Effect of glucocorticosteroids on epidermal Langerhans cells.

The effects of topical and systemic administration of various glucocorticoids on the density of epidermal Langerhans cells (LC) were studied in guinea pigs. Glucocorticoids, such as betamethasone dipropionate and valerate, caused a marked decrease in LC demonstrable by staining for cell membrane ATPase activity and Ia antigens. By electronmicroscopy, LC also showed morphologic alterations. The observed decrements in LC density correlated with the concentration and known vasoconstrictive potency of the glucocorticoids administered. The anti-inflammatory action of glucocorticoids in skin disorders may, at least in part, be through their ability to alter epidermal LC, thus interfering with the antigen-presenting functions of these cells.

Route of contact sensitization and in vitro lymphocyte transformation.

A guinea pig skin extract conjugate with dinitrofluorobenzene elicited significant in vitro transformation of cultured lymphnode lymphocytes from 19 of 27 guinea pigs sensitized by footpad injection of dinitrochlorobenzene in Freund's complete adjuvant, as compared to only 1 of 26 guinea pigs topically sensitized to dinitrochlorobenzene. Topically sensitized guinea pigs appear to be more appropriate models for contact allergy in man than guinea pigs sensitized by other methods. Other sensitization procedures are likely to produce more heterogeneous forms of sensitization, with features of contact allergy, tuberculin-type allergy, antibody-mediated hypersensitivity and cutaneous basophile hypersensitivity.

The role of Langerhans cells in allergic contact hypersensitivity. A review of findings in man and guinea pigs.

Evidence in favor of a role for Langerhans cells in contact allergic hypersensitivity reactions has been reviewed. This includes mononuclear cell to Langerhans cell apposition and damage to some Langerhans cells at sites of specific challenge to a variety of contact allergens. Such apposition occurs in actively sensitized patients and guinea pigs and in passively sensitized guinea pigs. In addition, in passively sensitized guinea pigs Langerhans cells circulate in dermal vessels resembling lymphatics and are much increased in the dermis after challenge with the contact allergen. These observations, together with the existing knowledge that Langerhans cells occur in the lymph nodes and thymus, suggest that these cells may be involved not only in contact allergic reactions but also in other immunologic reactions, particularly in cell-mediated reactions in the skin.

The role of Langerhans cells in allergic contact hypersensitivity. A review of findings in man and guinea pigs. 1976.

Evidence in favor of a role for Langerhans cells in contact allergic hypersensitivity reactions has been reviewed. This includes mononuclear cell to Langerhans cell apposition and damage to some Langerhans cells at sites of specific challenge to a variety of contact allergens. Such apposition occurs in actively sensitized patients and guinea pigs and in passively sensitized guinea pigs. In addition, in passively sensitized guinea pigs, Langerhans cells circulate in dermal vessels resembling lymphatics and are much increased in the dermis after challenge with the contact allergen. These observations, together with the existing knowledge that Langerhans cells occur in the lymph nodes and thymus, suggest that these cells may be involved not only in contact allergic reactions but also in other immunologic reactions, particularly in cell-mediated reactions in the skin.

Effect of indomethacin on alteration of ATPase-positive Langerhans cell density and cutaneous sunburn reaction induced by ultraviolet-B radiation.

