Epicutaneous sensitization with superantigen induces allergic skin inflammation

BACKGROUND: Atopic dermatitis (AD) is characterized by skin infiltration with eosinophils and lymphocytes and expression of Th2 cytokines in acute skin lesions. The skin of patients with AD is frequently colonized with enterotoxin-secreting strains of Staphylococcus aureus. Staphylococcal enterotoxins have been implicated in the exacerbations of the inflammatory skin lesions in patients with AD. OBJECTIVE: We sought to determine whether epicutaneous (EC) sensitization of mice with staphylococcal enterotoxin B (SEB) results in allergic skin inflammation. METHODS: BALB/c mice were EC-sensitized with SEB. Their skin was examined for allergic inflammation and cytokine expression, and their splenocytes were examined for cytokine secretion in response to SEB. RESULTS: EC sensitization with SEB elicited a local, cutaneous, inflammatory response characterized by dermal infiltration with eosinophils and mononuclear cells and increased mRNA expression of the Th2 cytokine IL-4 but not of the Th1 cytokine IFN-gamma. EC-sensitized mice mounted a systemic Th2 response to SEB evidenced by elevated total and SEB-specific IgG1 and IgE. Although EC sensitization with SEB resulted in selective depletion of SEB-specific T-cell receptor Vbeta8+ cells from the spleen and sensitized skin, splenocytes from SEB-sensitized mice secreted relatively more IL-4 and less IFN-gamma than did saline-sensitized controls, consistent with Th2 skewing of the systemic immune response to the superantigen. CONCLUSION: These results suggest that EC exposure to superantigens skews the immune response toward Th2 cells, leading to allergic skin inflammation and increased IgE synthesis that are characteristic of AD.     

Glutathione-S-transferase induces murine dermatitis that resembles human atopic dermatitis

Background The molecular and functional basis of allergen-induced inflammation seen in atopic dermatitis (AD) remains undefined. Objective The objective of this study is to establish a murine model to dissect the pathological mechanisms of inflammatory reactions leading to the development of AD. Methods An inbred strain of mice. BALB/c, when injected peritoneally with 30 μg of recombinant Sj26 protein (rSj26). a glutathione S-transferase of Schistosoma japonicum worm, developed systematic dermatitis 21 days after immunization. The pathology of the dermatitis was examined by histological evaluation and immunostaining. The immediate skin hypersensitivity was demonstrated by scrum transfer and skin test. Epicutaneous patch test was used to demonstrate the antigen-specific late phase response. Results Significant responses of rSj26-specific IgE were detected 2 weeks after immunization., and such changes paralleled formation of skin lesions. The diseased skin pathology showed inflammatory changes such as infiltration of mononuclear cells and eosinophils in the dermis and mild spongiosis in the epidermis. Numerous IgE bearing cells were also detected in the dermis. Peripheral blood showed eosinophilia at the same time. In addition, rSj26-specific positive skin test and epicutaneous patch test could be demonstrated in rSj26-sensitized mice. Conclusions These results suggest that rSj26 is capable of eliciting atopic dermatitis-like lesions in BALB/c mice. This can be a useful animal model for elucidating allergen-induced immune responses and the development of various therapeutic interventions of atopic dermatitis in humans.     

Transforming growth factor‐bβ1 suppresses atopic dermatitis‐like skin lesions in NC/Nga mice

