Immunpathogenese der Psoriasis

Psoriasis is a chronic inflammatory disease of the skin and the joints. Multiple factors contribute to the initiation of psoriasis. They include specific genetic characteristics such as major histocompatibility antigens and psoriasis susceptibility genes, as well as trigger factors, namely streptococcal infections. Today, psoriasis is considered as a T‐lymphocyte mediated autoimmune disease, even though the putative autoantigen remains unknown. Bacterial proteins with similarity to structural proteins of keratinocytes are potential target antigens. As in other autoimmune diseases, inflammatory cytokines of the innate immune system initiate a cascade that activates inflammation locally in the skin, in the circulation and most likely also in lymph nodes. IFN‐γ‐producing CD4⁺ Th1‐lymphocytes seem to be of central importance in the pathogenesis of psoriasis as they critically influence differentiation and functioning of antigen presenting cells, mast cells, neutrophils and endothelial cells. This inflammatory cascade simultaneously provokes neoangiogenesis in the dermis and proliferation of keratinocytes. Based on this hypothesis, cytokines or anti‐cytokine antibodies that either inhibit T‐cell mediated inflammation or transform disease‐inducing, pro‐inflammatory Th1‐lymphocytes into a phenotype with anti‐inflammatory properties were tested in psoriasis. As both approaches improved psoriasis, they strongly support the current concept that views psoriasis as a Th1‐lymphocyte mediated disease.     

The 130-kDa glycoform of CD43 functions as an E-selectin ligand for activated Th1 cells in vitro and in delayed-type hypersensitivity reactions in vivo

Selectins are carbohydrate-binding molecules involved in constitutive lymphocyte homing and chronic and acute inflammation processes. Th1 lymphocytes participate in cell-mediated inflammatory reactions, where the selectins play a role and predominate in delayed-type hypersensitivity (DTH) reactions of the skin. Of the many candidate ligands for selectins, only P-selectin glycoprotein ligand 1 (PSGL-1), which also acts as an E-selectin ligand, has been characterized extensively at molecular, cellular, and functional levels on T cells. Here, we report that the glycosylated form of CD43 expressed in Th1 cells is a functional E-selectin-specific ligand in vitro. Furthermore, we have generated PSGL-1(-/-)/CD43(-/-) double-deficient mice (double knockout (DKO)) to demonstrate the relevance of CD43 as an E-selectin ligand in vitro and in vivo. Under flow conditions, DKO Th1 cells exhibited impaired E-selectin binding as compared with wild-type, PSGL-1(-/-), or CD43(-/-) Th1 cells. DKO mice also showed diminished ear inflammation in response to dinitrofluorobenzene-induced DTH that correlated with a reduced number of T cells in infiltrates in the challenged ear. These results demonstrate that both PSGL-1 and CD43 are major E-selectin ligands and are likely to be important during leukocyte recruitment in the development of inflammatory reactions.     

Gender aspects in skin diseases

Gender differences in medicine have been recognized in anatomy, physiology, as well as in epidemiology and manifestations of various diseases. With respect to skin disorders, males are generally more commonly afflicted with infectious diseases while women are more susceptible to psychosomatic problems, pigmentary disorders, certain hair diseases, and particularly autoimmune as well as allergic diseases. Significantly, more female sex‐associated dermatoses can be identified than the male sex‐associated dermatoses. Dermatoses in the genital area differ between men and women. Gender differences also exist in the occurrence and prognosis of certain skin malignancies. The mechanisms underlying gender differences in skin diseases remain largely unknown. Differences in the skin structure and physiology, effect of sex hormones, ethnic background, sociocultural behaviour and environmental factors may interact to exert the influences. A better understanding of gender differences in human health and diseases will allow the development of novel concepts for prevention, diagnosis and therapy of skin diseases.     

