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The cutaneous microbiota contributes to skin barrier function, ensuring effective protection against pathogens and contributing to the maintenance of epidermal integrity. Dysbiosis is frequently present in atopic dermatitis (AD), a chronic inflammatory disease associated with skin barrier defects. Dysbiosis is associated with reduced bacterial diversity and marked Staphylococcus aureus colonization, which is favoured in the case of certain local AD-specific properties such as reduced skin acidity, eased bacterial adhesion and decreased antimicrobial peptide production. Furthermore, S. aureus-associated skin dysbiosis, via the production of staphylococcal virulence factors, may also participate in the immunopathology of AD by altering the epidermal barrier and inducing an inflammatory response. However, there are currently no arguments for recommending screening for, and treatment of S. aureus-associated dysbiosis outside the setting of cutaneous superinfection. Nonetheless, modulation of the skin microbiota may hold promise for AD management. Here, we describe the relationships that exist between the skin microbiota and AD.

Psoriasis is a multifactorial skin pathology resulting from genetic susceptibility and environmental triggers that lead to epidermal and immune dysfunction. There is now strong evidence that non-lesional (NL) psoriatic skin, despite its normal appearance, represents an intermediate state between healthy and lesional skin. Changes observed in NL skin mainly affect the skin barrier, keratinocytes, innate and adaptive immune responses, the microbiota and neurogenic tissue innervation. Several epidermal barrier defects are commonly observed in NL skin compared to healthy skin, including an elevated pH, delayed barrier function repair after injury and lower expression of epidermal differentiation complex proteins. NL keratinocytes also show a predisposition for activation and proliferation, and an increased sensitivity to cytokine or microbial triggers, probably linked to their unique transcriptome and proteome, associated with their intermediate state between healthy and lesional cells. In addition, the accumulation of pathogenic IL-17-producing resident memory T cells, which can (re)instigate the formation of new lesions, characterises both the NL and never-lesional skin of patients with psoriasis. Although the contribution of NL skin dysbiosis to psoriasis pathophysiology remains to be clarified, the expression of numerous pruritogenic mediators appears to be involved in disease progression due to an iterative itch-scratch cycle. In summary, the NL skin of patients with psoriasis exhibits numerous hallmarks of dormant psoriasis. The fact that these alterations are mostly located in the epidermis suggests that they are readily accessible to topical treatments, which could prevent the recurrence/spread of this chronic disease.

Background: Chronic venous disease (CVD) is secondary to venous hypertension, leading to vascular inflammation and tissue changes. The impact of CVD on skin structure and barrier function is not well characterized., Objective: We aimed to assess the characteristics of skin alterations in mild-to-moderate CVD by non-invasive techniques based on a prospective exploratory study., Material & Methods: Female subjects (30-75 years) with CVD (Stage C2 to C4, CEAP classification) were eligible. Stage C0-C1 CVD subjects were used as controls. Women with leg surgery or a medical history that could impact the results were excluded. The skin changes on lesional (LS) and non-lesional (NLS) areas were assessed by biometric analysis including skin echography, viscoelasticity evaluation, confocal microscopy and trans epidermal water loss (TEWL) measurements., Results: Thirty-four subjects were enrolled. Based on computation of 26 biometric parameters using Principal Component Analysis, a significant difference between LS and NLS zones, regardless of the CEAP class, was evidenced. C2-C4 subjects presented with dermal thickening suggesting oedema associated with decreased cell density, while no difference in skin viscoelasticity was observed compared to the C0-C1 control group. Epidermal structural modifications were associated with increased TEWL correlating with CVD severity., Conclusion: Skin alterations in CVD patients are detectable by non-invasive methods. These findings may help to better assess new therapeutic strategies.

