Prevalence of gold contact hypersensitivity in the west of Scotland

373 patients attending for routine patch testing were tested with 0.5% and 0.05% gold sodium thiosulfate (GST). 8 (2.1%) patients had a positive patch test, and a further 4 (1.0%) patient reactions which were interpreted as irritant 2 out of 8 patients with a positive patch test to GST suspected gold allergy prior to testing, and both of these patients reported that their eczema resolved if they avoided gold jewellery. This is the lowest prevalence of hypersensitivity to GST reported and suggests that gold contact allergy may not be as widespread as has been recently proposed.     

Rapid transepithelial antigen transport in rat jejunum: impact of sensitization and the hypersensitivity reaction

BACKGROUND & AIMS: Intestine from sensitized rats develops a rapid secretory response to luminal antigen challenge that depends on activation of subepithelial mast cells. The aim of this study was to determine the timing and route of the transepithelial protein antigen transport. METHODS: Rats were sensitized to horseradish peroxidase (HRP). After 10-14 days, jejunal segments were resected, mounted in Ussing chambers, and challenged with HRP on the luminal side. RESULTS: Electron microscopy of tissue specimens fixed at 2 minutes (before mast cell activation) showed enhanced endocytic uptake of HRP in enterocytes of HRP-sensitized rats compared with ovalbumin-sensitized or saline-injected controls. At this time, HRP was distributed throughout epithelial cells and was already evident in the lamina propria. In contrast, HRP was restricted to the apical region of enterocytes in controls. At 30 minutes (after mast cell activation), in HRP-sensitized rats only, HRP was also located within tight junctions and the paracellular region between epithelial cells. Tissue conductance was increased in HRP-sensitized rats beginning 30 minutes after HRP addition and correlated with the overall flux of HRP across the tissue. CONCLUSIONS: The results show that specific sensitization enhances the initial uptake and transcytosis of antigen across intestinal epithelium. Subsequent to activation of mast cells, antigen transport is further enhanced by penetration through the paracellular pathway.     

Prevalence and sources of occupational contact sensitization to acrylates in Italy

An avulsion of the anterior cruciate of an 11 year old girl was internally fixed with a transepiphysial screw. Two years later, anterior epiphysiodesis was evident, causing hyperextension of the knee. To avoid this complication, we recommend early removal of transepiphysial metalwork in children. Arthroscopical intrafocal fixation is proposed as a safe alternative.     

Prospective study of the significance of contact sensitization caused by metal implants

Cell nuclei of mouse hepatoma contain various proteoglycans (PG) which include heparan sulfate proteoglycan (HS-PG), dermatan sulfate proteoglycan (DS-PG), and chondroitin sulfate proteoglycan (CS AC-PG). The latter is not found in cell nuclei of normal mouse liver. Heparan sulfate (HS) and dermatan sulfate (DS) are the main constituents of carbohydrate chains of nuclear proteoglycans of tumor and normal cells, respectively. Changes in the composition of nuclear PG during malignant transformation are discussed considering the concept of their possible involvement in the regulation of cell mitotic activity.     

Inhibition of irritation and contact hypersensitivity by ethacrynic acid

The immunosuppressive effect of topical ethacrynic acid (ECA) was tested on both the induction and elicitation phases of contact sensitization in a mouse model. ECA (0.5% in vehicle) reduced the sensitization response by >50% when the sensitizer was either dinitrochlorobenzene (DNCB), oxazalone (OX) or para-phenylenediamine (PPD), and was applied 1 day later to the ECA-pretreated skin site. The immunosuppressive effect of combining ECA with either hydrocortisone or with cis-urocanic acid was also tested. An additive suppressive effect was observed with ECA in both combinations. The effect of ECA (1% in vehicle) on blocking the elicitation phase was also examined in a mouse ear edema assay. ECA was highly effective in preventing the challenge response in mice previously sensitized to either DNCB, OX or PPD. ECA (1% in vehicle) was also tested for its ability to inhibit contact irritation. ECA (1% in vehicle) was highly effective in preventing ear edema due to topically applied skin irritants including arachidonic acid, capsaicin, lactic acid, phorbol myristate acetate, trans-retinoic acid, and sodium lauryl sulfate. ECA may be useful for both prophylaxis and therapeutic treatment of diverse skin conditions including contact dermatitis, eczema, and other related allergic skin disorders.     