We have investigated the effect of ultraviolet-B (UVB) irradiation on the density of epidermal ATPase-positive Langerhans cells, and the modulation of this effect by indomethacin (IND). Depilated backs of albino guinea pigs were exposed to varying doses of UVB (10-550 mJ/cm2). Skin biopsies were taken serially. There was an UVB dose-dependent decrease in the density of dendritic epidermal Langerhans cells, as identified by their membrane ATPase activity. This was accompanied by thinning and shortening, or disappearance of dendritic processes. Such changes were followed by a gradual recovery of the cell density to preirradiation level by day 21. Despite the high doses of UVB given, the maximal decrease in the density of ATPase-positive cells was only 58%. Topical application of IND, a prostaglandin-synthetase inhibitor, after irradiation resulted in a decrease of the erythema; however, the decrease in the density of ATPase-positive cells was still observed. In contrast, guinea pigs that received IND topically prior to irradiation showed a decrease erythemal response, but failed to show any decrease in the density of ATPase-positive cells. Administration of IND orally for 3 days prior to UVB exposure did not prevent the decrease in the cell density. The protective effect of topical IND, applied prior to irradiation, may be explained by its in vitro absorbance at both the UVB and UVA ranges. Topical application of IND 20 min prior to exposure to UVB in 2 human subjects resulted in an increase in the minimal erythema dose, giving a sun protection factor of 1.6, which is comparable to that produced by an equimolar concentration of para-aminobenzoic acid solution. The sun-protective property of IND, together with its activity as a prostaglandin synthetase inhibitor, indicate that it potentially could be a useful sunscreen agent. Its clinical safety and efficacy, however, remain to be determined.

Effect of combined topical glucocorticoids and ultraviolet B irradiation on epidermal Langerhans cells.

The combined effect of topical glucocorticoids and ultraviolet B (UVB) irradiation on ATPase+ epidermal Langerhans cells in vivo was investigated in the guinea pig model. Glucocorticoids did not significantly enhance the response to UVB radiation, in the dosage range from 90-550 mJ/cm2 of UVB, suggesting that both agents were acting in a similar fashion. The solvent ethanol, however, potentiated the effect of UVB exposure due, at least in part, to increased penetration of the UVB into the epidermis. The recovery of ATPase+ Langerhans cells was significantly slower after high (greater than 165 mJ/cm2) than after more moderate doses (90-145 mJ/cm2) of UVB radiation.

Effect of glucocorticoids and gamma radiation on epidermal Langerhans cells.

The effect of 750 rads of gamma radiation on the rate of return of epidermal Langerhans cells (LC) following suppressive doses of topical glucorticoids was studied in guinea pigs. Gamma radiation alone had no effect on the LC as assessed by staining for cell membrane ATPase activity and Ia antigen. It did, however, delay the expected return of Ia but not ATPase surface markers on the LC after perturbation with glucocorticoids. The delayed return of surface Ia antigen is possibly related to a radiation-induced defect in the production of a required lymphokine and/or in intracellular Ia transport. Although our data do not rule out a cytolytic effect of steroids on the LC, they do strongly suggest that, at least in part, glucocorticoids act on the LC by altering cell surface characteristics.

Effect of triggering epidermal Fc gamma receptors on the interleukin-2- and interleukin-6-induced upregulation of Ia antigen expression by murine epidermal Langerhans cells: the role of prostaglandins and cAMP.