BACKGROUND: Atopic dermatitis is a chronic, relapsing inflammatory disorder characterized by pruritic and eczematous skin lesions. Transforming growth factor (TGF)-beta1 has been implicated in the suppression of inflammatory responses. OBJECTIVE: The purpose of this study is to determine whether TGF-beta1 suppresses skin lesions in a mouse model of atopic dermatitis. METHODS: We used the NC/Nga strain of mice as an in vivo model of atopic dermatitis. The effects of exogenous TGF-beta1 on atopic dermatitis-like skin lesions in NC/Nga mice were evaluated clinically, histologically and immunologically. RESULTS: Subcutaneous injection of recombinant TGF-beta1 macroscopically suppressed eczematous skin lesions in NC/Nga mice associated with reduced serum immunoglobulin E (IgE) levels. Histological analysis showed that TGF-beta1 significantly inhibited the infiltration of inflammatory cells such as mast cells and eosinophils into the skin of NC/Nga mice. Spontaneous interferon (IFN)-gamma production from splenocytes of NC/Nga mice was down-regulated by the treatment with TGF-beta1 and neutralizing antibody against IFN-gamma inhibited skin lesions in NC/Nga mice. The inhibitory effect of TGF-beta1 on the skin lesions lasted at least 1 week after cessation of the treatment. CONCLUSION: These findings indicate that TGF-beta1 suppressed atopic dermatitis-like skin lesions in NC/Nga mice at least in part through down-regulation of IFN-gamma. These results suggest that TGF-beta1 may have a therapeutic potential for atopic dermatitis.     

Application of concentrated deep sea water inhibits the development of atopic dermatitis-like skin lesions in NC/Nga mice

ABSTRACT: BACKGROUND: Mineral water from deep-sea bedrock, formed over thousands of years, is rich in minerals such as Ca, Mg, Na, K, Fe and others. Our present study was to investigate the preventive effects of natural deep-sea water on developing atopic dermatitis (AD). METHODS: We elicited AD by application of DNCB (2,4-dinitro-chlorobezene) in Nc/Nga mouse dorsal skin. Deep Sea water (DSW) was filtered and concentrated by a nanofiltration process and reverse osmosis. We applied concentrated DSW (CDSW) to lesions five times per week for six weeks, followed by evaluation. 1% pimecrolimus ointment was used as positive control. The severity of skin lesions was assessed macroscopically and histologically. Levels of inflammatory mediators and cytokines in the serum were detected by Enzyme-linked immunosorbent assay (ELISA) and the levels of CD4+ and CD8+ spleen lymphocytes were determined by flow cytometry analysis. RESULTS: DNCB-treated mice showed atopic dermatitis-like skin lesions. Treatment of mice with CDSW reduced the severity of symptoms in the skin lesions, including edema, erythema, dryness, itching, and transepidermal water loss (TEWL). Histological analyses demonstrated that epidermal thickness and infiltration of inflammatory cells were decreased after CDSW treatment. Given these interesting observations, we further evaluated the effect of CDSW on immune responses in this AD model. Treatment AD mice with CDSW inhibited up-regulation of IgE, histamine, and pro-inflammatory cytokines in the serum. Also, the CD4+/CD8+ ratio in spleen lymphocyte was down-regulated after treatment with CDSW. Finally, cytokines, especially IL-4 and IL-10 which are important for Th2 cell development, were reduced. CONCLUSIONS: Our data suggests that topical application of CDSW could be useful in preventing the development of atopic dermatitis.     

Allergic manifestations in autoimmune gastrointestinal disorders

Allergic disorders target a young population, are increasing in both incidence and prevalence and are associated with significant disease burden. They result from the complex interplay between (epi)genetic and environmental factors, resulting in a Th2 inflammatory process targeting the epithelium of the respiratory tract (allergic rhinitis and asthma), skin (atopic dermatitis), and gastrointestinal tract (food allergy). Although the exact pathogenic mechanisms remain elusive, an altered immune system response in the gut is increasingly recognized as a relevant step. Allergic and gastrointestinal autoimmune disorders share several epidemiological, pathogenic and risk factors and several treatment modalities. Here we revise the current literature and show that allergic disorders are highly prevalent in gastrointestinal autoimmune diseases, including celiac disease, inflammatory bowel disease, autoimmune pancreatitis, and autoimmune cholangiopathies. No data are available for some autoimmune diseases, such as autoimmune gastritis and autoimmune enteropathy. To ensure the comprehensive care of patients with autoimmune gastrointestinal disorders, along with disease-specific factors, the presence of allergic disorders should be evaluated and treated when present, possibly targeting shared molecular pathways. Future studies are needed to define the exact pathogenic mechanisms underpinning the association between allergic and autoimmune diseases of the gastrointestinal tract.     

