Cross-elicitation responses to 2-methoxymethyl-p-phenylenediamine in p-phenylenediamine highly allergic volunteers using allergy alert test: the Italian experience.

Summary: Background. Allergic contact dermatitis after exposure to p-phenylenediamine (PPD)-containing hair dye products is a common and important clinical problem. Because there is a high rate of cross-elicitation of allergic contact dermatitis to other important hair dye products (such as p-toluene diamine [PTD] and other aminophenol hair dyes) in PPD allergic patients, safer alternative dyes with excellent hair coloring options are needed. We studied 2-methoxy methyl-PPD (Me-PPD), a chemical derivative of PPD for tolerance versus cross-elicitation in a cohort of eight PPD-allergic volunteers. Objective. To study tolerance to Me-PPD in a PPD highly allergic Italian cohort. Methods. Eight volunteers with a history of contact dermatitis to hair dyes or other PPD-containing chemicals and positive patch tests to 1% PPD in petrolatum, were recruited to study their immediate and delayed skin reactivity to PPD, vehicle control and 2-methoxy-methyl-PPD (Me-PPD), using the allergy alert test (simulating hair dyeing conditions) on volar forearm skin. This is a short-contact open patch test. Results. All eight volunteers reacted to PPD allergy alert test (100%); none reacted to vehicle (0%), and seven of eight reacted to Me-PPD allergy alert test (88%). However, in those seven volunteers who exhibited cross-elicitation to Me-PPD, their aggregate skin test reactivity to Me-PPD was significantly less than that of PPD (figure 3, p minore 0.0062, highly significant, paired two-tailed, students t test). Conclusions. Me-PPD may offer a safer alternative for PPD-allergic patients with an absent or reduced elicitation response in the allergy alert test simulating hair dye use conditions. Even patients with strong patch test reactions, with appropriate selection by allergy alert test and counselling, may be able to tolerate hair dyeing with Me-PPD containing products.

A case of hypersensitivity to progesterone presenting as an eczematous eruption.

Hypersensitivity to progesterone is a rare condition, and it represents a hypersensitivity reaction to endogenous progesterone. Here we report a case of a woman who presented to our attention for evaluation of a rash for a few years on her posterior elbows, forearms, and right lateral lower extremity. We report this case because it describes a rare clinical entity, with an atypical clinical presentation pemphigoid-like, that is rarely described in literature.

Dopaminergic receptors in the human skin.

Dopamine is a neurotransmitter which plays an important role in many human organs including the skin. In this study we will examine the presence and the distribution of D1 and D2 dopamine receptors in a particular zone of the human skin. Samples of the human plantar skin were harvested during autopsies after the consent of relatives of the dead donors. In this study the following experimental procedures were performed: 1) drawing of the human plantar skin; 2) cutting of tissues; 3) staining of tissues; 4) staining of the nerve fibres; 5) radio-binding methods for labelling D1 and D2 dopamine receptors; 6) light microscope autoradiography; 7) quantitative analysis of images and 8) statistical analysis of data. The dopamine receptors D1 are distributed particularly in the dermis layer of the human plantar skin. They are numerous in lower epidermal layers (with exclusion of the corneal layer) and few in subcutaneous tissue. On the contrary D2 dopamine receptors are prominent in the subcutaneous tissue near the vessels. Quantitative analysis of images and statistical analysis of the data confirm all our results. The specific distribution of D1 and D2 dopamine receptors in the human plantar skin is in close relation with the functions of a particular zone of the human skin that supports the weight of all the body. Moreover the character of dopamine receptors distribution is very important for further understanding the role of these receptors in the human skin.

Allergic contact dermatitis: epidemiology, molecular mechanisms, in vitro methods and regulatory aspects. Current knowledge assembled at an international workshop at BfR, Germany.

Contact allergies are complex diseases, and one of the important challenges for public health and immunology. The German 'Federal Institute for Risk Assessment' hosted an 'International Workshop on Contact Dermatitis'. The scope of the workshop was to discuss new discoveries and developments in the field of contact dermatitis. This included the epidemiology and molecular biology of contact allergy, as well as the development of new in vitro methods. Furthermore, it considered regulatory aspects aiming to reduce exposure to contact sensitisers. An estimated 15-20% of the general population suffers from contact allergy. Workplace exposure, age, sex, use of consumer products and genetic predispositions were identified as the most important risk factors. Research highlights included: advances in understanding of immune responses to contact sensitisers, the importance of autoxidation or enzyme-mediated oxidation for the activation of chemicals, the mechanisms through which hapten-protein conjugates are formed and the development of novel in vitro strategies for the identification of skin-sensitising chemicals. Dendritic cell cultures and structure-activity relationships are being developed to identify potential contact allergens. However, the local lymph node assay (LLNA) presently remains the validated method of choice for hazard identification and characterisation. At the workshop the use of the LLNA for regulatory purposes and for quantitative risk assessment was also discussed.