Therapeutic patient education (TPE) allows patients to better understand their disease and cope with treatment. TPE programmes have not yet been evaluated for chronic spontaneous urticaria (CSU). To investigate the cognitive and behavioural impact of TPE on CSU patients. CSU patients were selected who completed a TPE programme. A pre-post comparison was performed using a skill/knowledge questionnaire, based on six educational objectives, before and after the intervention. The course of CSU was also analysed, according to daily hive count and itch intensity. All of the 61 enrolled patients improved their knowledge and skills following TPE, with greatest improvement in itch management and use of alternatives to scratching. CSU activity was reduced at the end of the programme in 60% of patients. TPE improves knowledge and skills for CSU patients. Further research is needed to demonstrate the positive impact of TPE on CSU activity.

The aetiologies of recurrent angioedema (AE) comprise the frequent histaminergic AE and the rare bradykinin-mediated AE. Diagnosis must be done carefully because they do not have the same treatment. Diagnosis strategy is clinical. The most specific symptoms for bradykinin AE are: isolated AE without wheals, long duration of the attack, abdominal localisation. The unique useful biological tests for the diagnosis of bradykinin AE are C1Inh exploration which is altered in hereditary AE (HAE) types I and II. No other biological test is useful in clinical practice at present. In case of suspicion of bradykinin AE with normal C1Inh, physicians must think of drug-induced AE. Hereditary AE with normal C1Inh may be associated with a mutation on gene F12 in 20% of cases. For 80% of patients without mutation, the diagnosis must be done very carefully.

Background: Porcine skin is increasingly being employed as a model of human skin in various research fields, including pharmacology, toxicology and immunology, with particular interest in percutaneous permeation and organ transplantation. Porcine skin shows several anatomical and physiological similarities, but also some differences, with human skin, but few in depth comparative studies are so far available., Objectives: To study the immunohistochemical properties of normal porcine skin in comparison with human skin., Materials and Methods: We performed a histological and immunohistochemical study on frozen and formalin-fixed, paraffin-embedded skin biopsies from domestic swine and normal human skin, using a panel of 93 monoclonal or polyclonal antibodies recognizing various human and porcine skin cell types or structures., Results: We found that several antibodies used to detect normal human skin cells showed equivalent immunoreactivity on normal porcine skin. However, some antibodies commonly used to detect human skin antigens remained unreactive on porcine skin., Conclusions: Our findings highlight the main immunohistochemical properties of porcine skin in comparison with those of human skin and provide a morphological and immunohistochemical basis useful to researchers using porcine skin.

The links between chronic urticaria, IgE sensitization and allergy have been much discussed but little studied. We investigated IgE sensitization and allergy in 128 adult chronic urticaria patients during 2006-2008. During a one-day hospitalisation, the patients answered a standardized questionnaire and underwent blood serum analysis, physical tests and skin prick-tests. IgE sensitization to environmental allergens was defined by the positivity of at least one skin prick test and/or elevated levels of serum IgE ≥ 300 Kui/L. The chronic urticaria was considered allergic if: i) a high correlation between positive skin prick tests to a clinically relevant allergen and the case history was found; ii) complete remission of urticaria occurred within two months of allergen withdrawal. Of 105 patients with interpretable skin prick tests, 46.7% were IgE sensitized. Two patients had clinically relevant positive skin prick tests but their chronic urticaria had many other triggering factors and neither was in complete remission after withdrawal of these allergens. IgE sensitization is higher in chronic urticaria patients than in the global adult population, suggesting that it is one important etiopathogenic factor in chronic urticaria. However, it cannot be considered as the expression of an IgE-mediated allergy but as a chronic inflammatory disease, more frequent in IgE sensitized people and favoured by multiple factors, among which IgE-mediated allergy is exceptional.

The exposure of atopic dermatitis (AD) patients to aeroallergens or food allergens can exacerbate or maintain the disease. Atopy patch tests (APTs) are able to identify these triggering factors and consist of the epicutaneous application of allergens for 48 hours, with an evaluation of the eczematous lesions induced after 48 and 72 hours, according to the reading criteria of the European Task Force on Atopic Dermatitis (ETFAD). APTs show a higher specificity than skin prick and specific IgE tests, since the pathophysiological mechanism of the reaction induced is very similar to that which occurs in AD lesions. The standardization of APTs to aeroallergens has brought a certain reliability to this method, which is not the case for food APTs, in which the positive predictive value must be improved to avoid any unnecessary dietary restrictions. Thus, optimization of APTs and progress in the knowledge of the pathophysiology of eczemas could help to develop new immunobiological diagnostic methods and specific immunotherapy for AD.

