Increased immune response in the acute phase of systemic lupus erythematosus and psoriatic arthritis caused by serum factors.

In the acute phase of systemic lupus erythematosus the serum contains factors, with molecular weights ranging from 780,000 daltons to 1.5 million daltons, which induce blast transformation of autologous lymphocytes. In addition to the high-molecular weight components, low-molecular weight factors (75,000 and 160,000 daltons) which also induce an increase in lymphocytic transformation have also been demonstrated. In contrast to the high-molecular weight components the low-molecular factors stimulate the transformation of autologous and homologous lymphocytes. During transformation, lysis of autologous target fibroblasts occurs. The low-molecular weight mitogenic components remain stable after 30 min at 56 degrees C. The significance of such mediators for the pathogenesis of systemic lupus erythematosus is discussed.

Polyclonal B cell activation in the acute phase of systemic lupus erythematosus--aspects of pathogenic significance.

B lymphocytes from patients suffering from systemic lupus erythematosus show increasing rates of spontaneous transformation in prolonged cultivation (144 hr). An additional B cell stimulation could be detected following the addition of sera from lupus erythematosus patients (isolated during the acute phase of disease) to the culture medium. In addition enriched mitogenic serum components from lupus sera increase the 3H-thymidine uptake of Brucella abortus primed B cells of healthy controls. The incorporation of 3H-thymidine with respect to the Brucella antigen concentration is described.

Inhibition of skin allograft rejection and acute graft-versus-host disease by cis-urocanic acid.

Ultraviolet B radiation initiates a suppression of the delayed-type hypersensitivity response accompanied by a generation of antigen-specific suppressor cells and an alteration of antigen-presenting function. In previous studies we and other investigators could achieve a prolongation of graft survival by a treatment of the recipient with UVB light or 8-methoxy-psoralen plus UVA light (PUVA). One of the mediators of the systemic immunomodulatory effects of ultraviolet light or PUVA may be urocanic acid, which is isomerized in the skin by ultraviolet light from its cis- to the trans-isomer. In this work we present evidence that cis-urocanic acid, generated in vitro by a treatment with UVB light or PUVA, is able to prolong the survival of allogeneic MHC disparate skin grafts in mice. In contrast, the rejection of second set grafts was not suppressed. Unirradiated (trans-urocanic acid) had no effect on allograft rejection. In a murine model cis-, but not trans-urocanic acid, prevented or delayed an acute lethal graft-versus-host disease. These experiments demonstrate the potent systemic immunomodulatory effects of cis-urocanic acid in vivo.

Inhibition of cutaneous contact hypersensitivity by calcium transport inhibitors lanthanum and diltiazem.

Epidermal Langerhans cells (ELC) are bone marrow-derived immune cells that are important in allergic contact dermatitis. We examined the influence of calcium transport inhibitors, lanthanum and diltiazem hydrochloride, on allergic contact dermatitis induced by 1-chloro-2,4-dinitrobenzene (DNCB) in BALB/c mice. Systemic lanthanum at a dose of 0.08 mg/kg and topical lanthanum (50 microliters of 10% solution) were given 5 d before DNCB sensitization. Systemic diltiazem (30 mg/kg per dy) was given for 3 d during sensitization with DNCB. In all animals, challenge with topical DNCB to the ear skin was performed 5 d after sensitization and ear swelling was measured. Twenty four hours post-DNCB challenge, animals receiving systemic lanthanum demonstrated a 56% decrease in contact hypersensitivity (ear swelling) compared with non-lanthanum-treated animals (0.08 +/- 0.03 mm vs 0.18 mm +/- 0.02 mm, p less than 0.01). Topical lanthanum produced a 58% decrease in contact hypersensitivity (0.20 +/- 0.02 mm vs 0.41 +/- 0.03 mm, p less than 0.01). The DNCB-induced ear swelling also resolved more quickly in animals treated with lanthanum. Systemic diltiazem produced a 67% decrease in ear swelling (0.05 +/- 0.01 mm vs 0.15 +/- 0.02 mm, p less than 0.001). A decrease in epidermal Langerhans cell density of 13 to 14% was produced by systemic lanthanum, detected by both ATPase staining and Ia staining, respectively (p less than 0.05). Approximately 20% of the Langerhans cells were morphologically abnormal, having become "rounded," and lacking normal dendritic processes. From these results, we infer that calcium transport across the cell membrane of ELC may be important in the regulation of their function. Lanthanides and other calcium-channel blockers may be useful pharmacologic agents to probe these phenomena.

