Hand eczema in children referred for patch testing: North American Contact Dermatitis Group Data, 2000-2016.

BACKGROUND: Little is known about the aetiologies and relevant allergens in paediatric patients with hand eczema (HE). OBJECTIVES: To characterize the aetiologies and determine the proportion of positive and currently relevant allergens in children/adolescents (age < 18 years) with HE referred for patch testing. METHODS: A retrospective analysis (2000-2016) of North American Contact Dermatitis Group data was performed. RESULTS: Of 1634 paediatric patients, 237 (14·5%) had involvement of the hands. Final physician diagnoses included allergic contact dermatitis (49·4%), atopic dermatitis (37·1%) and irritant contact dermatitis (16·9%). In multivariable logistic regression models, employment was the only association with increased odds of any HE or primary HE. Children with HE vs. those without HE had similar proportions of positive patch tests (56·1% vs. 61·7%; χ2 -test, P = 0·11). The five most common currently relevant allergens were nickel, methylisothiazolinone, propylene glycol, decyl glucoside and lanolin. In multivariable logistic regression models of the top 20 relevant allergens, HE was associated with significantly higher odds of currently relevant reactions to lanolin, quaternium-15, Compositae mix, thiuram mix, 2-mercaptobenzathiazole and colophony. The allergens with the highest mean significance-prevalence index number were methylisothiazolinone, carba mix, thiuram mix, nickel and methylchloroisothiazolinone/methylisothiazolinone. CONCLUSIONS: Children with HE who were referred for patch testing had a high proportion of positive patch tests, which was similar to the proportion found in children without HE. Children with HE had a distinct and fairly narrow profile of currently relevant allergens.

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.

Synergism between interferon-gamma and cytokines or lipopolysaccharide in the activation of the HIV-LTR in macrophages.

Macrophages (møs) obtained from transgenic mice carrying the HIV long terminal repeat-chloramphenicol acetyl transferase (LTR-CAT) sequence were used to study the influence of various biologic response modifiers (BRMs) on the activation of LTR-directed CAT expression. It was found that LPS or IL-6 alone induced moderate levels of CAT expression, whereas IFN-gamma or TNF-alpha had no significant effect. Co-exposure of møs to IFN-gamma and either LPS, IL-6, or TNF-alpha led to significant synergistic increases in CAT levels. Levels were also synergistically augmented when møs were exposed first to IFN-gamma (priming), washed, and then exposed to either LPS, IL-6, or TNF-alpha. Although IL-6 was synergistic with subsequently added IFN-gamma, the reverse sequence of addition was more effective. LPS and TNF-alpha were inactive when added before IFN-gamma. Initial priming signals were rapid as exposure for 3 h to IFN-gamma was sufficient to prepare the cells for subsequent activation by other BRMs. These results suggest that the duration of latency and progression of HIV infections may be greatly influenced by events such as intercurrent infections that cause IFN-gamma production, thereby priming møs to respond to other cytokines that have been reported to be constitutively elevated during the course of infection with HIV (e.g., IL-6 and/or TNF-alpha).

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)

Cimetidine-induced augmentation of allergic contact hypersensitivity reactions in mice.

BALB/c mice were treated with cimetidine (100 mg/kg) or saline, intraperitoneally, twice daily, from days 0-2 or days 7-9 after sensitization with 0.1%, 2,4,6-trinitro-1-chlorobenzene (TNCB) on day 0. On day 7, the mice were challenged with 1% TNCB to one ear. Ear swelling responses (as an index of sensitization), serum histamine levels, and biopsy specimens of challenged ears were evaluated in groups of cimetidine- or saline-treated mice at 0, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, and 48 h after challenge. Additional controls included mice injected with saline or cimetidine and challenged with, but not sensitized to, TNCB (irritant controls). Treatment with cimetidine during the induction but not the elicitation of allergic contact hypersensitivity (ACH) produced a significant enhancement of the response throughout the first 48 h. There was no effect of cimetidine on antigen-presenting cells within the epidermis which might account for this enhancement. Similarly, no difference in mast cell morphology or serum histamine levels between cimetidine- and saline-treated groups was observed. Histologically, the cimetidine-treated animals showed a more intense cellular infiltrate, which was most noticeable at 24 to 48 h, at which time numerous subcorneal and perifollicular neutrophilic abscesses were observed. To further investigate the mechanism of action of cimetidine, mice were injected with cyclophosphamide (150 mg/kg) 2 d prior to sensitization. Mice treated with cyclophosphamide alone or in combination with cimetidine showed no additive or synergistic effect upon the ear swelling response. We conclude that enhancement of ACH by cimetidine is independent of any effect on mast cells or antigen-presenting cells, but may relate to a cimetidine-induced inhibition of the induction of T-suppressor cells at the time of sensitization.