Longitudinal health surveillance in a cohort of Gulf War veterans 18 years after first exposure to depleted uranium.

As part of a longitudinal surveillance program, 35 members of a larger dynamic cohort of 79 Gulf War I veterans exposed to depleted uranium (DU) during combat underwent clinical evaluation at the Baltimore Veterans Administration Medical Center. Health outcomes and biomonitoring results were obtained to assess effects of DU exposure and determine the need for additional medical intervention. Clinical evaluation included medical and exposure histories, physical examination, and laboratory studies including biomarkers of uranium (U) exposure. Urine collections were obtained for U analysis and to measure renal function parameters. Other laboratory measures included basic hematology and chemistry parameters, blood and plasma U concentrations, and markers of bone metabolism. Urine U (uU) excretion remained above normal in participants with embedded DU fragments, with urine U concentrations ranging from 0.006 to 1.88 µg U/g creatinine. Biomarkers of renal effects showed no apparent evidence of renal functional changes or cellular toxicity related to U body burden. No marked differences in markers of bone formation or bone resorption were observed; however, a statistically significant decrease in levels of serum intact parathyroid hormone and significant increases in urinary calcium and sodium excretion were seen in the high versus the low uU groups. Eighteen years after first exposure, members of this cohort with DU fragments continue to excrete elevated concentrations of uU. No significant evidence of clinically important changes was observed in kidney or bone, the two principal target organs of U. Continued surveillance is prudent, however, due to the ongoing mobilization of uranium from fragment depots.

Langerhans cells in allergic contact dermatitis.

Allergic contact dermatitis (ACD) is a common skin disease that has significant socio-economic impact. ACD is mediated by a T-cell mediated inflammatory reaction. Langerhans cells (LCs) are an epidermal DCs subset specialized in antigen presentation. After hapten exposure, LCs play a major role as in induction adaptive immune response against allergens. LCs recognize, take up and process haptens and migrate to the local draining lymph nodes. However, LCs specific functions and the LCs migration to local draining lymph nodes are not yet clearly defined. Recent advance in the knowledge of LCs function has increased in the past decades including the evidence for a tolerogenic function of LCs. The present review will focus on the role for LCs response to contact allergens.

Th17/Tc17 infiltration and associated cytokine gene expression in elicitation phase of allergic contact dermatitis.

BACKGROUND: Allergic contact dermatitis (ACD) is a typical delayed-type hypersensitivity to sensitizing haptens mediated by T cells. Th1/Tc1 cells are currently considered to be the primary effectors in ACD. There is little information concerning the role played in ACD in humans by Th17/Tc17 cells, a recently defined subpopulation of effector T cells. OBJECTIVES: In the present report we attempted to characterize Th17/Tc17 cells in the infiltrates of the skin in the elicitation phase of ACD. METHODS: Th17 as well as Th1/Th2 cytokine gene expression was examined by semiquantitative real-time polymerase chain reaction in paired samples of positive patch test biopsies and normal skin from 11 patients allergic to nine different allergens. The in situ characterization of interleukin (IL)-17-producing cells was carried out using anti-RORC and anti-T-cell subset antibodies by double immunofluorescence. RESULTS: Compared with normal paired skin samples, gene expression of transcription factor for human Th17 cells, RORC, and Th17-related cytokines IL-17A, IL-17F and IL-23 was significantly increased in positive patch test biopsies. The mRNA for interferon-gamma and IL-4 was also increased. In the dermal infiltrates, about 20% of the infiltrating cells were IL-17-producing cells as they expressed RORC, and such RORC-expressing cells were detected in both CD4+ (approximately 30%) and CD8+ (approximately 20%) subsets. CONCLUSIONS: This is the first demonstration of Th17/Tc17 cells in the elicitation phase of human ACD, showing that they are a regular participant in the immunopathology of this common allergic reaction regardless of the nature of the triggering allergen.

Photoprotection by thalidomide in patients with chronic cutaneous and systemic lupus erythematosus: discordant effects on minimal erythema dose and sunburn cell formation.