Characteristics of antigen-presenting cells involved in contact sensitization of normal and UV-irradiated mice

Exposure of mice to ultraviolet (UV)-B (280-320 nm) radiation alters their immune response to contact-sensitizing haptens applied to UV-irradiated skin. Under these conditions, the contact-hypersensitivity response is reduced, and hapten-specific suppressor T lymphocytes can be found in the spleen. Considerable evidence suggests that the epidermal Langerhans cell is one of the principal targets of this effect of UV irradiation that leads, ultimately, to suppressor cell formation. We are using a combination of cell-surface markers and light and electron microscopy to determine whether differences can be detected in the antigen-presenting cells involved in contact sensitization of normal and UV-irradiated mice.     

Contribution of therapist warmth to the contact desensitization treatment of acrophobia.

Varied therapist warmth in the contact desensitization treatment of acrophobia. 19 height-fearful volunteers (18–63 yrs old) were assigned to 1 of 3 groups: a warm therapist, a cold therapist, and a waiting control group. Behavioral and attitudinal measures of height avoidance were collected prior to treatment, immediately following treatment, and at a 1-mo follow-up (e.g., the Fear Survey Schedule, the Height Avoidance Test, the Expectancy Questionnaire, and the Therapist Warmth Questionnaire). Both treatment groups showed significant improvement when compared to the waiting list group, but no consistent differences were found between the warm and cold therapist groups. Results are discussed in terms of the relative contribution of therapist relationship factors. (3 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Mice deficient in IL-1beta manifest impaired contact hypersensitivity to trinitrochlorobenzone

Mice rendered deficient in IL-1 beta by gene targeting in embryonic stem cells develop and grow normally in a protected laboratory environment. Endotoxin-stimulated peritoneal macrophages from IL-1beta-deficient mice showed normal synthesis and cellular release of IL-1alpha after treatment with 5 mM ATP demonstrating that IL-1beta is not necessary for expression and release of the IL-1alpha isoform. Mice deficient in IL-1beta showed unaltered sensitivity to endotoxic shock, with or without pretreatment with D-galactosamine. In contrast, IL-1beta-deficient mice showed defective contact hypersensitivity responses to topically applied trinitrochlorobenzene (TNCB). This defect could be overcome either by application of very high doses of sensitizing antigen, or by local intradermal injection of recombinant IL-1beta immediately before antigen application. These data demonstrate an essential role for IL-1beta in contact hypersensitivity and suggest that IL-1beta acts early during the sensitization phase of response. They suggest an important role for IL-1beta in initiation of the host of response at the epidermal barrier.     

Histamine involvement in UVB- and cis-urocanic acid-induced systemic suppression of contact hypersensitivity responses

Studies in experimental models have implicated histamine and prostanoids in ultra-violet B (UVB)- and cis-urocanic acid (UCA)-induced systemic immunosuppression. This study examined the hypothesis that UVB irradiation and cis-UCA suppressed contact hypersensitivity responses to hapten by induction of histamine, which in turn evoked a prostanoid-dependent component of immunosuppression. BALB/c mice were administered with a cis-UCA monoclonal antibody, a combination of histamine types 1 and 2 receptor antagonists, or indomethacin. Mice were sensitized to 2,4,6-trinitrochlorobenzene (TNCB) on their ventral surface 5 days after UVB irradiation, or cis-UCA or histamine administration. Ears were challenged with TNCB 5 days later. Cis-UCA antibody inhibited the suppressive effects of UVB by approximately 60% and confirmed that suppression of contact hypersensitivity responses by UVB was due, at least in part, to mechanisms involving cis-UCA. Histamine suppressed contact hypersensitivity responses and the effects of cis-UCA and histamine were not cumulative, suggesting that cis-UCA and histamine signal largely through the same pathway. The immunosuppressive effects of histamine were not affected by the cis-UCA antibody, consistent with the model that histamine acts downstream of cis-UCA. Administration of histamine receptor antagonists and indomethacin each approximately halved the UVB- and cis-UCA-induced systemic suppression of contact hypersensitivity responses. The effects of the reagents that inhibited the action of histamine and prevented prostanoid production were not cumulative, and suggested involvement in the same pathway. These results support the involvement of cis-UCA, histamine and prostanoids, in a sequence, in UVB-induced systemic suppression of contact hypersensitivity responses.     