Serum-mediated inhibition of the interferon-gamma-induced HLA-DR expression on monocytes in patients with psoriasis.

Psoriatic patients have a decreased proportion of monocytes expressing class II major histocompatibility complex antigens (DR+ monocytes) in their peripheral blood. The expression of the DR antigen on monocytes after culture in the presence of either autologous lymphocytes (endogenous interferon-gamma, IFN-gamma) or exogenous IFN-gamma was investigated. In normal AB serum the lymphocytes of the majority of the patients showed a spontaneous IFN-gamma production which was sufficient for DR antigen induction, while the monocytes displayed approximate normal susceptibility to exogenous IFN-gamma as judged by DR antigen expression. However, the sera of psoriatic patients contained one or more factors that interfered with the IFN-gamma-mediated DR antigen expression on cultured monocytes of the same patients. Restoration of IFN-gamma-induced DR antigen expression on monocytes in the presence of the patient's sera was achieved by the addition of superoxide dismutase, 2-mercaptoethanol, or indomethacin. The clinical significance of these observations is discussed.

Inhibition of Langerhans cell ATPase and contact sensitization by lanthanides--role of T-suppressor cells.

Lanthanides are rare earths, elements 55-71 in the periodic table, that are of interest in biologic systems as isomorphic competitors for calcium binding sites. Lanthanides were tested for their inhibitory influence on the Ca++/Mg(++)-dependent ATPase of epidermal langerhans cells in vitro, and on the immunologic function of Langerhans cells in vivo. The trivalent ions of lanthanides, lanthanum, and cerium completely inhibited the ATPase staining of Langerhans cells in vitro. When mice were sensitized with dinitrofluorobenzene on skin sites pretreated with topical lanthanum chloride, and challenged on untreated ear skin, a markedly reduced contact hypersensitivity response was observed. This hyporesponsiveness was found to be antigen specific, and could be passively transferred to naive syngeneic animals recipients by CD4-CD8+ spleen cells. These results suggest that inhibition of the epidermal Langerhans cell surface ATPase by application of topical lanthanum and the induction of antigen-specific immunologic tolerance may be related events.

Decrease of HLA-DR antigen expression by human monocytes during cultivation in absence of exogenous or endogenous interferon-gamma.

The kinetics of HLA-DR antigen expression by human peripheral blood monocytes during cultivation in vitro was studied. Immediately after separation by glass adherence, about 60% of monocytes expressed DR antigens as judged by indirect fluorescence staining with a monoclonal antibody (BL-DR/1). Monocytes carefully depleted of lymphocytes, gradually lost their DR antigens during cultivation in the absence of exogenous interferon-gamma (IFN-gamma). However, addition of a few lymphocytes to the adherent cells prevented the decrease of DR antigen expression. Furthermore, it was shown that doses as low as 1 IU/ml of IFN-gamma are sufficient to induce DR antigen expression by cultured monocytes. Experiments with cyclosporin A suggest that lymphocytes contaminating the monocyte preparations can produce spontaneously sufficient amounts of IFN-gamma for maintenance of the DR antigens on monocytes.

Inhibitory effects of sulfonated shale oils (ammonium bituminosulphonates, Ichthyols) on enzymes of polyenoic fatty acid metabolism.