BACKGROUND: Thalidomide is an anti-inflammatory and immunomodulatory agent with proven efficacy in several refractory inflammatory skin conditions including photoexacerbated skin diseases. The effects of thalidomide on ultraviolet (UV)-induced cutaneous damage in humans have not been extensively studied. We describe the results of minimal erythema dose (MED) testing in nonlesional skin of three patients with chronic cutaneous lupus erythematosus (CCLE) before and after treatment with thalidomide. OBJECTIVES: To determine whether thalidomide treatment provides clinical and histological evidence of photoprotection from acute UV injury. METHODS: MED testing was performed in nonlesional skin of three patients with CCLE before and after treatment with thalidomide. Skin biopsy specimens were taken from MED sites for in situ immunochemistry. RESULTS: In each patient, the MED to UVB irradiation was significantly higher while the patient was receiving thalidomide treatment than in the absence of thalidomide, suggesting a systemic photoprotective effect. Thalidomide treatment had no significant effect on markers of apoptosis including sunburn cell formation and terminal deoxynucleotidyl transferase-mediated biotinylated deoxyuridine triphosphate nick end labelling, which identifies single-strand breaks in DNA. CONCLUSIONS: Thalidomide inhibits acute UVB erythema at 24 h after exposure, as a 100-mg daily dose of this drug for 4 weeks conveyed a sun protection factor of 1.56 to > 4.0. We conclude that inhibition of UVB-induced inflammation may, in part, explain the therapeutic benefits of this agent on photosensitive diseases.

Targeting tumor necrosis factor alpha. New drugs used to modulate inflammatory diseases.

Since its discovery, the understanding of the roles for TNF-alpha in human biology and disease has grown. Receptors for TNF are found on virtually all cell types, and many physiologic processes seem to be altered by TNF-alpha. The understanding of how TNF-alpha is involved in the pathophysiology of diseases, such as inflammatory diseases, has allowed the development of new drugs that can interfere with excess TNF-alpha and thus has allowed novel therapies for rheumatoid arthritis and Crohn's disease. As the role of TNF-alpha in other diseases becomes better understood, such TNF-alpha-modulating drugs may find further applications. In the skin, TNF-alpha is prominent cytokine that seems to be important in allergic and irritant contact dermatitis and inflammatory skin conditions. Modulating TNF-alpha activity in the skin may provide therapeutic benefits for a variety of skin conditions (Table 4). Tumor necrosis factor-alpha levels are elevated in skin lesions of psoriasis. A few reports have already suggested that etanercept and infliximab may offer a therapeutic effect in patients with psoriasis. Clinical studies evaluating the true efficacy of these drugs in psoriasis are under way. Specifically, the authors and others are involved in a double-blind, placebo-controlled study to assess the efficacy of etanercept for psoriasis. Thalidomide has been used off-label with some success to treat a number of dermatologic diseases, including several inflammatory skin conditions. Etanercept and infliximab might perhaps prove efficacious for inflammatory skin conditions as well. Finally, it is possible that drugs targeting TNF-alpha may have yet-unrecognized serious side effects. Because TNF-alpha seems to be a central cytokine in UVR-induced apoptosis, the chronic use of TNF-alpha-altering drugs might increase the risk for skin cancers. Tumor necrosis factor-alpha also plays some role in cutaneous wound healing; the effect these drugs might have on this process is also unknown at this time. Certainly, much is already [table: see text] known about TNF-alpha and how it plays many central roles. This understanding has allowed the development of useful new drugs for intractable disease. As the understanding of TNF-alpha and other cytokine biology increases, so will the number of potential therapeutic agents.

Recombinant human antibody single chain variable fragments reactive with Candida albicans surface antigens.

A combinatorial phage display library expressing human immunoglobulin heavy and light chain variable regions was used to identify phage clones capable of binding to the surface of Candida albicans blastoconidia. Single chain antibody variable fragments (scFv) derived from three clones detected C. albicans antigens by indirect immunofluorescence assay (IFA), enzyme-linked immunosorbent assay (ELISA), and Western blotting. The antigens detected were conserved among different strains of C. albicans and several other Candida species. Two scFv clones detected antigens specifically expressed by C. albicans blastoconidia; the third detected antigens in both blastoconidia and filamentous forms of C. albicans. The antigens containing the epitopes recognized by all three scFv could be extracted from blastoconidia by dithiothreitol, suggesting attachment to the cell wall via sulfhydryl bonds. Epitope detection by the scFv was sensitive to treatment of C. albicans blastoconidia with sodium periodate, but not proteinase K, indicating the cognate epitopes were composed of carbohydrate. Antigenic determinants for each of the three scFv were detected by immunohistochemical staining of skin sections from a model of cutaneous candidiasis, demonstrating expression in vivo. Through selection for the ability to bind intact organisms, the phage display system provides a means to rapidly identify monoclonal binding ligands to Candida surface antigens. Being entirely human, mature antibodies generated from the scFv have potential utility in the treatment of candidiasis.

