Anna Sz. Kenderessy

The interleukin-8 receptor: a potential target for antipsoriatic therapy?☆

Interleukin-8 is assumed to play a central role in the pathogenesis of psoriasis. Since an increased expression of the interleukin-8 receptor has been observed both in polymorphonuclear leukocytes and in affected psoriatic epidermis, we were interested in whether the interleukin-8 receptor could be a molecular target of antipsoriatic compounds. Cyclosporine, calcitriol, calcipotriol or dithranol caused a dose-dependent decrease in interleukin-8 binding to cultured human keratinocytes, while interleukin-8 binding to granulocytes was not affected. In addition, the interleukin-8-induced human leukocyte antigen-DR (HLA-DR) expression of keratinocytes was nearly completely blocked by treatment of the cells with these substances. The inhibition of the keratinocyte interleukin-8 receptor and its function by antipsoriatic drugs may contribute to their therapeutic action.

Expression of monocyte/macrophage markers (CD13, CD14, CD68) on human keratinocytes in healthy and diseased skin.

The results of several investigations prove that, in special circumstances, human keratinocytes (HKs) synthesize and express cell surface moieties characteristic of effector and/or accessory cells of the immune system, such as CD16, CD36, HLA‐DR, and intercellular adhesion molecule‐1 (CD54), which are all detectable on the surfaces of macrophages. In the present study, skin biopsies from healthy volunteers, from positive tuberculin skin tests, and from patients with acute urticaria (AU), lichen planus (LP), psoriasis vulgaris (PV), mycosis fungoides (MF), and purpura pigmentosa chronica (PPC) were investigated by means of a multistep immunoperoxidase method to examine the reactivity of the HKs with a panel of monoclonal antibodies (MABs) characteristic of monocyte/macrophage cell lines. In biopsies obtained from positive tuberculin tests and from clinically involved skin of patients with LP, PV, MF, or PPC, a multifocal, positive peroxidase reaction was observed on the membranes of HKs of the basal and suprabasal cell layers when the MABs OKM13 (CD13), OKM14 (CD14), and Dako‐Macrophage (CD68) were used. In contrast, specific staining of the HKs was not observed with the same antibodies in the biopsies of healthy volunteers or of patients with AU or in the uninvolved skin specimens obtained from the other patients. The HKs of PV, LP, MF, PPC, and AU patients and those of the healthy subjects all failed to give positive reactions when MABs against CD11b, CD15, or CD33 were used. The published data supplement the known surface characteristics of HKs, reflecting their stage of activation and differentiation.

Inflammatory mediators are involved in the Candida albicans killing activity of human epidermal cells.

We earlier reported that freshly separated human epidermal cells (ECs) are capable of the phagocytosis and killing of the cells of a living micro-organism, Candida albicans [5]. This activity of ECs appeared to be greatly enhanced by sublethal UV irradiation in vitro [6]. A body of evidence has gradually accumulated indicating that human ECs, as a cell population in the outermost boundary layer of the organism, are actively engaged in both local and systemic immune reactions, and thus in non-MHC-restricted cytotoxicity. Antibodies, such as anti-Leu 11b, anti-Leu M2 and anti-OKM5, recognizing an epitope on natural killer cells, monocytes and granulocytes, crossreact with human EC [15, 16, 19, 20]. An increase in OKM5 § phagocytic cells has been detected in the human epidermis after UV irradiation in vivo [4]. These observations lend support to the view that human ECs may themselves have a particular role in the surveillance against invading micro-organisms, e.g Candida albicans. The possible mediators implicated in this defense mechanism are far from clarified. Inflammation appears to be important in these phenomena, however, for inflammatory reactions are always present following exposure of the epidermis to injurious influences. In earlier reports from our laboratory, we provided indirect evidence of the roles of interleukin-I (a compound similar in function and physicochemical characteristics to EC-derived thymocyte-activating factor), PGE2, and platelet-activating factor (PAF) in the UV-induced Candida killing activity of ECs [6, 8].

Enhancement of Candida albicans killing activity of separated human epidermal cells by ultraviolet radiation

Ultraviolet irradiation enhanced the Candida albicans killing activity of freshly separated human epidermal cells in vitro. The stimulation was dose‐dependent and was not due to soluble extracellular factors acting on non‐irradiated epidermal cells. The enhancement of the killing activity remained unchanged when epidermal cells were depleted of Langerhans cells. Protein synthesis inhibitors and prostaglandin antagonists abrogated the ultraviolet‐induced augtnentation of killing activity.