The two commercial pharmaceutical preparations of ammonium bituminosulphonates, Leukichthol and Dark Ichthyol, were shown to inhibit the formation of 5S-hydroxy-6E,8Z,11Z,14Z-eicosatetraenoic acid (5-HETE) from external arachidonic acid by human polymorphonuclear leukocytes stimulated by ionophore A-23187 in a dose-dependent manner. Pure arachidonate 15-lipoxygenases from rabbit reticulocytes and soya beans, and the particulate prostaglandin endoperoxide synthase from sheep vesicular glands, were also inhibited. With the reticulocyte lipoxygenase, the Ichthyols suppressed the enzyme activity by two different mechanisms: (1) a prolongation of the lag period typical of lipoxygenase catalysis, and (2) by a lowering of the maximal enzymatic activity after the end of lag period. As expected, the first effect was reversed by the addition of the lipoxygenase product 13S-hydroperoxy-9Z,11E-octadecadienoic acid (13-HpODE). Ammonium bituminosulphonates are thus universal inhibitors of lipoxygenase activities, and the latter are of potential importance in inflammatory dermatoses.

Stimulation of the recruitment of epidermal Langerhans cells by splenopentin.

Splenopentin (SP-5: Arg-Lys-Glu-Val-Tyr), a pentapeptide corresponding to the residues 32-36 of the splenic hormone splenin, increases dose-dependently the number of bone marrow colonies (M and GM colonies). Therefore, we tested the stimulatory effect of SP-5 on the recruitment of epidermal Langerhans cells in skin deprived of these cells. A high dose of cyclophosphamide or dexamethasone led to a drastic decrease of LC density in murine skin with slow and incomplete restoration. SP-5 accelerated Langerhans cell recruitment and led to pretreatment levels of Langerhans cell density in the skin. These results indicate that SP-5 may possibly be used to treat disorders (e.g., HIV infection) where impaired Langerhans cell density and function can lead to secondary cutaneous infections.

The influence of interferon-gamma, interleukin-2, prostaglandin E2, and cyclosporine on the polyclonal and anti-DNA antibody secretion in lymphocyte cultures derived from patients with systemic lupus erythematosus.

The influence of various immunoregulatory substances was studied in lymphocyte cultures derived from patients suffering from systemic lupus erythematosus (SLE) by using the model of spontaneous secretion of polyclonal immunoglobulin G (IgG)/immunoglobulin M (IgM) and anti-DNA autoantibodies. Compared with healthy donors, lymphocytes derived from patients with active SLE disease showed an elevated secretion of total IgG as well as anti-DNA-IgG in vitro, which was associated with an increase in the proportion of activated (HLA-class II +) T cells in their peripheral blood. Recombinant interferon-gamma increases the total IgG/IgM as well as anti-DNA-IgG/IgM secretion, which suggests that it has a possible role in the pathogenesis of SLE disease. Recombinant interleukin-2 and prostaglandin E2 normalize the high, spontaneous total IgG secretion, but elevate anti-DNA-IgG/IgM secretion. These results suggest that autoreactive B-cell clones are regulated differently in SLE patients. Cyclosporine inhibits total IgG/IgM secretion in all patients and anti-DNA-IgG/IgM secretion in six of eight patients. The possible therapeutic use of such immunomodulatory substances in SLE disease is discussed.

Histochemical, immunohistochemical and ultrastructural studies on the action of glucocorticoids on epidermal Langerhans cells (ELC) of murine skin.

We studied the influence of the glucocorticosteroids dexamethasone and prednisolone on epidermal Langerhans cells (ELC) in the ear skin of BALB/c mice. ELC were detected by HLA II-antigen-expression and ATPase staining. The number of ELC was counted by normal light and immunofluorescence microscopy. Both, dexamethasone and prednisolone decreased the number of ELC and the intensity of the reaction for HLA II and ATPase significantly. In the electron microscope, ELC were identified by their light cytoplasm, the lobulated nucleus and typical Birbeck Granula (BG). After systemic application of dexamethasone or prednisolone the ultrastructure was changed with respect to a loss of typical BG and occurrence of numerous small vacuoles without electron dense content instead of BG.