Increased Th2 activity and diminished skin barrier function cooperate in allergic skin inflammation

Atopic dermatitis (AD) is a chronic inflammatory skin disease induced by a complex interaction between susceptibility genes encoding skin barrier components and environmental allergen exposure that results in type 2 cytokine production. Although genetic lesions in either component can be risk factors for disease in patients, whether these pathways interact in the development of AD is not clear. To test this, we mated mice with T‐cell specific expression of constitutively active Stat6 (Stat6VT) that spontaneously develop allergic skin inflammation with Flaky tail (Ft) mice that have mutations in Flg and Tmem79 genes that each affect skin barrier function. Our results demonstrate that over 90% of the Stat6VT transgenic mice carrying the Ft alleles (Stat6VTxFt^?/?) develop severe atopic dermatitis lesions by 3–5 months of age, compared with only 40% of Stat6VT mice that develop disease by 6–7 months of age. Further, histopathological analysis of skin tissues from Stat6VTxFt^?/? mice revealed extensive thickening of the dermis with increased inflammatory infiltrates as compared with Stat6VT mice. Our study suggests that skin barrier defects and altered Th2 responses independently cooperate in the pathogenesis of allergic skin inflammation, similar to effects observed in patients with AD.     

Sulfuretin alleviates atopic dermatitis-like symptoms in mice via suppressing Th2 cell activity

Atopic dermatitis (AD) is a chronic skin inflammatory disease characterized by uncontrolled Th2 cells response to environmental allergens. Long-term topical application of corticosteroids for treating AD may induce severe side effects. Sulfuretin is a major flavonoid found in Rhus verniciflua and carries antioxidant and anti-inflammatory properties. Its therapeutic effect on AD has not been characterized. We first studied the cytotoxic and regulatory effects of sulfuretin on differentiated Th2 cells. Next, we evaluated therapeutic effect of sulfuretin on AD-like damages caused by 2,4-dinitrochlorobenzene (DNCB) in a mouse model. Serum IgE level, overall symptomatic score, and cytokine accumulation at the lesions were measured. Lastly, we investigated the regulatory mechanism of sulfuretin on GATA3 pathway in primary mouse CD4⁺ cells. Study on in vitro differentiated Th2 cells showed sulfuretin inhibited IL4 production in dose-dependent manner without any cytotoxicity. In vivo study showed 10 μM sulfuretin alleviated the AD symptoms including skin lesion severity, scratching incidence, IgE serum level, and proinflammatory cytokine accumulation at local skin lesion site. Mechanistic study suggested sulfuretin attenuated Th2 cytokine production by suppressing GATA3 expression. Our results demonstrate that sulfuretin could be used as therapeutic application for treating AD.     

Therapeutic effects of combination using glucosamine plus tacrolimus (FK-506) on the development of atopic dermatitis-like skin lesions in NC/Nga mice

Tacrolimus (FK-506) has been found to exhibit potent inhibitory effects on spontaneously developed dermatitis. We previously showed that glucosamine prevents the development of Atopic dermatitis (AD)-like skin lesions in NC/Nga mice. The aims of our study were to investigate the synergistic therapeutic efficacy of combination of glucosamine plus FK-506 in dermatophagoides farina (Df)-induced AD-like skin lesions in NC/Nga mice and to determine the underlying therapeutic mechanisms. The Df-induced NC/Nga mice with a clinical score of 8 were used for treatment with glucosamine (500 mg/kg) alone, FK-506 (1.0 mg/kg) or in combination. The synergistic effects of combination therapy were evaluated by dermatitis scores, skin histology and immunological parameters such as IgE, Th2-mediated cytokines and chemokines, CD3(+) T cells and CLA(+) T cells. Combined therapy using glucosamine plus FK-506 improved the development of AD-like skin lesions as exemplified by a significant decrease in total skin symptom severity scores. The suppression of dermatitis by combined therapy was accompanied by a decrease in the plasma level of IgE and in the splenic level of IL-5, IL-13, TARC and eotaxin. Histological finding indicated that the dermal infiltration of inflammatory cells including mast cells and eosinophils was greatly reduced. Particularly, immunohistological evaluation reveals a reduction in CD3(+) T cells and CLA(+) cells in the combined therapy. Our findings suggest that combination therapy of glucosamine plus FK-506 was more synergistic efficacy than single-modality treatment with either alone to improve the development of established dermatitis in NC/Nga mice model. This combined immunosuppressive therapy may provide an effective therapeutic strategy for the treatment of AD.     