Topical application of T-2 toxin inhibits the contact hypersensitivity response in BALB/c mice

T-2 toxin, a trichothecene mycotoxin, has previously been shown to alter immune functions and promote skin tumors. We demonstrate that topically applied T-2 toxin reduces the ear swelling response to oxazolone challenge in BALB/c mice. For this reduction in ear swelling to occur, toxin application must be at, or within, 1 h after challenge. Dose-response studies showed a 44% reduction in ear swelling with 30 ng of T-2 toxin as compared with a similar reduction with 300 ng of dexamethasone. T-2 toxin did not affect Ag transport from the challenge site to the draining lymph nodes as measured by FITC transport. However, T-2 toxin significantly reduced both MHC class II (Ia) expression and Ag presentation at the same concentrations. Because T-2 toxin, a known protein synthesis inhibitor, was found to inhibit protein synthesis in epidermal cell cultures as measured by [3H]-leucine incorporation, cycloheximide was also examined. Cycloheximide reduced both oxazolone-induced ear swelling and Ag presentation in a similar manner to T-2 toxin. One mechanism of action for T-2 toxin in reducing the contact hypersensitivity response is via inhibition of protein synthesis and effective Ag presentation by epidermal Langerhans cells. This may involve alterations in Ia Ag expression, although a role for class II in the induction phase of the contact hypersensitivity response has not been established definitively.     

Blockade of CD40-CD40 ligand pathway induces tolerance in murine contact hypersensitivity

Interactions between CD40 on antigen-presenting cells and its ligand (CD40L) on T cells has been implicated in T cell-mediated immune responses. Previously, we have shown that contact hypersensitivity (CHS), a cell-mediated cutaneous immune response in reaction to haptens, could be subclassified based on whether the hapten primed for Th1 or Th2 cytokines in cells isolated from draining lymph nodes. We also found that tolerance to a Th2-priming hapten could be induced only by simultane blockade of the CD40-CD40L and B7-CD28 at the time of sensitization. Here we demonstrate that blockade of CD40-CD40L signaling alone induces long-lasting unresponsiveness to the Th1 hapten 2,4-dinitrofluorobenzene (DNFB), and inhibits antigen-specific T cell proliferation in vitro. We find that CD40-CD40L signaling is required in the sensitization but not elicitation phase of DNFB-induced CHS, as treatment of mice with anti-CD40L monoclonal antibody (mAb) does not affect the response to hapten challenge in previously sensitized and untreated animals. Examination of cytokine production shows that anti-CD40L mAb decreases interferon-gamma production by draining lymph node cells from DNFB-sensitized mice, and reciprocally increases interleukin (IL)-4 production. Consistent with this Th1 to Th2 immune deviation, anti-CD40L mAb prevents the induction of IL-12 mRNA in regional lymph nodes, an event which is normally seen within 12 h following hapten sensitization. In contrast, suppression of CHS by CTLA4Ig decreased the production of all cytokines by draining lymph node cells. Together, these data show that blockade of the CD40-CD40L pathway by itself is sufficient to induce tolerance to DNFB-induced CHS, and that this is associated with blockade of IL-12 induction and Th1 to Th2 immune deviation.     

Calcitonin gene-related peptide is necessary for ultraviolet B-impaired induction of contact hypersensitivity

Since nerve termini on Langerhans cells (LC) contain calcitonin gene-related peptide (CGRP), and since ultraviolet B radiation (UVR) causes CGRP to be released from cutaneous nerve endings, we examined whether CGRP participates in the immune aberrations caused in skin by UVR. First, intradermally injected CGRP, in a dose-dependent manner, reduced LC density and impaired CH induction when hapten was painted on the injected site. Second, CGRP antagonist restored CH induction after UVR. Third, anti-TNF-alpha Abs injected before CGRP prevented the loss of LC density and restored CH induction. Fourth, CGRP failed to impair CH induction in mast cell-deficient mice. Fifth, CGRP induced mast cells to release TNF-alpha. We conclude that CGRP plays an essential role in the loss of CH induction after UVR. These data indicate that UVR, by causing the release of CGRP from cutaneous nerve endings, triggers mast cell release of TNF-alpha, which impairs CH induction.     

