombinant interferon- - r IFN-₂ recombinant interferon-₂ - nrIFN- nonrecombinant interferon- - IL-2 interleukin-2 - EC epidermal cells - K keratinocytes - M melanocytes     

Effect of UVB radiation on the biosynthesis of HLA-DR antigens

Summary HLA-DR molecules on the surface of immunocompetent cells are thought to represent target structures for the immunomodulating effects of UV radiation during the induction of an immune response. We therefore investigated the effect of UVB radiation on the de novo synthesis of HLA-DR--chains in the cytoplasm and the expression of - and -chains on the surface of the human lymphoblastoid B-cell line Raji. Raji cells were UVB irradiated before biochemical experiments were performed. Cells were then metabolically labeled or radioiodinated and detergent lysates immunoprecipitated using antibodies directed against the - or the - and -chain of the HLA-DR molecule. Over a wide dose range, UVB-irradiated Raji cells were shown to still express HLA-DR determinants on their surface and, even more importantly, to be capable of synthesizing HLA-DR-, - and -chains in a normal fashion. Despite this, the functional capacity of Raji cells was impaired in a dose-dependent manner. UV radiation thus seems to exert its immunomodulating effects primarily at a different level than the incriminated immune-response-associated antigens, which are expressed as recognition structures on the surface of immunocompetent cells.     

Photopromotion of sister chromatid exchanges by psoralen derivatives

Summary Several derivatives of 8-methoxypsoralen and 4,58-trimethylpsoralen were compared with respect to their photopromotion of sister chromatid exchanges. Peripheral blood leukocytes from heparinized blood of human volunteers were cultivated for 24 h. Selected flasks received psoralens (6.5×10^–8 M) and/or were irradiated (UV-A, 365 nm, 0.9 J/cm²). Bromodeoxyuridine (20 g/ml) was added and flasks were further incubated for 48 h when colchicine was added. Spreads of mitotic chromosomes were prepared, stained with Hoechst 33258 and Giemsa, and scored for the number of sister chromatid exchanges (SCEs) per 100 chromosomes. Results were: Control (16.5); 8-methoxypsoralen (23.9); 5-methyl-8-methoxypsoralen (25.7); 4-methyl-8-methoxypsoralen (27.8); 4,5-dimethyl-8-methoxypsoralen (31.9); 4-methoxymethyl, 4,58-trimethylpsoralen (42.9); 4aminomethyl, 4,58-trimethylpsoralen-hydrochloride (59.1); 4hydroxymethyl,4,58-trimethylpsoralen (75). In general, the psoralens with strong affinity for DNA as determined by K _D values promoted more SCEs than did those with lower affinity. Trimethylpsoralen and its derivatives promoted more SCEs than did 8-methoxypsoralen and its derivatives, which may be indicative of relative DNA cross-linking potential.     

Characterizing anxiety in melanoma patients

Background: Over half of melanoma patients experience significantly elevated anxiety levels leading to psychological distress and delays in diagnosis and treatment. Objective: To identify melanoma patients likely to experience high levels of anxiety, we characterized the contributing factors and coping strategies and investigated potential anxiety-alleviating interventions. Method: Surveys were sent to 94 melanoma patients at Womens College Hospitals Pigmented Lesion Clinic assessing self-reported anxiety, contributing factors, coping strategies, and potential assisting services. Results: Risk factors for anxiety include female gender (p = 0.002) and increasing age (p = 0.004) but not melanoma depth. Major factors contributing to anxiety are prognosis, fear of death, and the attitude of the diagnosing doctor. Major coping strategies include family support, doctor assistance, and self-distraction. Potentially useful services for decreasing anxiety include the provision of detailed information pamphlets. Conclusion: Melanoma patients likely to experience high anxiety can be predicted and managed in ways that minimize the distress experienced.

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Antécédents: Plus de la moitié des patients atteints de mélanome présentent des niveaux très élevés danxiété, menant à une détresse psychologique ce qui retarde le diagnostic et donc les traitements. Objectifs: Identifier les patients atteints de mélanome qui pourraient souffrir de niveaux élevés danxiété, décrire les facteurs qui contribuent à cette condition et les stratégies dadaptation et explorer les interventions susceptibles datténuer lanxiété. Concept: Le sondage a été envoyé à 94 femmes souffrant de mélanome, à la Pigmented Lesion Clinic du Womens College Hospital, leur demandant deffectuer une auto-évaluation de lanxiété, des facteurs qui y contribuent, des stratégies dadaptation et des services daide possibles. Résultats: Les facteurs de risque de lanxiété comprennent le fait dêtre de sexe féminin (p = 0.002) et lâge (p = 0.004) mais non la gravité du mélanome. Les principaux facteurs qui causent lanxiété sont le pronostic, la peur de mourir et lattitude du médecin qui pose le diagnostic. Parmi les principales stratégies dadaptation se trouvent 1appui de la famille, laide du médecin et les sources de distraction personnelle. Les services qui seraient utiles dans latténuation de lanxiété comprennent la disponibilité de brochures informatives détaillées. Conclusion: Il est possible de repérer les patients atteints de mélanomes susceptibles de vivre une anxiété intense et de les aider à gérer et à minimiser leur détresse.

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Presented at the Dermatology Associates Continuing Medical Education Rounds, 5 November 2002.     