Experimental atopic dermatitis is dependent on the TWEAK/Fn14 signaling pathway

Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) acts through its receptor fibroblast growth factor inducible 14 (Fn14), and participates in skin inflammation. Both TWEAK and Fn14 are highly expressed in skin lesions of patients with atopic dermatitis. The purpose of this study was to further explore the effect of Fn14 inhibition on experimental atopic dermatitis. Experimental atopic dermatitis was induced in the wild-type and Fn14 knock-out BALB/c mice. The effect of TWEAK/Fn14 interaction on keratinocytes was studied in an in-vitro model of atopic dermatitis. Fn14 deficiency ameliorates skin lesions in the mice model, accompanied by less infiltration of inflammatory cells and lower local levels of proinflammatory cytokines, including TWEAK, TNF-α and interleukin (IL)-17. Fn14 deficiency also attenuates the up-regulation of TNFR1 in skin lesions of atopic dermatitis. Moreover, topical TWEAK exacerbates skin lesion in the wild-type but not in the Fn14 knock-out mice. In vitro, TWEAK enhances the expressions of IL-17, IL-18 and IFN-γ in keratinocytes under atopic dermatitis-like inflammation. These results suggest that Fn14 deficiency protects mice from experimental atopic dermatitis, involving the attenuation of inflammatory responses and keratinocyte apoptosis. In the context of atopic dermatitis-like inflammation, TWEAK modulates keratinocytes via a TNFR1-mediated pathway.     

Innate and adaptive type 2 immunity in lung allergic inflammation

Allergic inflammation is a type 2 immune disorder classically characterized by high levels of immunoglobulin E (IgE) and the development of Th2 cells. Asthma is a pulmonary allergic inflammatory disease resulting in bronchial hyper-reactivity. Atopic asthma is defined by IgE antibody-mediated mast cell degranulation, while in non-atopic asthma there is no allergen-specific IgE and more involvement of innate immune cells, such as basophils, group 2 innate lymphoid cells (ILC2), and eosinophils. Recently, protease allergens were shown to cause asthmatic responses in the absence of Th2 cells, suggesting that an innate cell network (IL-33/TSLP-basophil-ILC2-IL-5/IL-13 axis) can facilitate the sensitization phase of type 2 inflammatory responses. Recent evidence also indicates that in the chronic phase, these innate immune cells directly or indirectly contribute to the adaptive Th2 cell responses. In this review, we discuss the role of Th2 cytokines (IL-4 and IL-13) and innate immune cells (mast cells, basophils, ILC2s, and dendritic cells) in the cross-talk between innate and adaptive inflammatory responses.     

Bovine milk fat enriched in conjugated linoleic and vaccenic acids attenuates allergic dermatitis in mice

Background Orally administered milk fat enriched in conjugated linoleic acid (CLA) and trans‐vaccenic acid (VA) (‘enriched milk fat’), produced by supplementing the diet of pasture‐fed cows with fish and sunflower oil, has been shown previously to suppress the development of allergic airway disease in mice. Objective To investigate whether topical or oral application of enriched milk fat and its two major fatty acids cis‐9, trans‐11 CLA (c9,t11‐CLA) and VA inhibit allergic dermatitis in mice. Methods Allergic dermatitis was induced in C57BL/6 mice by epicutaneous sensitization of tape‐stripped skin with ovalbumin (OVA). Enriched milk fat and its two major fatty acids were either topically applied to the OVA‐sensitized skin, or orally fed to mice by supplementation of the diet. Blood and skin tissues were collected for analysis after the third skin sensitization. Results Both topical and oral administration of enriched milk fat and its two major fatty acids led to significant suppression of allergic dermatitis as evidenced by reduced clinical and histological scores of affected skins, infiltration of inflammatory cells, and circulating allergen‐specific IgE levels, compared with treatment with normal milk fat or the base control diet. C9,t11‐CLA and VA individually inhibited multiple facets of allergic dermatitis when topically applied, and their combination produced a strong additive effect. Conclusion and Clinical Relevance Enriched milk fat, and its two major fatty acids c9,t11‐CLA and vaccenic acid attenuate allergic dermatitis in mice. Cite this as: X. Sun, J. Zhang, A. K. H. MacGibbon, P. Black and G. W. Krissansen, Clinical & Experimental Allergy, 2011 (41) 729–738.     

