Neurotensin serum levels and skin gene expression are increased in atopic dermatitis.

BACKGROUND: Neurotensin (NT) participates in immune responses, but the mechanisms are not known. We have previously shown that NT augments the ability of corticotropin-releasing hormone (CRH) to increase mast-cell-dependent vascular permeability in rodents. We also showed that NT stimulates human mastcell release of vascular endothelial growth factor, and that CRH is increased in the serum of patients with atopic dermatitis (AD), an inflammatory skin condition involving mast cells. OBJECTIVES: To measure serum levels of NT, and lesional skin expression of NT and the main NT receptor (NTR-1) in AD, and to compare it with skin expression in chronic urticaria (CU) and urticaria pigmentosa (UP). METHODS: Serum NT was measured with a Milliplex microbead array. Skin NT and NTR-1 gene expression was determined with quantitative polymerase chain reaction. Immunohistochemistry was performed using a mouse monoclonal antibody for NT, and a rabbit polyclonal antibody for NTR-1. Mast cells were counterstained with Leder dye. RESULTS: Neurotensin is significantly elevated in the serum of patients with AD compared with healthy controls (P = 0.0001). NT gene expression is also significantly increased in lesional skin of patients with AD compared with controls (P = 0.0194). Moreover, immunohistochemistry of AD lesions shows NT > NTR-1 staining of perivascular cells, many of which are identified as mast cells after staining with Leder dye. There was no statistically significant difference in NT and NTR-1 lesional skin gene expression in patients with either CU or UP. CONCLUSIONS: These results suggest that interactions between NT and mast cells may occur and contribute to AD pathogenesis.

Serum neurotensin (NT) is increased in psoriasis and NT induces vascular endothelial growth factor release from human mast cells.

BACKGROUND: Psoriasis involves skin inflammation that often worsens with stress, but the mechanism of this effect remains obscure. We have shown that corticotropin-releasing hormone (CRH) is increased in the serum of patients with psoriasis. A peptide, neurotensin (NT), can trigger skin histamine release and augment the ability of CRH to increase skin vascular permeability. OBJECTIVES: To investigate the serum level of NT, and the expression of genes for NT and NT receptor-1 (NTR-1) in lesional and nonlesional skin of patients with psoriasis, compared with normal controls. Also, to study the effect of NT on human mast cell release of vascular endothelial growth factor (VEGF), which is increased in psoriatic skin. METHODS: Serum was obtained from patients with psoriasis (n = 56) and controls (n = 33); NT levels were measured with the Milliplex microbead assay. Biopsies were obtained from the lesional and nonlesional skin of patients with chronic plaque psoriasis (n = 40), who had not received any treatment for at least 15 days and were free of any systemic inflammatory diseases. Control skin samples were obtained from healthy subjects (n = 30). Expression of genes for NT and NTR-1 in the skin was evaluated by quantitative reverse transcriptase-polymerase chain reaction. LAD2 human mast cells were stimulated by NT (1 µmol L(-1)) for 24 h and VEGF was measured by enzyme-linked immunosorbent assay. RESULTS: Serum NT was increased in patients with psoriasis, while expression of genes for NT and NTR-1 in lesional skin was decreased compared with controls. NT induced VEGF release from mast cells and was augmented by interleukin-33. CONCLUSION: NT may play a role in psoriasis pathogenesis and its worsening by stress, at least in part through activation of skin mast cells.

Urticaria pigmentosa associated with acute stress and lesional skin mast-cell expression of CRF-R1.

A 38-year-old woman presented with a pronounced increase in symptoms and proliferation of urticaria pigmentosa (UP) after acute psychological stress, which was quantified using the Spielberger's State-Trait Anxiety Inventory. Immunohistochemical examination of a skin biopsy from a new UP lesion showed a large number of activated mast cells expressing corticotrophin-releasing factor receptor-1 (CRF-R1) and there was high serum CRF. This is the first documented report to our knowledge of UP worsening associated with acute stress, possibly through activation of skin mast-cell CRF-R1.

Clinical features and natural history of acquired cold urticaria in a tertiary referral hospital: a 10-year prospective study.

BACKGROUND: Acquired cold urticaria (ACU) represents a heterogeneous group of disorders that share a common clinical feature: the development of urticaria or angioedema after cold exposure. We present epidemiological and clinical data of subjects with ACU, natural progression and we examine possible parameters that could correlate with disease severity. METHODS: During a 10-year period in all subjects with ACU, detailed record of personal history, laboratory testing, cold stimulation testing (CST), atopy assessment and disease severity took place. In a re-evaluation visit at the end of the surveillance period, ACU progression was assessed from patients in a subjective way. RESULTS: Four thousand one hundred fifty-seven individuals with chronic urticaria were referred, and 352 (198 males, 154 females, 8.47% of patients with chronic urticaria) presented definite symptoms of physical urticarias, while 95 individuals (49 males, 46 females, 27% of patients with physical urticarias) were detected with ACU. Sixty-two participants were included in study analysis. Thirty-two patients (51.6%) were female; the mean age was 41.5 +/- 15.6 years, while the mean age at disease onset was 32.5 +/- 15.6 years; half were < or = 30 years old at disease onset. The mean duration of surveillance was 9.0 +/- 6.9 years. During this time interval, 18 patients (29.0%) showed the same or even worse symptomatology, 26 patients reported some improvement (41.9%), while in 18 patients, symptoms resolved completely (29.0%); the mean time to resolution was 5.6 +/- 3.5 years. Disease severity was the only variable statistically significantly related to disease progression (P = 0.004). CONCLUSIONS: Cold urticaria is a chronic persistent disorder with occasional severe clinical manifestations.