Evidence for cell-mediated autoimmunity in patients with pemphigus vulgaris and bullous pemphigoid.

SummaryLymphoid cells from 4 of 5 patients diagnosed as pemphigus vulgaris (PV) and 6 of 7 patients diagnosed as bullous pemphigoid (BP) demonstrated specific cell-mediated immunity by the production of migration inhibitory factor (MIF) in the presence of autologous epidermal saline extracts. Clinical treatment of these patients with immunosuppressive agents resulted in a state of unresponsivenes of their lymphoid cells to similar concentrations of the antigen. Controls consisted of lymphoid cells from patients with bullous burns or various drug allergies which failed to show significant MIF production in the presence of autologous skin extract. These studies suggest that both PV and BP patients posses cell-mediated immunity (CMI) to their own autologous tissue antigens and this CMI may play a role in the pathogenesis of these diseases.ZussammenfassungDer autologe Epidermis-Extrakt löste bei 4 von 5 an Pemphigus vulgaris (PV) und bei 6 von 7 an bullösem Pemphigoid (BP) leidenden patienten eine Leukocytenmigrationshemmung aus. Das auf ähnliche Weise hergestellte Antigen verursachte bei Patienten mit bullöser Verbrennung oder Arzneimittel-Allergie keine Migrationshemmung. Die migrationshemmende Wirkung klang zur Zeit der Symptomfreiheit sichenden erhaltenden Therapie ab. Diese Befunde deuten darauf hin, daß die PV- und die BP-Kranken über gegen epidermale Antigene gerichtete celluläre Autoimmunreaktion verfügen.

Autoimmune anti‐T cell antibodies in the sera of patients with mycosis fungoides

The serum of persons with mycosis fungoides contains IgG antibody believed to be specific for T cells, similar to the auto-antibodies reported in patients with systemic lupus erythematosus, Hodgkins disease and sarcoidosis. The antibody is present during the active, and disappears during the inactive, phase of the disease.

Suppressor activity of peripheral blood mononuclear cells in patients with chronic discoid lupus erythematosus

SummarySignificantly increased suppressor activity of peripheral blood mononuclear cells was demonstrated in patients suffering from chronic discoid lupus erythematosus.ZusammenfassungDie signifikant erhöhte Suppressoraktivität der mononukleären Zellen des peripherischen Blutes wurde bei Patienten mit chronischdiscoidem Lupus erythemathosus demonstriert.

Prealbumin as a hapten carrier protein in certain varieties of dermatitis.

SummaryA significant decrease of serum prealbumin levels and an increased proportion of prealbumin bearing lymphocytes in peripheral blood have been found in patients of hapten-induced diseases. Prealbumin deposition in the vessel walls, and/or prealbumin positive cells (granulocytes, lymphocytes, macrophages) in the dermis have been observed in patients with proved drug allergy as well as allergic contact dermatitis using immunofluorescence technique. The eluates from membrane of lymphocytes of patients with drug allergy contained a mitogenic substance, probably antigen and sometimes prealbumin as well. These results also support the earlier suggested hypothesis that the prealbumin may act as a hapten carrier protein.ZusammenfassungDie Verfasser fanden bei Hapten-bedingten Krankheiten den Präalbumingehalt im Serum verringert und die relative Zahl der Präalbumin-tragenden Lymphocyten erhöht. Ihre immunfluorescenzmikroskopischen Untersuchungen ließen bei allergischer Kontaktdermatitis- und Arzneimittelallergie-Patienten in den Gefäßwänden Präalbuminablagerung und in der Dermis Präalbumin-positive Entzündungszellen (Granulocyten, Lymphocyten, Makrophagen) feststellen. Bei arzneimittelallergischen Patienten konnte von der Membran der Lymphocyten ein mitogen wirksames Agens, offenbar ein Antigen, eluiert werden, welches in einigen Fällen auch Präalbumin enthielt. Diese neueren Befunde unterstützen ebenfalls die frühere Hypothese der Autoren von der Hapten-tragenden Rolle des Präalbumins.