Basophils in skin inflammation

Basophils represent less than 1% of peripheral blood leukocytes. Under physiological conditions, basophils principally circulate in peripheral blood, while mast cells reside in peripheral tissues. Like mast cells, they express the high-affinity IgE receptor on their cell surface and release chemical mediators. Because of morphological and functional similarities, basophils have long been considered to be redundant "circulating mast cells" and minor (probably negligible) players in inflammation. Mouse and human basophils cannot be stained in routinely processed histological specimens, and thus, our understanding of tissue basophils in allergic inflammation had been limited. However, recent studies in mice have revealed that basopihls play non-redundant roles from mast cells. Basophils function as a source of IL-4, IL-13, and CCL22, thereby contributing Th2 immunity. They are also capable of presenting antigens. Basophils are essential for the development of IgE-mediated chronic allergic skin inflammation in mice. Recent immunohistochemical studies with an basophil-specific antibody revealed that, in humans, varying numbers of basophils infiltrate skin lesions of inflammatory diseases, such as atopic dermatitis, urticaria, prurigo, and eosinophilic pustular folliculitis. Basophils may play important roles in a variety of inflammatory skin diseases than previously thought.     

Mice lacking the transcription factor RelB develop T cell-dependent skin lesions similar to human atopic dermatitis

Mice with a targeted disruption of the Rel / NF-kappaB family member RelB develop a complex inflammatory phenotype and hematopoietic abnormalities. RelB-deficient (relB(- / -)) mice were clinically normal until 4 - 10 weeks after birth when thickening of the skin and hair loss developed. Histological and immunohistochemical evaluation of relB(- / -) skin lesions revealed hyperkeratosis and marked epidermal hyperplasia. Many CD4(+) T cells and eosinophils mixed with lesser numbers of CD8(+) T cells and neutrophils were present in the dermis. There was a moderate increase of MHC class II-positive dermal dendritic cells and dermal mast cells. Increased expression of Th2 cytokines correlated with increased mRNA levels of eotaxin and CCR3 in relB(- / -) skin. The dermatitis did not develop in the offspring of relB(- / -) mice crossed with transgenic mice that lack peripheral T cells, demonstrating that the skin lesions were T cell dependent. The dermatitis observed in RelB-deficient mice had many similarities with atopic dermatitis in human patients including infiltrating CD4(+) T cells and eosinophils in the skin, increased number of eosinophils in the blood and increased serum IgE. Thus, the relB(- / -) mouse should be a useful model to study the pathogenesis of this common allergic human disease.     

Intrinsic asthma: not so different from allergic asthma but driven by superantigens?