The Impact of Chronic Skin Disease on Daily Life (ISDL): a generic and dermatology-specific health instrument

BACKGROUND: In dermatological research and clinical practice, there is a need for comprehensive self-report instruments that assess a broad spectrum of health implications of chronic skin diseases, including generic and skin-specific aspects of disease-related quality of life. The advantages of dermatology-specific, multidimensional instruments over generic instruments or single-dimensional quality-of-life measures are in the detailed and specific information they provide about health areas that are affected by the skin condition and that may change through therapeutic intervention. OBJECTIVES: The development of a multidimensional health status inventory for chronic skin diseases (Impact of Chronic Skin Disease on Daily Life, ISDL) is described. The dermatology-specific part of the inventory assesses dimensions of physical functioning, more specifically skin status, physical symptoms of itch, pain and fatigue and scratching responses as well as disease-related stressors like stigmatization. The generic part gauges dimensions of psychological functioning, disease-related impact, illness cognitions and social support by means of existing scales validated for other chronic diseases. METHODS: Reliability and validity of the questionnaire were studied in various samples of patients with psoriasis and atopic dermatitis. RESULTS: The ISDL showed high reliability and test-retest reliability in both patient groups. Convergent validity was indicated by moderate to strong correlations with other validated questionnaires. The scales proved sensitive to change both for dermatological ultraviolet B radiation therapy and cognitive behavioural treatment for itching. CONCLUSION: With its convincing results for reliability and validity the present evaluation supports the usefulness and applicability of the instrument for different chronic skin diseases.     

Neuropeptide control mechanisms in cutaneous biology: physiological and clinical significance

The skin as a barrier and immune organ is exposed to omnipresent environmental challenges such as irradiation or chemical and biologic hazards. Neuropeptides released from cutaneous nerves or skin and immune cells in response to noxious stimuli are mandatory for a fine-tuned regulation of cutaneous immune responses and tissue maintenance and repair. They initialize host immune responses, but are equally important for counter regulation of proinflammatory events. Interaction of the nervous and immune systems occurs both locally - at the level of neurogenic inflammation and immunocyte activation - and centrally - by controlling inflammatory pathways such as mononuclear activation or lymphocyte cytokine secretion. Consequently, a deregulated neurogenic immune control results in disease manifestation and frequently accompanies chronic development of cutaneous disorders. The current understanding, therapeutic options, and open questions of the role that neuropeptides such as substance P, calcitonin gene-related peptide, vasoactive intestinal peptide/pituitary adenylate cyclase-activating polypeptide, neuropeptide Y, or others play in these events are discussed. Progress in this field will likely result in novel therapies for the management of diseases characterized by deregulated inflammation, tissue remodeling, angiogenesis, and neoplasm.     

T lymphocyte chemotaxis and skin diseases

Abstract Recent advances in our understanding of the mechanisms of T lymphocyte motility and chemotaxis, particularly in aspects of lymphocyte-endothelial adhesion, transendothelial cell migration, and T-lymphocyte response to chemotactic gradients have contributed to our knowledge of how T lymphocytes accumulate during the initiation, the development and the control of inflammatory skin responses. In this review, we will summarize the present situation of studies on T lymphocyte adhesion and chemotaxis. The 3 major steps in T lymphocyte chemotaxis, e.g., recognition of extracellular chemotactic gradients, transduction into ap-propriate intracellular signals, and generation of motion, will be out-lined. Skin-homing T lymphocytes, chemokines and other chemoattractants will also be discussed in relation to skin diseases.     

Possible roles of basophils in chronic itch

Basophils are blood granulocytes and normally constitute <1% of blood peripheral leucocytes. Basophils share some morphological and functional similarities with mast cells, and basophils were once regarded as redundant and negligible circulating mast cells. However, recent studies reveal the indispensable roles of basophils in various diseases, including allergic and pruritic diseases. Basophils may be involved in itch through the mediation of a Th2 immune response, interaction with other cells in the skin and secretion of a wide variety of itch‐related mediators, for example histamine, cytokines and chemokines (IL‐4, IL‐13, IL‐31 and TSLP), proteases (cathepsin S), prostaglandins (PGE2 and PGD2), substance P and platelet‐activating factor. Not only pruritic skin diseases (eg, atopic dermatitis, irritant contact dermatitis, chronic urticaria, prurigo, papulo‐erythroderma of Ofuji, eosinophilic pustular folliculitis, scabies, tick bites and bullous pemphigoid) but also pruritic systemic diseases (eg, primary sclerosing cholangitis and polycythemia vera) may be affected by basophils.     