Cutaneous drug reactions.

Cutaneous drug reactions are the most frequently occurring adverse reactions to drugs. Among hospitalized patients, the incidence of these reactions ranges from 1 to 3%. The frequency of cutaneous reactions to specific drugs may exceed 10%. These reactions may range from mildly discomforting to those that are life-threatening. Anti-infective and anticonvulsant agents are among the drugs most commonly associated with adverse reactions in the skin. We describe and illustrate the clinical morphology of the most common cutaneous drug reactions, as well as drugs that most commonly precipitate specific reactions. The varied nature of the reactions that do occur, even with specific agents, indicates a multiplicity of mechanisms available whereby cutaneous drug reactions may be initiated. Although a variety of terms have been proposed for categorizing cutaneous drug reactions, we propose that reactions are best defined based upon mechanisms, where known. In this review, we assess the current knowledge of four categories of cutaneous drug reactions: immediate-type immune-mediated reactions, delayed-type immune-mediated reactions, photosensitivity reactions, and autoimmune syndromes. Moreover, we describe evidence that viral infection is an important predisposing factor for the development of cutaneous drug reactions upon drug administration. Finally, we review the current knowledge of the type and mechanisms of cutaneous drug reactions to several categories of drugs.

Clinical, histological, and immunophenotypic characteristics of injection site reactions associated with etanercept: a recombinant tumor necrosis factor alpha receptor: Fc fusion protein.

OBJECTIVE: To study injection site reactions (ISRs) associated with etanercept therapy. DESIGN: Retrospective chart review, along with prospective analysis of selected patients experiencing ISRs associated with etanercept therapy. SETTING: Academic rheumatology/immunology unit and dermatology clinic. SUBJECTS: Patients with rheumatoid arthritis, juvenile rheumatoid arthritis, inflammatory seronegative arthritis, psoriatic arthritis, psoriasis, or inflammatory bowel disease. INTERVENTIONS: Skin biopsy specimens were taken from selected patients experiencing ISRs. MAIN OUTCOME MEASURES: Incidence of IRSs and histological and immunophenotypic analysis of ISRs in 3 patients undergoing prospective study. RESULTS: Twenty-one (20%) of 103 of all patients receiving etanercept reported ISRs, all within the first 2 months of inception of therapy. The reactions occurred 1 to 2 days after the last injection and resolved within a few days. Moreover, eventual waning of reactions was observed, with none proving to be dose limiting. Histological examination of all biopsy specimens showed an inflammatory infiltrate composed of predominantly lymphoid cells and some eosinophils, in a perivascular cuffing pattern, without evidence of leukocytoclastic vasculitis. The infiltrating lymphoid cells were predominantly activated mature (HLA-DR(+)/CD3(+)/CD4(-)/CD8(+)) cytotoxic T lymphocytes, with a small number of CD4(+) cells. A biopsy specimen from a recall ISR showed strong HLA-DR expression by epidermal keratinocytes. CONCLUSIONS: Injection site reactions associated with etanercept therapy are common, and may be an example of a T-lymphocyte-mediated delayed-type hypersensitivity reaction, with waning over time due to eventual induction of tolerance.

Contact hypersensitivity.

Contact hypersensitivity is a simple in vivo assay of cell-mediated immune function in which exposure of epidermal cells to exogenous haptens results in a delayed-type hypersensitive reaction that can be measured and quantified. The Langerhans cell is the critical antigen-presenting cell in this reaction which initiates sensitization to haptens by presenting antigens to CD4-bearing T lymphocytes which, in turn, secrete lymphokines and recruit other cells to the site of the reaction. In the protocol described here, mice are shaved and the skin of their abdomens is exposed to a hapten. After 6 days (the afferent phase), the baseline ear thickness is measured prior to initiation of the efferent phase. Finally, the ear is treated epicutaneously with the hapten solution and ear thickness is measured in approximately 24 hr. The change in ear thickness after allergen treatment can be used to calculate the percent suppression of contact hypersensitivity.

Minocycline-induced hyperpigmentation in patients with pemphigus and pemphigoid.