Theophylline as "add-on" therapy in patients with delayed pressure urticaria: a prospective self-controlled study.

Delayed pressure urticaria (DPU) is a skin condition that involves the gradual development of wheals and edema at sites of physical pressure. Its pathogenesis is not clear and histamine-1 receptor (H-1R) antagonists provide only partial relief. In this prospective, clinical study, we investigated the effect of theophylline, which has a long history of benefit in allergic asthma, added to cetirizine in patients with DPU. Twenty three patients received during period 1 cetirizine (10 mg po QD) and theophylline (200 mg po BID) for 6 months, followed by period 2 of 1 month washout with only rescue medication as needed, and then by period 3 with cetirizine (10 mg QD plus placebo (BID) for 5 more months. The addition of theophylline resulted in statistically significant improvement over cetirizine alone by 2 months and continued for the duration of treatment. Treatment of cultured human mast cells with theophylline (10 microM) did not inhibit allergic histamine release, but the in vivo beneficial effect of theophylline may require significant pretreatment period to manifest itself, or may involve inhibition of other mast cell dependent mediators. A double-blind study, accompanied by serum histamine and tryptase levels, should be in order.

Asymptomatic sensitisation to grapes in a sample of workers in the wine industry.

AIMS: To assess the prevalence of sensitisation to grapes (Vitis vinifera var. agiorghitiko) in a population with repeated exposure to grape allergens through direct cutaneous contact as well as through the gastrointestinal tract. METHODS: One hundred and twenty subjects were enrolled in each of four groups: grape harvesters, winery workers in selection of grapes, winery workers operating de-stemming/crushing/pressing machines, and administrative personnel. Sensitisation to grapes was examined by skin prick-to-prick tests with fresh fruit and juice. RESULTS: Eight harvesters and five workers in grape selection had positive reaction to the grapes tested. No machine operators or administrative personnel had positive tests. The likelihood of sensitisation was estimated at 3.7% per year of occupation by logistic regression analysis. None of the employees reported symptoms associated with sensitisation to grapes. CONCLUSION: Asymptomatic sensitisation to grapes was detected only in workers handling the fruit, suggesting that sensitisation is more likely to occur through cutaneous exposure and/or minor wounding than through the gastrointestinal tract. Prevalence rates were high and the clinical impact needs to be further investigated.

Alopecia areata and affected skin CRH receptor upregulation induced by acute emotional stress.

BACKGROUND: Recent evidence indicates that acute stress can precipitate a number of dermatological conditions, including alopecia areata. This effect may be mediated by corticotropin-releasing hormone (CRH) released locally in the skin from dorsal root ganglia or immune cells. CRH typically acts through activation of specific receptors that are either type 1 or types 2 alpha and 2 beta. CRH, or related peptides such as urocortin, could have proinflammatory effects directly or through activation of mast cells leading to destruction of the hair root. OBJECTIVES: To investigate the expression of CRH receptors on the affected skin of patients who developed alopecia areata following acute emotional stress. METHODS: Scalp skin biopsies were obtained from 1 normal volunteer and 3 patients after ring infiltration of the relevant site with lidocaine. The biopsies were frozen and were later processed for in situ hybridization for CRH receptors type 1 or types 2 alpha and 2 beta. Sections showing positive results were photographed. RESULTS: The skin from the normal volunteer showed weak background expression of all three receptor types. However, skin from the affected sites of all 3 patients studied showed intense expression only on the type 2 beta receptor around the hair follicles. CONCLUSION: Acute emotional stress may precipitate alopecia areata by activation of overexpressed type 2 beta CRH receptors around the hair follicles leading to intense local inflammation.

Familial cases of poikiloderma of Civatte: genetic implications in its pathogenesis?

Poikiloderma of Civatte (PC) is a rather common, benign skin condition of obscure etiopathogenesis: cumulative exposure to UV radiation, hormonal changes associated with the menopause, and photo-allergic mechanisms have been implicated. We present seven cases of PC among the members of two unrelated Greek families, who have not shared common extrinsic influences. Literature review revealed no other reported familial cases. Familial tendencies, as well as the not unusual occurrence of PC in individuals with minimal sun exposure, and who are not using perfumes or cosmetics, provide support for the hypothesis that a genetic predisposition to the disease may exist; this predisposition is possibly transmitted as an autosomal dominant trait.

Effect of stress and other psychological factors on the pathophysiology and treatment of dermatoses.