Following incubation of murine epidermis in medium containing either interleukin-2 or interleukin-6, there is significant upregulation in the density of Ia+ epidermal Langerhans cells (to 159% and 175% of control, respectively). This cytokine-induced upregulation is abrogated by either rabbit or human IgG due to triggering of Fc gamma receptors. In contrast, human IgA does not inhibit the effect of interleukin-2 or interleukin-6. Using different isotypes of murine IgG, we have demonstrated that all subclasses are capable of inhibiting the cytokine-induced enhancement of Ia antigen, although IgG1 and IgG2b must be heat aggregated to be effective. The IgG-mediated events are dependent on prostaglandin synthesis because they can be blocked by the cyclooxygenase inhibitor indomethacin, 10 micrograms/ml. The responsible PG appears to be PGD2; in contrast to its known inhibitory effect on macrophages, PGE2 does not inhibit the upregulation of Ia antigen on Langerhans cells. In addition, these IgG-mediated events are dependent upon the generation of cAMP because they can be blocked by the adenylate cyclase inhibitor 2',5'-dideoxyadenosine, 1 mM. Despite the apparently central role of PGD2 and cAMP in this process, triggering of the Fc gamma R by different isotypes of IgG blocks upregulation of Ia via at least two different pathways. The inhibition caused by aggregated IgG1 or IgG2b, which bind to Fc gamma RII on Langerhans cells, is abrogated by para-bromophenacylbromide, an inhibitor of phospholipase A2. In contrast, the inhibition caused by monomeric IgG2a, which binds to Fc gamma RI most likely on keratinocytes, or monomeric IgG3, which probably binds to this same Fc gamma RI, is abrogated by staurosporine, an inhibitor of protein kinase C, as well as by W7, a calmodulin antagonist. Finally, 1,2 dioctanoyl-rac-glycerol, an activator of protein kinase C, mimics the Ig-mediated events. Based on these findings, as well as studies using monoclonal antibodies to the murine Fc gamma receptors I and II, we conclude that, as is the case in murine macrophages, triggering of an epidermal Fc gamma RI, most likely on keratinocytes, results in the generation of cAMP via a Ca(++)-dependent protein kinase C pathway, whereas triggering of an epidermal Fc gamma RII, most likely on Langerhans cells, results in the elevation of cAMP via a phospholipase A2-mediated pathway. In contrast to the situation for macrophages, PGD2 is a vital intermediate in both pathways, perhaps because Langerhans cells have receptors for only this prostaglandin.(ABSTRACT TRUNCATED AT 400 WORDS)

Immunosuppressive effects of transforming growth factor beta: inhibition of the induction of Ia antigen on Langerhans cells by cytokines and of the contact hypersensitivity response.

Recent reports show that transforming growth factor (TGF)-beta exerts a variety of immunosuppressive activities. The present study focuses on the effects of TGF-beta 1 on expression of Ia antigen by Langerhans cells. Although TGF-beta 1, in concentrations from 0.001 to 100 micrograms/ml, has no effect on constitutive expression of Ia antigen on these cells, the in vitro up-regulation of Ia antigen on the surface of LC by interleukin (IL)-1, tumor necrosis factor-alpha, interferon-gamma, IL-3, and granulocyte/macrophage-colony stimulating factor is inhibited by the concomitant addition of 1 microgram/ml TGF-beta 1. In contrast, TGF-beta 1 has no effect on the up-regulation induced by IL-2 or IL-6. In this report, the activity of TGF-beta closely resembles that of Cyclosporine A (CsA). Similar results are seen in vivo when either TGF-beta 1 (5 micrograms, intraperitoneally [ip], daily on days 0-3) or CsA (1 mg, subcutaneously [sc], twice daily on days 0-3) are given together with IL-2 (500 U, intraperitoneally [ip], twice daily on days 1-3) or interferon-gamma (4,000 U, ip, twice daily on days 1-3). Given the important role of Ia expression in cell-mediated immune reactions, the effect of TGF-beta on contact sensitivity was next investigated. In doses of 5 micrograms, ip, daily on days 6-8, TGF-beta inhibits the expression of contact reactivity in animals sensitized on day 0 and challenged on day 7. In contrast, no effect is observed on the induction of contact sensitivity in mice given TGF-beta 1 on days--1 to 2, sensitized on day 0, and challenged on day 7. The possible importance of antagonism between TGF-beta and other cytokines, especially IFN-gamma, involved in the elicitation of contact hypersensitivity reactions is discussed.

Relative lack of systemic effects of mometasone furoate on Langerhans cells of mice after topical administration as compared with other glucocorticosteroids.

The effects of topically applied mometasone furoate were compared with those of other glucocorticosteroids, in particular fluocinolone acetonide, in assays of murine epidermal Ia+ Langerhans cell density. No evidence of systemic effects, as determined by a decline in the density of Ia+ LC in distant sites, was detected after local topical applications (5 times a week) of mometasone furoate 0.001% for periods of up to 3 weeks. Other steroids, even in such very low concentrations, and mometasone furoate in higher concentrations, produced systemic effects on Ia+ LC when used for longer than 5 d. The recovery time of Ia+ Langerhans cells is significantly shorter after application of mometasone furoate than after fluocinolone acetonide. However, with both compounds, recovery occurred more rapidly after 3 weeks than after a 1- or 2-week interval of compound administration.