BACKGROUND: Immunosuppressive medications typically used to treat the immunobullous disorders pemphigus vulgaris, pemphigus foliaceous, and bullous pemphigoid can have serious adverse effects. The tetracycline family of antibiotic drugs has been shown to be effective in the treatment of these conditions with a more favorable side effect profile. Minocycline hydrochloride use has been associated with various forms of hyperpigmentation, and its incidence is well reported in acne vulgaris and rheumatoid arthritis. We examined a series of 9 patients treated with minocycline for pemphigus or pemphigoid, most of whom have developed cutaneous hyperpigmentation. OBSERVATIONS: Seven of 9 patients treated with minocycline, 50 mg daily (1 patient) or 100 mg twice daily (8 patients), for pemphigus vulgaris, pemphigus foliaceous, or bullous pemphigoid developed hyperpigmentation, which necessitated discontinuing therapy. Five of these patients had experienced notable clinical improvement of their immunobullous disease with minocycline therapy. The average duration of treatment was 8.2 months (range, 1-25 months). The second most common adverse effect in our group was oral candidiasis, which occurred in 2 patients. CONCLUSIONS: We found a favorable response to minocycline therapy in 5 of 9 patients. However, 7 patients developed localized hyperpigmentation as early as 1 month after starting medication use. This incidence of minocycline-induced hyperpigmentation is significantly higher in immunobullous disease than in acne vulgaris or rheumatoid arthritis. This increased incidence may be related to an increase in pigment deposition complexed with collagen during the remodeling process, subclinical inflammation, or glucocorticosteroid-induced skin fragility. The hyperpigmentation process was reversible, as most of our patients had fading of their pigmentation after minocycline cessation.

Dermatologic changes associated with roquinimex immunotherapy after autologous bone marrow transplant.

BACKGROUND: Roquinimex (Linomide) is an immunotherapeutic agent used in conjunction with autologous bone marrow transplantation (ABMT) for treatment of acute and chronic myelogenous leukemia (AML and CML). This agent may induce graft-versus-host reactions (GVHR) as well as graft-versus-leukemia (GVL) effects. OBJECTIVE: We documented the incidence of acute cutaneous GVHR associated with roquinimex immunotherapy. The presence or absence of autologous GVHR was also correlated with a potential GVL effect in patients with CML treated with ABMT and subsequent roquinimex immunotherapy in the period after the transplant. METHODS: Fifteen patients undergoing bone marrow transplantation and roquinimex immunotherapy for CML were followed up, and clinicopathologic data were analyzed. RESULTS: Acute cutaneous GVHRs were observed in 6 of 15 patients (40%) treated with roquinimex. Ten of 11 evaluable patients receiving roquinimex exhibited eccrine sweat gland necrosis (ESGN) (90.9%), which was independent of the acute GVHR. Neither bone marrow engraftment status nor the survival rates of patients with and without GVHR was significantly different. CONCLUSION: Roquinimex immunotherapy enhances the incidence of GVHR and was associated with a high rate of ESGN in patients with CML who were undergoing ABMT. There was no significant association between ESGN and acute GVHR. Acute autologous GVHR caused by roquinimex did not correlate with a GVL effect in our study of 15 patients with CML.

Allergens and irritants transcriptionally upregulate CD80 gene expression in human keratinocytes.

The human CD80 costimulatory molecule is an important signal between professional antigen-presenting cells and T helper cells. The immunobiology of CD80 expression by keratinocytes, especially during allergic and irritant contact dermatitis, however, is less well understood. CD80 cell surface expression and gene transcription by keratinocytes was increased when keratinocytes were exposed to certain allergens (chemicals that induce inflammation via hapten-specific T cells) and irritants (chemicals that are toxic to epidermal cells). Therefore, the human CD80 promoter was cloned and luciferase reporter constructs containing various promoter fragments were engineered. Promoter mapping of these CD80 constructs in transiently transfected keratinocytes showed that a construct containing the proximal 231 bp immediately upstream of the transcription start site of the CD80 promoter was most active in keratinocytes and was inducible to a level ranging from 2- to 10-fold higher in keratinocytes treated with certain allergens and irritants, compared with untreated keratinocytes. This pattern of promoter fragment activity in keratinocytes is identical to that found in professional antigen-presenting cells. This is the first demonstration that the CD80 promoter is active in keratinocytes and that this activity is further increased in keratinocytes treated with certain allergens and irritants. These data suggest that allergens and irritants may, in part, break peripheral tolerance by their direct effects on keratinocyte costimulatory molecule expression, thereby facilitating interactions with epidermotropic T helper cells via the CD80-CD28 or CTLA-4 pathways.