Irritant and allergic contact dermatitis are common inflammatory skin diseases induced by repeated skin contact with low molecular weight chemicals, called xenobiotics or haptens. Although both diseases may have similar clinical presentations, they can be differentiated on pathophysiological grounds. Irritant contact dermatitis (ICD) is a non-specific inflammatory dermatitis brought about by activation of the innate immune system by the pro-inflammatory properties of chemicals. Allergic contact dermatitis (ACD) corresponds to a delayed-type hypersensitivity response with a skin inflammation mediated by hapten-specific T cells. Recent progress in the pathophysiology of chemical-induced skin inflammation has shown that ICD and ACD are closely associated and that the best way to prevent ACD is to develop strategies to avoid ICD. The immunological diagnosis of ICD or ACD requires investigation of the presence (ACD) or absence (ICD) of antigen-specific T cells. The detection of T cells can be performed in the skin (collected from ACD lesions or positive patch tests) and/or in the blood, particularly by using the enzyme-linked immunospot assay (ELISPOT). This method, recently developed in ACD to metals, offers a new biological tool enabling the immunobiological diagnosis of ACD.

A retrospective epidemiological survey of generalized pustular psoriasis (GPP) was carried out in France in 2005. 121 dermatological wards received a questionnaire concerning the patients treated in 2004. It related to demographic data, morbidity, mortality, failures and the therapeutic practices of each ward. CNAMTS, the main French health insurance, was also questioned about its registry concerning GPP.112 wards (92.5%) answered the questionnaire, totalling 99 cases (sex ratio male/female: 0.77, mean age 52.5 years +/- 18), which were handled by 46 wards. Incidence and prevalence were estimated in 2004 at a minimum of 0.64 and 1.76/million respectively. Incidence deduced from the CNAMTS data in 1998 and 2001 was similar. The treatment habits were the same in the 46 wards, which used acitretin as first line treatment (89%), followed by methotrexate (8%). High potency dermatocorticosteroids (DC) were most often used (87%). Complications and death were noted in 17% and 2% of the cases respectively, recalcitrant GPP in 42%. Immunobiologics were required in 13% of patients. Univariate analysis showed that treatment failure was related to: i) management in a university ward (OR: 2.9, p = 0.03) probably reflecting the management of the more severe cases ii) prescription of high or very high potency DC as first line local therapy (OR: 7.6, p = 0.05) iii) therapies other than retinoids as first line systemic therapy (OR: 5.5, p = 0.04). The systemic treatment is well codified but future studies will have to confirm the usefulness of DC in the management of GPP.

Atopic dermatitis (AD) is a chronic inflammatory skin disease mediated by allergen-specific T cells which are recruited and activated in lesional skin. Methotrexate (MTX) is an old systemic agent used at low dosage for the treatment of psoriasis, another T cell-mediated skin disorder. Since MTX has been shown to improve the clinical symptoms of eczema in a model of antigen-specific dermatitis in mice, we postulated that it could be an effective treatment of AD. In the present open retrospective study, we report our results on the treatment of moderate to severe AD by MTX. Twenty patients (17 to 68-years-old) with low responses to routine therapies were treated (three months to 2 1/2 years) with a weekly dose of MTX ranging from 7.5 to 25 mg. The evaluation was made on physician's global assessment after 3 months of MTX use, and showed that 75% (15/20) of patients improved after 3 months of MTX use, among which 13/20 with an improvement>70%. The beginning of improvement was observed between the fourth and the eighth week after MTX was initiated. Tolerance was good. However, nausea and increase of liver enzymes were observed in 5 patients and required discontinuation of MTX in 2 patients. In conclusion, MTX seems to be an effective and safe treatment of AD. Placebo-controlled clinical trials are needed to confirm our observations and to define more precisely the effectiveness and safety of MTX in adult AD.