Mechanism of in vitro photohemiolysis in erythropoietic protoporphyria (EPP).

Four photosensitive patients with EPP showed markedly elevated RBC protoporphyrin levels. In vitro exposure of. a monolayer of their RBC in buffered saline to 3 x 10(6) ergs/mm2 of 4000 Å irradiation (= 45 minutes under a bank of fluorescent black lights) produced complete hemolysis within 24 hours; normal RBC showed negligible hemolysis after similar exposure. All of the cellular potassium was released from the patients' cells before the onset of significant hemolysis. Hemolysis was largely prevented by suspending the patients' cells in a 1:1 mixture of isotonic buffered NaCl and isotonic sucrose. These findings suggest that the initial photochemical lesion is of a "small hole" nature, creating channels through which small ions (but not sucrose) can diffuse. Since the effect of the intracellular colloid is offset by addition of sucrose to the external medium, the lesions appear to be less than 10 Å in diameter.

The Langerhans cell, as a representative of the accessory cell system, in health and disease.

Cell surface receptors and antigens present on Langerhans' cells (LC) suggest a close relationship between LC and interdigitating cells (IDC) in lymph node sections or lymphoid dendritic cells (LDC) in cell suspensions. One of the reported differences is that Fc receptors (FcR) which are present on LC, are absent on LDC. This difference can at least partly be explained by a laboratory artefact: FcR on murine LC are irreversibly modulated by the Ig that contaminates the bovine albumin commonly used for gradients. Furthermore, the demonstration of FcR on murine LC requires prolonged exposure to EA at 4 degrees C. A significant percentage of nonadherent, low density, Ig- lymph node cells also express such FcR. These cells can stimulate syngeneic mixed lymphocyte reactions as can LC isolated from epidermis. Consideration of LC as cutaneous representatives of the accessory cell system led to an investigation of their numbers in epidermal sheets of patients with acquired immunodeficiency syndrome (AIDS). A marked reduction in Ia+, ATPase+, OKT6+ LC was found as compared to controls, suggesting that accessory cell deficiency may play a role in the extreme immunodeficiency seen in AIDS patients.

Hyperimmunoglobulin E syndrome.

A 24-year old woman had the major features of the hyperimmunoglobulin E syndrome: recurrent staphylococcal skin infections (from the age of 6 months), an extremely elevated serum immunoglobulin E level (25,000 units/ml), and defective neutrophil chemotaxis. This patient also had peripheral blood eosinophilia and cutaneous candidiasis. There was a family history of asthma, but the patient herself did not have a history of asthma or hay fever, and, on examination, had no evidence of atopic dermatitis. The patient has not had any systemic infections. Results of the skin biopsy showed dermal edema and a perivascular infiltrate with eosinophils and an increased number of mast cells. The clinical spectrum of the hyperimmunoglobulin E syndrome may include atopic dermatitis, mucocutaneous candidiasis, systemic infections, and/or the features of Job's syndrome.

High-dose tetracycline therapy in severe acne.

High daily doses of tetracycline (in most instances 2,000 mg) were administered over periods of 3 to 33 months to 31 patients suffering from unusually severe, disfiguring, and treatment-resistant forms of acne (papulopustular, cystic, and conglobated). The acne cleared in 14 patients, improved greatly in 13, improved only insignificantly in 3, and failed to improve in 1. Side-effects occurred in 15 of the 31 patients but necessitated cessation of treatment in only three.

Eruptive nevocytic nevi after severe bullous disease.