Biological response modifiers and their potential use in the treatment of inflammatory skin diseases

In recent years, a more detailed understanding of the pathogenesis of several inflammatory skin diseases, combined with the developments within biotechnology, has made it possible to design more selective response modifiers. Biological response modifiers hold the potential for greater effectiveness and fewer side-effects than the current systemic therapies now used for severe psoriasis, contact dermatitis and atopic dermatitis. In the pathogenesis of inflammatory skin diseases, the immune system plays a pivotal role, and this is where biological response modifiers such as monoclonal antibodies, recombinant cytokines, or fusion proteins may be effective. Several biological response modifiers have already shown positive results in phase II/III clinical trials in skin diseases, and many new biological response modifiers are in progress.     

The management of dry skin with topical emollients – recent perspectives

Dry skin (xerosis) is a common symptom of a number of chronic skin diseases, such as atopic dermatitis, but can also be caused by environmental factors, such as cold weather and frequent showering. The condition can cause unsightliness of the skin, discomfort, itching, and can have a negative impact on patients' quality of life. This article will cover recent developments in the understanding of xerosis and its management with emollients. The stratum corneum consists of corneocytes and lipid‐enriched intercellular bilayers. These are both produced from keratinocytes in a process called epidermal differentiation. Disturbed epidermal differentiation, resulting in the impairment of stratum corneum intercellular lipid bilayers and natural moisturizing factor, is the root cause of xerosis. The constituent ingredients of emollients should, therefore, address the different factors that contribute to dry skin and, most importantly, attempt to restore epidermal differentiation. The use of lipids, physiological lipids, humectants and antipruritics will help to restore the lipid lamellae, improve skin hydration, skin elasticity and prevent itching. The ideal emollient will include these ingredients plus an agent to support epidermal differentiation. Selecting the correct emollient product and using it regularly are vital factors in the management of xerosis.     

IL-21 in the pathogenesis and treatment of skin diseases

Interleukin-21 (IL-21) is a potent immunomodulatory cytokine, with pleiotropic effects on both innate and adaptive immune responses. These actions include positive effects, such as enhanced proliferation of lymphoid cells, increased cytotoxicity of CD8(+) T cells and natural killer cells, and differentiation of B cells into plasma cells. IL-21 is also produced by Th17 cells and is a critical regulator of Th17 development. IL-21 has potent antitumor activity, but is also associated with the development of autoimmune disease. Many of these activities are critically involved in the pathogenesis of several skin diseases such as psoriasis, atopic dermatitis, lupus erythematosus, and melanoma. Here we review recent advancements on the understanding of the role of IL-21 in skin diseases and how this knowledge can be translated into innovative therapeutic approaches.     

Common burden of chronic skin diseases? Contributors to psychological distress in adults with psoriasis and atopic dermatitis

BACKGROUND: Chronic skin diseases, such as atopic dermatitis and psoriasis, are known to affect quality of life by heightening psychological distress. Knowledge about factors contributing to psychological distress is essential for supporting physicians in diagnostic and multidisciplinary treatment options for patients psychologically at risk. OBJECTIVES: To examine whether generic physical, psychological and social factors relevant to patients with chronic diseases might contribute to psychological distress in adults with psoriasis and atopic dermatitis. METHODS: Self-report data on clinical skin status, physical symptoms of itching and fatigue, impact of the disease on daily life, illness cognitions and social support were collected from 128 patients with psoriasis and 120 patients with atopic dermatitis (aged over 16 years). RESULTS: For patients with either skin disease, clinical status and physical symptoms of itching scarcely affected psychological distress. Instead, higher levels of fatigue, perceived helplessness and less social support best predicted psychological distress in patients with both skin diseases in multiple regression analyses. CONCLUSIONS: Results demonstrate that generic physical, psychological and social aspects play a role in chronic skin diseases and suggest that multidisciplinary care for patients with psoriasis and atopic dermatitis can be greatly improved by integrating common screening and treatment components for chronic diseases.     