Corticosteroids are often used in the treatment of acute or chronic urticaria. However, their effects on mastocyte activation as well as on the histamine-induced dermal oedema remain poorly investigated. The aim of the present study was to investigate the effects of corticosteroids (CS) on the development of acute experimental urticaria induced by prick-tests with histamine and codeine. This experimental model corresponds to the common form of urticaria. CS were administered at the site of the histamine and codeine prick tests in order to test for a direct effect on the development of acute urticaria. Two types of experiments were performed: 1) after a 48-hour period of topical CS application on the forearm, 7 healthy volunteers were skin prick-tested with histamine and codeine simultaneously in duplicate, one series in the pretreated area and the other in a non-treated area. 2) six other volunteers were prick-tested with histamine and codeine on their forearm, in duplicate. Immediately after testing, intradermal methyprednisolone was injected at the site of the prick-tests in the last series. Skin wheal and flare responses were measured after 20 mns and statistically compared with and without CS treatment. Whereas short-term CS topical application did not appear to modify cutaneous reactivity to histamine and codeine, local CS injection was associated with a significant increase in the flare induced by histamine and codeine (respectively + 18 +/- 3% and + 38 +/- 3%; P = 0.05). The wheal tended to be increased after injected CS. In conclusion, these results show that CS are neither able to prevent nor to improve experimental urticaria, i.e. wheal and flare, and even increase the histamine and codeine-induced erythema. That a similar result could apply to patients with chronic urticaria and with systemic CS remains to be studied.

Contact dermatitis is an inflammatory skin condition induced by exposure to an environmental agent. Eczema and dermatitis are used synonymously to denote a polymorphous pattern of skin inflammation characterized at least in its acute phase by erythema, vesiculation and pruritus. Substances responsible for contact dermatitis after single or multiple exposures are non protein chemicals, i.e. haptens, that induce skin inflammation through activation of innate skin immunity (irritant contact dermatitis) or both innate and acquired specific immunity (allergic contact dermatitis). The present review will focus on allergic contact dermatitis, a delayed-type hypersensitivity reaction, which is mediated by hapten-specific T cells. Recent advances in the pathophysiology of ACD have shown that the occurrence of ACD, as well as its magnitude and duration, is controlled by the opposite functions of CD8 effector T cells and CD4 regulatory T cells. From these studies ACD can be considered as a breakdown of cutaneous immune tolerance to haptens.

Allergic contact dermatitis (ACD) and contact hypersensitivity (CHS) are delayed-type hypersensitivity reactions which are mediated by hapten specific T cells. During the sensitisation phases, 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 skin painting induces the recruitment of T cells at the site of challenge which induces inflammatory signals and apoptosis of epidermal cells, leading to the development of a skin inflammatory infiltrate and of clinical symptoms. There have been major controversies on the respective roles of CD4+ and CD8+ T cells in the development of the CHS inflammatory reaction. Experimental studies from the last 10 years have demonstrated that, in normal CHS responses to strong haptens, CD8+ type 1 T cells are effector cells of CHS while CD4+ T cells are endowed with down-regulatory functions. The latter may correspond to the recently described CD4+ CD25+ regulatory T cell population. However, in some instances, especially those where there is a deficient CD8 T cell pool, CD4+ T cells can be effector cells of CHS. Ongoing studies will have to confirm that the pathophysiology of human ACD is similar to the mouse CHS and that the CHS response to weak haptens, the most frequently involved in human ACD, is similar to that reported for strong haptens.