Psychological factors precipitate or increase the morbidity of many dermatoses. There is increasing evidence that stress influences disease processes and contributes to the inflammation through vasoactive neuropeptides, lymphokines or other chemical mediators. Experimental results indicate that the endocrine, nervous and immune systems can no longer be considered autonomous, but involve complex bidirectional interactions between them. Dermatology holds a distinct position in psychosomatic medicine because it deals with an organ that can be readily seen and touched. The psychological states of anxiety, fear, shame, pleasure, and sexual excitation are visibly indicated by blushing, hair-rising, growing pale, itching or hyperhidrosis. The skin, therefore, clearly responds to many psychologic and stressful stimuli. As the skin is exposed to view, dermatoses elicit reactions from the patients' environment and the easy accessibility of the skin allows patients to interact directly with their lesions. In addition to the classic stress response involving increased levels of neuroendocrine hormones and autonomic neurotransmitters, stress also affects the immune system. Stress has been reported to cause decreased natural killer cell cytotoxicity, depressed mitogenic responses in lymphocytes, increased IgA levels, enhanced neutrophil phagocytosis and activation of interferon synthesis in lymphocytes. Psychodermatological syndromes can be classified according to the type and degree of causal relationship between the psychological etiology and the dermatoses. There is some overlap between the groups, but there is a satisfactory classification under three major headings that suggests an approach to treatment.

Contact allergens in patients with leg ulcers.

BACKGROUND: Contact dermatitis can complicate the treatment of leg ulcers and is an acquired phenomenon resulting from the use of topical medications. OBJECTIVE: To show the incidence of contact dermatitis reactions to topical medications applied to leg ulcers and to evidence changing trends in such reactions through comparison of two case series about 20 years apart. SUBJECTS AND METHODS: We studied two groups of patients with leg ulcers that were patch tested with contact allergens in 1973-1974 and in 1994-1995. RESULTS: One or more positive patch tests was present in 75% and 40% of the patients, respectively. A decrease in the incidence of positive reactions to neomycin, local anesthetics and parabens mix was seen in 1994-1995. The most important contact allergens in 1994-1995 were fragrance mix, colophony and the excipients wool alcohols and amerchol. Other relevant sensitizers were formaldehyde, neomycin and gentamycin. CONCLUSION: The changing trends in contact allergens over the last 20 years may be explained by changes in the components of topical agents used for treatment.

Recurrent condylomata acuminata: how routine immediate and delayed hypersensitivity parameters might provide a clue to their immunopathogenesis.

In 30 male patients suffering from recurrent condylomata acuminata, immediate hypersensitivity parameters (total IgE, PTT and prick tests) and delayed hypersensitivity against seven recall antigens (multi test) were studied. Thirty healthy male volunteers, matched in age, were the controls. Significantly higher immediate hypersensitivity activity was shown in the patient group. Qualitative evaluation of delayed type hypersensitivity showed that controls had a positive test 16 times more often than patients. A rather homogeneous suppression of delayed type hypersensitivity was found in the patient group mainly as regards the presumably most common antigens vs. the control group. This suppression was proved to be related to disease duration. The hypothesis of a CD4+ Th-2 lymphocyte predominance in recurrent condylomata, owed to longstanding or repetitive antigenic stimulation seems to adequately explain the findings of the present study.

Regulation of allergen-specific immune responses by CD4+ CD45R+ cells in patients with allergic contact dermatitis.

Circulating T lymphocytes from 20 patients with an immediate patch test reaction were tested for proliferative responses in vitro to contact allergens during both immediate and delayed skin reactions. T lymphocytes collected during the immediate patch test reaction responded specifically in the challenge allergens in the presence of autologous monocytes. Subset analysis revealed that the proliferation pattern was dominated by the CD4+ CD29+ T-cell subpopulation, whereas CD8+ or CD4+ CD45R+ cells did not respond. A similar pattern in T-cell subset proliferation was observed when cells were collected during a positive delayed skin reaction. In contrast, in the case of a negative delayed skin reaction, proliferative responses of lymphocytes to the specific allergens were dominated by CD45+ cells. The latter T-lymphocyte subset could greatly suppress in an allergen-specific manner the proliferation of CD29+ autologous cells. The in vitro allergen-specific proliferation of CD29+ or CD45R+ cells was restricted by the major histocompatibility complex class II (HLA-DR) gene products. It is suggested that allergen-specific immune responses take place in the induction and evolution of an immediate patch test reaction into a delayed one.

Etiologic factors in childhood chronic urticaria.

In order to identify the etiologic factors in childhood chronic urticaria, we studied 226 children, 122 boys and 104 girls, aged 1 to 14 (mean = 8.14) years with chronic urticaria and/or angioedema. The initial evaluation consisted of a thorough history, physical examination, and basic laboratory tests. Specific in vivo and in vitro tests were done according to the findings of the initial evaluation. Urticaria alone was present in 78.4% of the patients, angioedema alone in 6.6%, and both urticaria and angioedema in 15% of the patients. Chronic urticaria was attributed to physical factors in 6.2% of the patients, infections in 4.4%, aeroallergens in 2.2%, foods in 4%, food additives in 2.6%, and drugs in 1.8% of the patients. Overall, causal factors of chronic urticaria were found in 21.2% of the patients.