The mechanisms of intrinsic or non‐allergic asthma remain uncertain as allergens have no obvious role in driving the inflammatory process in the airways. However, IgE synthesis occurs in the airways, despite negative skin prick tests and serum‐specific IgE. Furthermore, the inflammatory process in the airways is very similar between allergic and non‐allergic asthma, with increased T‐helper type 2 (Th2) cells, mast cell activation and infiltration of eosinophils. This pattern of inflammation is associated with a similar expression of inflammatory mediators, including Th2 cytokines and eosinophilotactic chemokines. There is increasing evidence that microbial superantigens, particularly Staphylococcal enterotoxins are important in amplifying inflammation in atopic dermatitis and chronic rhinosinusitis, in atopic and non‐atopic patients. Superantigens may also be important in intrinsic asthma as airway epithelial cells may be colonized by Staphylococci and other superantigen‐producing microbes. Superantigens produced locally in the airways may lead to class switching of local B cells, resulting in polyclonal IgE production in the airways and also specific IgE against the superantigen (which functions as a ‘superallergen’). This leads to sensitization of mast cells, which can be activated by the usual asthma triggers, such as exercise. Superantigens also cause clonal expansion of T cells, resulting in increased Th2 cells and CD8⁺ cells, while suppressing regulatory T cells. Superantigens may also reduce responsiveness to corticosteroids, resulting in more severe asthma. Finally, cytotoxic autoantibodies may also be implicated as IgG antibodies directed against epithelial proteins, such as cytokeratin‐18, have been detected in intrinsic asthma, possibly as a result of epithelial damage and this may make epithelial cells more susceptible to microbial colonization. The therapeutic implications are that antibodies against local IgE and microbial superantigens or antibiotic therapy to eradicate the relevant superantigen‐producing microorganisms may improve the efficacy of conventional therapy with corticosteroids.     

Glucosamine improved atopic dermatitis-like skin lesions in NC/Nga mice by inhibition of Th2 cell development

Dysregulated Th subset responses, characterized by Th2‐dominant allergic inflammation, are thought to be central to the pathogenesis of atopic dermatitis (AD). Glucosamine has been shown to have immunosuppressive properties, but its effect on AD has not been examined. In this study, the immunoregulatory effects of glucosamine, using dermatophagoides farinae (Df)‐induced AD‐like skin lesions in NC/Nga mice, were investigated. The clinical scores were reduced significantly by the treatment with glucosamine at 10 and 20 mg/day. Histological analysis of the skin also revealed that treatment of glucosamine at 10 and 20 mg/day significantly reduced the inflammatory cellular infiltrate, including mast cells and eosinophils. The levels of serum IgE and Th2 cytokines in spleen cells were reduced, whereas no significant change was detected in IFN‐γ, a Th1 cytokine. To determine the mechanism associated with inhibition of the Th2 immune response, the effects of glucosamine on the selective differentiation pathway of the Th subset in vitro was examined in NC/Nga mice. The results showed that glucosamine suppressed the differentiation of naïve CD4⁺ T cells to Th2 cells in vitro. On the basis of in vivo and in vitro results of the NC/Nga mice, the immunobiological effects of glucosamine on peripheral blood mononuclear cells from patients with AD were examined. The production of Th2 cytokines, such as IL‐4 and IL‐5, was significantly decreased after in vitro administration of glucosamine, which suggest that glucosamine might be a useful immunomodulatory agent for the treatment of human AD.     

Effects of TNCB sensitization in DS-Nh mice, serving as a model of atopic dermatitis, in comparison with NC/Nga mice

BACKGROUND: It has been predicted that a type-1 and type-2 helper T cell (Th1/Th2) imbalance exists in atopic dermatitis (AD). In DS-Nh mice, an AD mouse model, Staphylococcus aureus increases on the skin surface. OBJECTIVE: To investigate whether the Th1-dominant response has an influence on the development of AD, we induced chronic allergic hypersensitivity with 2,4,6-trinitrochlorobenzene (TNCB ) in two AD mouse models: NC/Nga mice and DS-Nh mice. Th1 and Th2 cytokine production of splenocytes was assessed under stimulation with staphylococcal enterotoxin B (SEB) which induces a Th1 response in DS-Nh mice with or without TNCB sensitization. METHODS: We examined clinical skin changes, transepidermal water loss (TEWL), the number of S. aureus on the skin and the serum IgE levels in these mice treated repeatedly with TNCB under conventional conditions (free of fur mites). The splenocytes of DS-Nh mice were cultured with SEB and the cytokine levels in the supernatants were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Significant skin changes were observed on the skin even where TNCB was not applied in both mice treated with TNCB. Increases in S. aureus on the skin and serum IgE levels were detected in DS-Nh mice, but not in NC/Nga mice. In DS-Nh mice, IFN-gamma and IL-13 production of splenocytes increased in the mice treated with TNCB. CONCLUSION: These results suggest that there might be a different mechanism of dermatitis induction between NC/Nga and DS-Nh mice. Th1 responses might play an important role in the development of dermatitis and increase in serum IgE levels in DS-Nh mice through an increase in IL-13 production.     