In two patients, hundreds of nevocytic nevi (melanocytic nevi) appeared in sites of severe bullous dermatoses that were considered to be toxic epidermal necrolysis and erythema multiforme exudativum, respectively. This phenomenon may result from benign melanocytic hyperplasia accompanying keratinocytic hyperplasia during the healing process of some of the denuded areas of the skin.

Reversal by lymphokines of the age-related hyporesponsiveness to contact sensitization and reduced Ia expression on Langerhans cells.

Contact sensitivity responses were evaluated in young adult (3-5 months) and aged (16-26 months) BALB/c mice which were systemically treated with interleukin-2 (IL-2), interferon-gamma (IFN-gamma) or saline. Mice older than 16 months of age have deficient numbers of Ia+ Langerhans cells in addition to their well-known impaired T cell functions. They also have an impaired cell-mediated response to contact sensitization with 1-chloro-2,4,6-trinitrobenzene. This hyporesponsiveness in aged mice can be almost completely reversed by IL-2 and is marginally improved by IFN-gamma. Exposure of skin from aged mice to interleukin-2 or interferon-gamma, both in vivo and in vitro, causes increases in the density of Ia+ Langerhans cells to levels approximating those in young mice. Since IFN-gamma causes partial restitution while IL-2 fully restores the contact hypersensitivity in aged animals, we conclude that the hyporesponsiveness in aged mice results both from defective Ia antigen expression on the antigen-presenting Langerhans cells and from deficient T cell function.

Phase noise in surface-acoustic-wave filters and resonators.

Measurements of the phase noise modulation imparted on UHF carriers by surface-acoustic-wave (SAW) filters and resonators have been made using an HP 3047 spectrum analyzer. Three different types of SAW phase noise were observed. One type can be explained by temperature fluctuations. It is characterized by a spectral density of phase fluctuations which decreases as 1/f(2). The predominant noise mechanism in most SAW devices has a 1/f spectral density. The source of this noise is unknown, but it appears to be associated with both acoustic propagation and transduction. In filters fabricated on lithium niobate substrates, a third noise mechanism is evidenced. This mechanism produces nonstationary noise bursts that appear to originate in the transducer region. Experiments have been carried out on substrate materials, transducer metallizations, and over acoustic path lengths. The means by which low-frequency fluctuations are mixed to the carrier frequency have been studied.

Poison ivy dermatitis.

Eruptions caused by poison ivy (see Cover) and related plants are almost always a form of allergic contact dermatitis. Usually they can be readily recognized because of their characteristic streak- or line-like appearance. They usually clear within one to three weeks unless there is continued exposure to the allergen. Local treatment suffices in mild to moderate cases, but in more severe cases systemic corticosteroids can be added.

Allergic contact dermatitis and Langerhans cells: comments on recent developments.

Among the most interesting medical developments of the twentieth century is the revelation that the skin is an organ of major immunologic importance (about 95 percent of resident cells in the epidermis [keratinocytes and Langerhans cells] can serve immunologic functions). Allergic contact-type dermatitis and its underlying mechanism, allergic contact-type sensitization, have been a highly useful model in uncovering the facts that are the basis for this statement. The comments in this article deal with a few randomly selected findings that have been reported in the literature during the past twenty years. They include the probable role of the Birbeck granules in the process of antigen presentation by Langerhans cells; photomodulation of important immunologic reactions by ultraviolet radiation; a previously unrecognized form of contact allergy, apparently present only at clinically active sites of atopic dermatitis (and engendered by small protein antigens rather than by small molecular ["simple chemical"] compounds); and the first factual evidence that epidermal Langerhans cells may be subject to control by intraepidermally located parts of the peripheral nervous system.

Poison ivy dermatitis.

Eruptions caused by poison ivy and related plants are almost always a form of allergic contact dermatitis. Usually they can be readily recognized because of their characteristic streak-or-line-like appearance. They usually clear within one to three weeks unless there is continued exposure to the allergen. Local treatment suffices in mild to moderate cases, but in more severe cases systemic corticosteroids can be added.