Contact hypersensitivity is one of the most common skin diseases and its pharmacological control is an important clinical issue. We investigated the control of contact hypersensitivity by immunosuppressive drugs administered during sensitization or challenge. Mycophenolate mofetil, methotrexate and 5-fluorouracil completely inhibited contact hypersensitivity when administered during sensitization whereas they did not decrease inflammatory reaction when administered during challenge. Conversely, mitoxantrone, and cyclophosphamide, given as a single injection at the time of sensitization or challenge, completely inhibited the reaction, a property associated with T and B cell depletion. The data indicate that antimetabolites which are cell cycle dependent inhibit clonal expansion and subsequent differentiation of cytotoxic CD8+ T cells. Their lack of effect at the time of challenge indicates that T cell proliferation is not required for the expression of effector or regulatory T cell activation. Conversely lymphoablative drugs can inactivate or destroy differentiated cytotoxic T cells with rapid kinetics., (Copyright John Libbey Eurotext 2003)

The skin is directly in contact with environmental molecules which are present in the air or directly in contact with the epidermis. Despite the assumption that it has a barrier role which could prevent the penetration of molecules, the skin is permeable to all substances from the low molecular weight xenobiotics to the high molecular weight proteins. Only the degree of permeability varies depending on the physiological state of the skin and the chemical properties of molecules. Recent insights into the pathophysiology of allergic skin diseases have shown that allergen penetration is not the major factor in explaining why some patients become allergic while others maintain an immunological tolerance to the penetrating molecules. Indeed, the functional properties of some allergenic molecules able to induce activation of innate immunity appear to be far more important in the development of allergy than their ability to penetrate the skin easily.

Wrinkles are modifications of the skin associated with cutaneous ageing and develop preferentially on sun-exposed skin. The aim of the study was to analyse the clinicopathological features of wrinkles, among the different types of skin relief modifications. Despite its importance in dermato-cosmetology and skin ageing, few studies have been specifically devoted to wrinkles. In the present study, we analyzed the histological features of the pre-auricular wrinkle compared to retro-auricular skin, obtained from sixteen patients undergoing facial surgery; skin samples were immediately processed for routine histology and histochemical staining. Four types of skin depressions could be defined according to their depth: folds, permanent wrinkles, reducible wrinkles and skin micro-relief. Two different types of pre-auricular wrinkles were observed: (i) permanent wrinkles which were conserved after sampling and, (ii) reducible wrinkles which required in vivo staining to be visible at histology. Histological analysis of the epidermis and dermis of the skin forming the pre-auricular wrinkle revealed a normal skin morphology, identical to that of the skin immediately adjacent to the wrinkle. This was particularly striking for the reducible wrinkles which could not be individualized in the absence of in vivo staining. Both types of wrinkles comprised skin modifications observed in sun-exposed skin, however, in the upper dermis, permanent wrinkles showed a more pronounced accumulation of basophilic fibers, i.e. actinic elastosis, than reducible wrinkles did. These data suggest that the development of wrinkles could be secondary to actinic elastosis and to the disappearance of microfibrils and collagen fibers at the dermal-epidermal junction.

Ultraviolet B light is responsible for the development of skin cancer through inhibition of cellular immune responses in the skin. Here, we addressed the question of the mechanisms involved in UVB-induced immune suppression. We used a model of antigen-specific skin inflammation, the contact hypersensitivity (CHS) reaction to DNFB, which is mediated by CD8+ effector T cells and down-regulated by CD4+ T cells. We show that UVB have opposite effects on CD4+ and CD8+ T cells. UVB irradiation reduced the number of activated CD8+ T cells in the lymphoid organs and impaired their functional activity. This resulted in deficient infiltration of IFN-gamma producing CD8+ T cells at challenged site and consequently in the inability to develop an antigen-specific CHS reaction. This effect is mediated by CD4+ suppressor cells, since in the absence of CD4+ T cells (MHC class II-KO mice and CD4+ T cell-depleted mice), UVB have no immunosuppressive effects. Indeed, UVB-irradiated CD4+ T cell-deficient mice have a normal frequency of IFN-gamma-producing hapten-specific CD8+ T cells in the lymphoid organs and develop a normal CHS reaction to DNFB. Thus, in the absence of CD4+ T cells, UVB do not alter the priming of MHC class I-restricted CD8+ effector T cells. Collectively, these data show that UVB-induced immune suppression is secondary to preferential activation of CD4+ suppressor T cells and not to deficient priming and expansion of the effector CD8+ T cell population. This may have important implications for the prevention of UV-induced skin cancers.