Prominent involvement of activated Th1-subset of T-cells and increased expression of receptor for IFN-gamma on keratinocytes in atopic dermatitis acute skin lesions

BACKGROUND: Atopic dermatitis (AD) is an allergic skin disease mediated by antigen-specific IgE and an important role has been ascribed to CD4+ cells (Th cells). The objective of the study was to evaluate humoral and cellular immunological factors in the blood and the skin lesions of AD patients, and to analyze the presence of inflammatory cell-surface markers in blood and skin biopsies. METHODS: The parameters for monitoring of 40 AD patients included results of prick test to inhalant allergens and epicutaneous (patch) test to contact allergens; values of total IgE, serum immunoglobulins (IgG, IgA, IgM) and different cell markers in the sera (CD3, CD4, CD8, CD20, CD21, CD23, HLA-DR). We also analyzed the presence of inflammatory cell-surface markers (CD3, CD4, CD8, CD20, CD20, CD1a, CD23, CD29, CD45Ro, IFNgamma+ markers) in the biopsies of skin lesions from 10 AD patients and 5 healthy controls (HCs) by immunohistochemical analysis (method of avidin-biotin immunoperoxidase). RESULTS: Beside increased total serum IgE and positive skin tests, a significantly higher percentage of CD23+ cells with lower percentage of CD21+ cells was revealed in peripheral blood of AD patients in comparison to HCs. A positive epidermal expression of the majority of markers of T cells (CD3+, CD4+, CD8+, CD29+, CD45Ro+, IFNgamma+) and those of Langerhans' cells (LCs) (CD1a, CD23+), without those of B cells (CD20+) were noted in AD patients, but no in the skin of HCs. Furthermore, significant difference was also found between the two groups for increased expression of CD3, CD4, CD8, CD29, CD45Ro, IFNgamma+ markers (markers for IFNgamma receptor) and higher intraepidermal CD23+ LCs and intradermal CD1a+ LCs in AD skin lesions. CONCLUSIONS:The obtained results suggest involvement of various humoral factors with increased production of IgE and cooperation between Th subsets and LCs, with higher production of related cytokines, and disturbed cellular immunity, including epidermal LCs with IgE receptors of high and low affinity in AD. The annotation of activated Th1 cells with increased producing of IFNgamma in acute AD skin lesions is notable, and might lead to IFNgamma binding to keratinocytes and consequently inflammatory skin changes in the disease.     

Evidence for an inflammatory pathophysiology in idiopathic rhinitis

BACKGROUND: The pathophysiology of idiopathic rhinitis is unknown but the disease is classified as being non-allergic on the basis of negative serum IgE radioallergosorbent assay (RAST) and skin prick tests. In contrast, allergic rhinitis has a Th2 type inflammatory pathology mediated by IgE and mast cells. OBJECTIVE: To test the null hypothesis that there would be no difference in the cellular infiltrate for key Th2-associated inflammatory cells between allergic and idiopathic rhinitis. METHODS: We applied strict selection criteria in the recruitment of allergic and idiopathic rhinitis cases. In contrast to previous studies which used cytology or small biopsies, we studied all layers of the mucosa by using whole, full-thickness nasal turbinate specimens with an average length of 2.5 cm. Immunohistochemistry and in situ hybridization techniques were used to compare the distribution and cell populations of mast cells, IgE positive (IgE+) cells, eosinophils and plasma cells in perennial allergic (n = 11) and idiopathic (n = 17) rhinitis, and control nasal mucosal tissue (n = 9). RESULTS: Mast cells and IgE+ cells were significantly increased within the epithelium of allergic and idiopathic mucosa compared to normal mucosa (P < 0.05). More IgE+ cells were present in the allergic group compared to the idiopathic group with the majority of IgE+ cells being mast cells. Both rhinitic groups showed increased eosinophilia localized to the superficial submucosa compared to normal mucosa (P < 0.05). More plasma cells were present in the allergic rhinitic tissue. CONCLUSION: Idiopathic and allergic rhinitic mucosa show similarities in their inflammatory infiltrate suggesting that both groups share a highly localized Th2, IgE-mediated cellular immunopathology.     