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.

Mast cell participation during the elicitation of murine allergic contact hypersensitivity.

In order to evaluate mast cell participation in allergic contact hypersensitivity (ACH), BALB/c mice were sensitized with 0.1% trinitrochlorobenzene (TNCB). Immediately before challenge and at 1, 1.5, 2, 4, 6, 8, 12, 24, and 48 h after challenge with 1% TNCB, groups of animals had ear thickness measured, had blood collected for histamine determinations, and had both ears removed for histologic evaluation of mast cells. The increase in ear swelling was triphasic with peak increases at 1.5 h (14.3 +/- 1.6 X 10(-2) mm; mean +/- SEM), 8 h (19.9 +/- 1.8 X 10(-2) mm), and 24 h (30.2 +/- 2.9 X 10(-2) mm). A triphasic pattern of increased serum histamine was noted at 1-4 h (117% over control levels), at 12 h (131%), and at 48 h (133%). Examination of the tissue specimens from challenged animals showed modest (1+) degranulation of mast cells between 1 and 6 h with extensive (2+) degranulation at 12 h. In addition, hypogranulated mast cells were evident between 1 and 6 h, at 24 h, and at 48 h. There were no statistically significant differences in mast cell numbers at any time. Neither platelets nor other formed elements of the blood contributed to the increased blood histamine levels. These data show that mast cells are activated in a triphasic pattern during ACH, and thus suggest both early and late roles for the mast cell and its products in the evolution of ACH.

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.

Appearance of Langerhans cells in the epidermis of Tgfb1(-/-) SCID mice: paracrine and autocrine effects of transforming growth factor-beta 1 and -beta 2(1).

A striking immunologic abnormality of normal and SCID Tgfb1(-/-) mice is the total absence of Langerhans cells in their epidermis. Here we show that transfer of Tgfb1(+/-) SCID bone marrow causes, within a few weeks, the appearance of Langerhans cells in the epidermis of gamma-irradiated and unirradiated Tgfb1(-/-) SCID recipients. In addition, local injection of 2 x 10(5) latent transforming growth factor-beta1 cDNA-transduced cloned CD4+ T lymphocytes causes the appearance of Langerhans cells in the ear epidermis of Tgfb1(-/-) SCID mice. This effect is enhanced by antigen-specific activation of these T cells. Injection of recombinant active transforming growth factor-beta 2 into the ear of Tgfb1(-/-) SCID mice also results in the migration of Langerhans cells into the epidermis locally, but no epidermal Langerhans cells are seen after systemic injections of transforming growth factor-beta 2. Our results suggest that transforming growth factor-beta can act in paracrine as well as autocrine fashion to induce the differentiation of precursors into Langerhans cells. Furthermore, these results indicate that the relative roles of different transforming growth factor-beta isoforms in vivo may be influenced by their local availability and/or the regulation of their conversion from latent into active form.

The potential role of nutritional factors in the induction of immunologic abnormalities in HIV-positive homosexual men.

The literature is briefly summarized as to how several nutrients affect immune function, susceptibility to infection, and cancer susceptibility or progression. Nutritional deficiencies can impair immunity and so influence susceptibility to infectious agents, including ones that are common and relatively virulent in acquired immune deficiency syndrome (AIDS) patients. A variety of nutrients affect several of the immune functions that are defective in human immunodeficiency virus (HIV)-infected individuals. For example, beta-carotene increased the number of CD4+ cells; vitamin E decreased the number of CD8+ cells and increased the CD4+/CD8+ ratio; vitamin D decreased the CD4+/CD8+ ratio; and iron increased the number of peripheral lymphocytes in humans receiving supplementation. Furthermore, nutritional deficiencies can influence gastrointestinal function, while infectious diseases can influence nutrient requirements by altering the efficiency of absorption and the rate of tissue metabolism. Malnutrition, depressed serum zinc levels, and intestinal nutrient malabsorption have been found in AIDS patients. The above findings suggest that dietary manipulations might diminish the immune defects in HIV infection and enhance resistance to opportunistic infections. However, dietary alterations in immune defects are generally not well quantified and may be small relative to the magnitude of the defects observed in AIDS patients. Because conflicting or adverse effects have been reported for some nutrients, recommendations for dietary supplementation in HIV-infected individuals are premature and possibly hazardous. Further studies are much needed to relate dietary nutrient intakes to clinical outcomes.