Contribution of endothelial selectins and alpha 4 integrins to eosinophil trafficking in allergic and nonallergic inflammatory reactions in skin

The role of endothelial selectins in mediating eosinophil recruitment was assessed using the trafficking of 111In-labeled blood eosinophils in mouse skin. An intradermal injection of chemoattractants (leukotriene B4, macrophage inflammatory protein-l alpha, and eotaxin) resulted in a rapid accumulation of 111In eosinophils that was reduced 49 to 91% by anti-P-selectin mAb. An anti-E-selectin mAb was ineffective, although a combined E- and P-selectin blockade resulted in >95% inhibition of all responses. The accumulation of a pulse of 111In eosinophils at sites of active cutaneous anaphylaxis (ACA) at 4 to 8 h and at 20 to 24 h after Ag challenge was completely dependent upon E- and P-selectin in combination, but not in isolation. In contrast, at 20 to 24 h after Ag challenge in a delayed-type hypersensitivity (DTH) reaction in skin, 111In eosinophil accumulation was largely independent of endothelial selectins, even when L-selectin was also blocked. An anti-alpha 4 integrin mAb significantly reduced 111In eosinophil trafficking in both allergic reactions but was slightly more effective in the DTH reaction compared with the ACA reaction. These results show that P-selectin and to a lesser extent E-selectin mediate eosinophil recruitment in skin in acute inflammatory reactions. In allergic, late-onset inflammatory reactions, neither P- nor E-selectin alone are sufficient to mediate eosinophil accumulation; when combined, they are essential for trafficking in ACA but are less important in the DTH reaction. Whether alpha 4 integrin-based strategies will be more effective than selectin-based strategies at inhibiting eosinophil recruitment in human disease remains to be determined.     

Depressed Langerhans cell migration and reduced contact hypersensitivity response in mice lacking TNF receptor p75

Epidermal Langerhans cells (LC) belong to the dendritic cell family and represent the major APC within the skin. LC capture epicutaneous Ag, migrate into regional lymph nodes, and present Ag to T cells, thereby initiating primary immune response. The migratory properties of LC are an essential component of their function. The molecular mechanisms responsible for LC migration are far less defined. However, evidence has been accumulating to suggest that TNF-alpha, a major proinflammatory cytokine, plays an important role in promoting DC migration. To confirm the role of TNF-alpha in LC migration and to examine which type of TNF receptor signaling is involved in such an event, we utilized gene-targeted knockout mice lacking TNF receptor p55 or p75. The migration of LC was assessed by examining the frequency of hapten-bearing cells in draining lymph nodes following hapten FITC painting, and the accumulation of dendritic cells in draining lymph nodes after intradermal injection of TNF-alpha. While LC migration was normal in p55-deficient mice, the migration was markedly depressed in p75-deficient mice. Receptor p75-deficient mice also demonstrated a hyporesponsiveness in allergen-induced contact dermatitis, but a normal responsiveness in irritant-induced contact dermatitis. These results suggest that p75-dependent signaling plays a crucial role in the migration of LC and in the initiation of cutaneous immune responses.     

Distinct roles for B7 costimulation in contact hypersensitivity and humoral immune responses to epicutaneous antigen

Productive interactions between B7-1 and B7-2 costimulatory molecules on dendritic cells (DC) and CD28 on T cells are thought to be critical for successful antigen presentation. Epicutaneous application of haptens induces both contact hypersensitivity (CHS), an inflammatory cutaneous response mediated by CD8+ T cells, and an anti-hapten antibody response mediated by CD4+ helper T cells. The role of B7 costimulation in the immune response to oxazolone (Ox) was analyzed using mice lacking either B7-1 (B7-1-/-), B7-2 (B7-2-/-), or both (Db-/-) of these costimulatory molecules. The absence of both B7-1 and B7-2 results in diminished CHS. This inhibition is largely overcome at higher hapten sensitizing doses indicating the presence of compensatory pathways. In contrast, anti-Ox IgG1 and IgG2a responses were not detected in the absence of both B7-1 and B7-2, even at high sensitizing doses, indicating an obligatory role of B7 costimulation in IgG class switching. B7-1 and B7-2 have overlapping functions in both CHS responses and anti-hapten response. B7-2-/- mice demonstrated a modestly reduced CHS response only at very low doses of Ox (0.05%), but responded normally at higher Ox doses, and B7-1-/- mice had CHS responses indistinguishable from those of wild-type mice. Similarly, anti-Ox IgG responses were comparable in wild-type, B7-1-/- and B7-2-/- mice. Taken together, these studies reveal distinct roles for B7 costimulation in response to epicutaneous antigens with an obligatory role for IgG class switching and an important, but nonessential role for CHS responses.