Distribution of carbohydrate residues in normal skin

Summary Sections of biopsies of normal skin obtained from 11 individuals were incubated with 8 lectins using an avidin-biotin complex (ABC). All sections when incubated with the appropriate lectin showed the presence of the following carbohydrate residues: l-fucose, -(1–4)-d-GlcNAc)₂ (N-acetylglucosamine), acetylneuraminic acid, Gal--(1–3)-GalNAc (N-acetyl-galactosamine), -d-galactose, -d-glucose, and -d-mannose. In addition, sections of individuals with blood group A showed -d-GalNAc and sections of individuals with blood group B showed -d-galactose. In the stratum (str.) basale, carbohydrates were present in small quantities, but as the cells matured and moved upward, the incorporation of carbohydrates into the cell membranes increased considerably. In the str. granulosum, lectin reactivity was absent in many sections, probably due to masking by phospholipids. The dark cells in the eccrine glands showed reactivity with all lectins except in the one nonsecretor with blood group A₁, whose dark cells showed no l-fucose and -d-GalNAc. The endothelial cells of the blood vessels showed lectin reactivity except when incubated with concanavalin A. The sebaceous glands showed both cytoplasmic and membrane staining when incubated with various lectins.     

A Review of the Use of Infliximab to Manage Cutaneous Dermatoses

Background Infliximab is a chimeric monoclonal antibody that binds specifically to human tumor necrosis factor-alpha (TNF-), decreasing the effect of the cytokine in inflammatory diseases.Objective The aim of this study was to review the efficacy and safety of infliximab in the treatment of dermatological diseases.Methods A MEDLINE search (1966–January 2003), using the keyword infliximab was performed to find relevant articles pertaining to the use of infliximab in dermatology.Results Infliximab has been used in the following dermatological diseases: psoriasis, Behçets disease, graft versus host disease, hidradenitis suppurativa, panniculitis, pyoderma gangrenosum, SAPHO (synovitis, acne, pustulosis, hyperostosis and osteitis) syndrome, sarcoidosis, subcorneal pustular dermatosis, Sweets syndrome, toxic epidermal necrolysis, and Wegeners granulomatosis. There is a generally good safety profile for infliximab, which is similar to that when it is used to treat Crohns disease and rheumatoid arthritis.Conclusion Although not approved for use in dermatological diseases, there have been numerous reports of the efficacy of infliximab in cutaneous inflammatory diseases. The most promise lies in those diseases that have increased amounts of TNF- in the cutaneous lesions, such as psoriasis.

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SommaireAntécédents Linfliximab est un anticorps monoclonal chimérique qui se lie au facteur de nécrose des tumeurs alpha (TNF-), réduisant ainsi leffet de la cytokine dans les maladies inflammatoires.Objectif Passer en revue lefficacité et linnocuité de linfliximab dans le traitement des maladies de la peau.Méthodes Une recherche dans MEDLINE (de 1966 à janvier 2003) a été effectuée afin de trouver les articles pertinents à lusage de linfliximab en dermatologie, au moyen du terme clé « infliximab ».Résultats Linfliximab a été utilisé dans le traitement des affections suivantes: psoriasis, maladie de Behçet, maladie du greffon contre lhôte, hidrosadénite, panniculite, pyoderma gangrenosum, syndrome de SAPHO (synovite, acné pustulose palmo-plantaire, hyperostose et ostéite), sarcoïdose, dermatose pustuleuse sous-cornée, syndrome de Sweet, nécrolyse épidermique toxique et granumatulose de Wegener. Le profil dinnocuité de 1inflimixab est généralement bon, similaire au profil dinnocuité dans le traitement de la maladie de Crohn et de la polyarthrite rhumatoïde.Conclusion Bien que linfliximab ne soit pas approuvé pour le traitement des maladies de la peau, plusieurs rapports en prouvent 1efficacité contre les maladies inflammatoires cutanées. Le traitement à linfliximab semble le plus prometteur dans les maladies avec une forte présence de TNF- dans les lésions cutanées, telles que le psoriasis.

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Funding for the publication of this article was provided by Centocor, Inc., Malvern, PA, USA.     

Permeability barrier disruption alters the localization and expression of TNFα/protein in the epidermis

Previous studies have shown that (1) epidermal TNF mRNA levels are increased following acute disruption of the cutaneous permeability barrier; (2) this increase is maximal at 1 h and decreases to control levels by 8 h; and (3) in essential fatty acid-deficient (EFAD) mice, a chronic model of barrier perturbation, TNF mRNA levels are also elevated several-fold over controls. In the present study we determined, using immunocytochemical procedures, epidermal TNF protein levels following either acute of chronic barrier disruption and the localization of any increase. Frozen, paraffin and Antibed sections of skin were incubated with polyclonal anti-mouse TNF antisera and detection was accomplished by either immunoperoxidase or fluorescence procedures. We found that (1) TNF-immunoreactive protein was present in normal mouse epidermis, and was primarily localized to the upper nucleated layers where it displayed a diffuse cytosolic pattern; (2) acute disruption of the barrier with acetone or tape-stripping resulted in TNF staining that was more intense throughout all of the nucleated epidermal cell layers in comparison with normal epidermis; (3) the increase in TNF staining occurred as early as 2 h after barrier disruption; and (4) increased TNF staining was also observed in the stratum corneum of EFAD mice. These results indicate that epidermal TNF protein levels increase after both acute and chronic barrier disruption, and are consistent with the hypothesis that TNF may signal and/or coordinate portions of the cutaneous response to barrier disruption.