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.

Relationship between humoral immunoaugmenting properties of DHEAS and IgD-receptor expression in young and aged mice.

IgD-receptors are associated with augmented antibody production in vivo and are induced on CD4+ T cells by aggregated IgD in young but not in aged mice. In the current study orally or intraperitoneally administered DHEAS was found to enhance antibody production, as measured in a plaque-forming cell assay, and also to cause an increased expression of IgD-R on T cells in both young and aged mice. IgD-R+ T cells are enumerated by rosette cell formation with IgD-coated SRBC. Since, as shown previously, the immunoaugmenting effect of IgD-R+ T cells is blocked by injection of monomeric IgD, the effect of monomeric IgD was also examined in DHEAS-pretreated mice. The inhibitory effect obtained with monomeric IgD in these studies indicates that upregulation of IgD-R by DHEAS plays an important role in the immunoenhancing effect of this hormone. In addition, no significant effect of DHEAS was obtained on contact hypersensitivity to DNCB or on proliferative responses of T cells from young or aged mice. Aged but not young mice showed increases in the numbers of Ia+ epidermal Langerhans cells after DHEAS treatment.

The role of tar in Goeckerman therapy.

Seventeen patients with psoriasis were treated with 5% crude coal tar in an absorbent ointment base (Aquaphor) to one half of the body and with the absorbent ointment base alone to the other half. They received twice-daily erythemogenic doses of ultraviolet irradiation (UVR). Both modalities, crude coal tar and absorbent ointment base alone, combined with UVR were equally effective in improving psoriatic plaques. On the basis of this and previous studies, we question the therapeutic role of tar in the Goeckerman regimen.

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.

A sherlockian approach to contact dermatitis.

Identifying the etiology of allergic contact dermatitis requires detective work. Not all allergic reactions are eczematous in appearance. The most reliable clinical clue to the allergic nature of the dermatitis is its geographic distribution. Patch testing provides the list of culprit allergens. The mystery is solved when the suspected allergen is found to be relevant and the patient has been adequately instructed in allergen avoidance.

Contact urticaria caused by rubber. Analysis of seven cases.

Prior to 1979, there had been no reports of contact urticaria to rubber products. Since that time, many cases have been reported. At New York University, the first case, secondary to cornstarch allergy, was seen in 1985. Since that time, we have seen an additional six cases, five of them in the last year. Of these six cases, three were attributable to H. brasiliensis and three to the accelerators. Although the use of latex products has increased dramatically within the past 9 years in response to the epidemic of human immunodeficiency virus infections, it is not clear whether increased exposure alone accounts for the sudden increase in the number of patients with contact urticaria. Four of the patients presented here are hospital personnel involved in surgical procedures, in which, for decades, latex gloves have been used. Furthermore, two of our seven patients are paraplegics, who, as a group, have long had frequent exposure to rubber products. Two possibilities seem most likely: either the diagnosis has been missed by physicians for decades, or in response to the worldwide demand for latex products, the manufacture of latex has become altered in such a fashion that more products from which the allergens (accelerators and H. brasiliensis) are easily leached are now reaching the marketplace.

Allergic contact dermatitis to topical glucocorticosteroids.

During the past decade, the reported incidence of allergic reactions to topically applied glucocorticosteroids has increased significantly. The two cases reported here typify the presenting symptoms of the glucocorticosteroid-allergic persons. These cases also illustrate the extensive cross-reactivity among the different topical corticosteroids, as well as the potential for systemic contact dermatitis to occur following parenteral exposure. These cases are reviewed in the context of the many other reports in the literature of similar allergic reactions.

Allergic contact dermatitis to gold.

Gold is a relatively common allergen that appears to induce dermatitis about the face and eyelids, as well as at sites of direct cutaneous contact. In this study, 355 patients with suspected contact dermatitis were evaluated; 17 (4.8%) were found to be allergic to gold. Fifteen of these 17 patients were re-evaluated at > 2 months after patch testing. When contact with gold jewelry was discontinued, 7 of 15 (46.7%) of the gold-allergic patients reported that their dermatitis cleared. In 3 of 7 patients (42.9%), discontinuing contact with gold jewelry was the only modification to their behavior; whereas in 4 of 7 (57.1%), discontinuing contact with gold jewelry and other documented allergens was necessary to affect resolution. Despite continuous contact with gold (jewelry and/or dental appliances), 7 of 15 (46.7%) of our patients had complete clearing of their symptoms by avoiding other documented allergens. None of our patients required the removal of dental gold.