[Electrophoretic examination of protein distribution in guinea pig perilymph]. / Elektrophoretische Untersuchungen zur Proteinverteilung in der Meerschweinchen-Perilymphe

Perilymph and serum of guinea pigs were investigated using immunoelectrophoresis and polyacrylamide gel electrophoresis. The molecular weights of the perilymph proteins were estimated by electrophoresis in a linear polyacrylamide gel gradient (3-20%). The immunoelectropherograms and the polyacrylamide gel electropherograms of equivalent amounts of perilymph protein and serum protein are nearly the same. The immunological detection of the perilymph proteins indicates that they are serum proteins. The clear identification of the individual proteins fails because of missing monospecific antisera against the individual proteins of guinea pig. High-molecular proteins (range of the molecular weight estimation 67 000-290 000) are also detectable in the perilymph according to the molecular weight estimation.

[Inflammation-inhibiting effect of magnesium ions in contact eczema reactions]. / Entzündungshemmende Wirkung von Magnesium-Ionen bei der Kontaktekzem-Reaktion.

Water containing high concentrations of magnesium ions (e.g. Dead Sea water) is effective in the treatment of inflammatory skin diseases. Therefore, we examined the influence of Mg2+ on inflammation in allergic contact dermatitis induced by 1-chloro-2,4-dinitrobenzene (DNCB) in BALB/c mice. Animals challenged with 0.125% DNCB in the presence of magnesium chloride (28% and 14%) demonstrated significantly less pronounced contact dermatitis (ear swelling) than did animals challenged with DNCB alone (p less than 0.001 and p less than 0.01). In mice challenged with DNCB in combination with sodium chloride (14%) there was no statistically significant difference in the degree of ear swelling. These results were borne out in 5 patients known to be allergic to nickel, in whom magnesium chloride but not sodium chloride, suppressed nickel sulphate-induced contact dermatitis.

Influence of thymic hormones on mitogen-induced interferon production in lymphocytes. I. Augmentation of mitogen-induced immune interferon production by thymosin.

Thymosin (thymus fraction 5) in combination with concanavalin A influences both 3H-thymidine uptake in lymphocytes in vitro and the production of interferon. After in vivo pretreatment of adult mice with thymosin the mitogen-induced interferon production was about 3 times higher than in controls. The produced interferon is immune interferon (IFN gamma) as determined by rho H 2-sensitivity and lack of neutralization by mouse IFN beta-antibodies.

Persistent serum immune complexes in syphilis.

Serum immune complexes were estimated by a polyethylene glycol precipitation method in 51 patients with early syphilis. The immune complexes were increased in 41% of patients before treatment and decreased to normal limits in only 56% during treatment. The results of the specific antireponemal tests using dissolved immune complexes show that antibodies from the immune complexes are specific antibodies.

Stable lipid peroxidation products in human skin: detection, ultraviolet light-induced increase, pathogenic importance.

Products of lipid peroxidation (malonaldehyde, Schiff-bases) were detected in human skin. These products were increased after UV-light exposition, on chronically sun-exposed areas as well as with advancing age. Malonaldehyde cross linked epidermal glucose-6-phosphate-dehydrogenase and diminished their activity.

[Study on the mode of action of dithranol: increased lipid peroxidation and enzyme inhibition]. / Untersuchungen zum Wirkungsmechanismus von Dithranol: Erhöhte lipidperoxydation und Enzymhemmung

The results reported in connection with previously published data suggest the importance of increased lipid peroxidation in the epidermis after Dithranol treatment. Malonaldehyde, one of the main products of lipid peroxidation, reacts with epidermal phosphofructokinase and glucose-6-phosphate dehydrogenase to cause enzyme inactivation by cross-linking of the enzyme protein demonstrated by dodecyl sulphate electrophoresis. Enzyme inactivation leads to an inhibition of hexose monophosphate shunt and glycolysis. The effect on energy donating metabolism in psoriatic lesions is discussed.

Protective immunization against Treponema pallidum using specific immune complexes--an attempt.

Rabbits were immunized using isolated and dissolved specific immune complexes obtained from patients suffering from early syphilis. After immunization the rabbits were infected intradermally with living Treponema pallidum. Some of them did not develop lesions at the infection sites. In comparison to controls there was a delayed and reduced production of antibodies. The effect of immunization may be induced by a treponemal protein antigen as a constituent of the specific immune complexes.