Anti-inflammatory effects of sacran, a novel polysaccharide from Aphanothece sacrum, on 2,4,6-trinitrochlorobenzene-induced allergic dermatitis in vivo

BackgroundSacran is a newly discovered sulfated polysaccharide extracted from an algae, Aphanothece sacrum, grown in a river of the Kyushu region in Japan.ObjectiveTo evaluate sacran's inhibitory effect in 2,4,6-trinitrochlorobenzene (TNCB)–induced allergic dermatitis in NC/Nga mice.MethodsSacran was extracted by acid and alkaline treatment of A sacrum cyanobacterial biomaterials. To sensitize mice, 150 μL of 5% TNCB was applied epicutaneously on the abdomen of each mouse on day 1 and challenged with 15 μL of 1% TNCB applied on the ear skin of mice on day 8 and then every other day to induce skin lesions. Serum levels of inflammatory markers were measured and histopathologic examination of ear skin specimens performed. On the other hand, sacran's transepidermal water loss was evaluated in 11 volunteer women with dry skin.ResultsEpicutaneous application of sacran in mice has significantly inhibited the development of allergic dermatitis skin lesions and reduced the number of scratching behavior episodes (P < .01). In addition, sacran efficiently inhibited IgE (P < .001), tumor necrosis factor α (P = .02), interleukin 4, interleukin 5, and interferon γ (P < .01; vs buffer in the TNCB group) production and eosinophilic infiltration in the chemical allergen–exposed ear skin. In addition, sacran-treated body regions of human volunteers with dry skin significantly reduced transepidermal water loss levels compared with exogenous hyaluronic acid (P < .01), which is known to improve skin moisture and exert skin barrier repair activity.ConclusionsThis study suggests that sacran exerts anti-inflammatory effects by improving skin barrier function and reducing T_H2 cytokine production.     

Contribution of CD4+ and CD8+ T-cells in contact hypersensitivity and allergic contact dermatitis

Allergic contact dermatitis, also referred to as contact hypersensitivity, is one the most frequent inflammatory skin diseases, and is characterized by redness, papule and vesicles, followed by scaling and dryness. Allergic contact dermatitis is elicited upon skin contact with nonprotein chemicals, haptens, and corresponds to a cutaneous delayed type hypersensitivity reaction, mediated by hapten-specific T-cells. During the sensitization phase, both CD4⁺ and CD8⁺ T-cell precursors are activated in the draining lymph nodes by presentation of haptenated peptides by skin dendritic cells. Subsequent hapten painting on a remote skin site induces the recruitment and activation of specific T-cells at the site of challenge. This leads to apoptosis of keratinocytes, recruitment of inflammatory cells and development of clinical symptoms. Experimental studies from the last 10 years have demonstrated that, in normal contact hypersensitivity responses to strong haptens, CD8⁺ type 1 T-cells are effector cells of contact hypersensitivity through cytotoxicity and interferon-γ production, while CD4⁺ T-cells are endowed with downregulatory functions. The latter may correspond to the recently described CD4⁺CD25⁺ regulatory T-cell population. However, in some instances, especially when there is a deficient CD8⁺ T-cell pool, CD4⁺ T-cells can be effector cells of contact hypersensitivity. Ongoing studies will have to confirm that the pathophysiology of human allergic contact dermatitis is similar to the mouse contact hypersensitivity and that the contact hypersensitivity response to common weak haptens, most frequently involved in human allergic contact dermatitis, is similar to that reported for strong haptens.