Exosomes in chronic inflammatory skin diseases and skin tumors

Exosomes are membrane vesicles of endocytic origin that can mediate communication between cells and the transport of cellular components such as microRNAs, mRNAs, proteins and DNA. Recently, exosomes have been under investigation for their significant roles in both healthy physiology and disease states. Herein, we review the role of exosomes in chronic inflammatory skin diseases and skin tumors, especially focusing on systemic lupus erythematosus, psoriasis, atopic dermatitis, bullous pemphigoid and melanoma. Moreover, we emphasize the involvement of changes in exosome cargo in the regulation of these diseases.     

Gene expression of enzymes for tryptophan degradation pathway is upregulated in the skin lesions of patients with atopic dermatitis or psoriasis

BACKGROUND: Atopic dermatitis (AD) and psoriasis are common inflammatory skin diseases. Although many reports implicate Th2 cytokines in the pathophysiology of AD and Th1 cytokines in psoriasis, the precise etiology of these diseases remains elusive. OBJECTIVE: We investigated novel AD- or psoriasis-related genes to further understand the pathogenesis of these diseases. METHODS: We performed a comprehensive analysis of mRNA expression in skin biopsies from AD or psoriasis patients using DNA microarrays. Quantitative PCR was then used to monitor the expression of novel disease-related genes in human keratinocytes or pinnae from NC/Nga mice. RESULTS: Levels of mRNA for IDO (indoleamine 2,3-dioxygenase) and kynureninase, enzymes constituting the tryptophan degradation pathway, were found to be upregulated in the skin lesions as compared to the uninvolved skin of patients with AD or psoriasis. Expression of these two genes was induced in human epidermal keratinocytes stimulated with IFN-gamma in vitro. Moreover, in NC/Nga mice, the expression of kynureninase mRNA in the ear skin was induced following development of AD-like skin lesions. CONCLUSION: The tryptophan degradation pathway may play an important role in the pathophysiology of AD and psoriasis.     

In vivo and in vitro immune responses to trichophytin in dermatophytosis.

Cell-mediated immunity in patients with verified dermatophytosis was investigated by means of skin test and lymphocyte stimulation test (LST) using purified trichophytin, prepared by the ethylene glycol method, and commercially available trichophytin. The purified trichophytin seemed to be more specific and sensitive both in skin test and in LST. In the majority of cases skin-positive patients were also positive in LST, especially when T. mentagrophytes or E. floccosum was the causative organism. Patients with non-chronic infections also showed a close correlation between skin reactivity and LST. Patients with chronic mycosis or infected with T. rubrum, on the other hand, were often skin-negative. Their lymphocyte reactivity in vitro, however, was usually positive, thus showing a discrepancy in the ability of these two methods to measure cell-mediated immunity.     

The expression and function of galectins in skin physiology and pathology

The galectin family comprises β‐galactoside–binding proteins widely expressed in many organisms. There are at least 16 family members, which can be classified into three groups based on their carbohydrate‐recognition domains. Pleiotropic functions of different galectins in physiological and pathological processes through extracellular or intracellular actions have been revealed. In the skin, galectins are expressed in a variety of cells, including keratinocytes, melanocytes, fibroblasts, dendritic cells, lymphocytes, macrophages and endothelial cells. Expression of specific galectins is reported to affect cell status, such as activation or death, and regulate the interaction between different cell types or between cells and the extracellular matrix. In vitro cellular studies, in vivo animal studies and studies of human clinical material have revealed the pathophysiologic roles of galectins in the skin. The pathogenesis of diverse non‐malignant skin disorders, such as atopic dermatitis, psoriasis, contact dermatitis and wound healing, as well as skin cancers, such as melanoma, squamous cell carcinoma, basal cell carcinoma and cutaneous haematologic malignancy can be regulated by different galectins. Revelation of biological roles of galectins in skin may pave the way to future development of galectin‐based therapeutic strategies for skin diseases.     

Skin scratching switches immune responses from Th2 to Th1 type in epicutaneously immunized mice

BACKGROUND: The balance between Th1 and Th2 subsets is important with respects to susceptibility and resistance to particular infection or autoimmune diseases. However, the mechanism controlling Th1/Th2 balance remains unclear, although several factors have been reported to induce Th1/Th2 differentiation. Atopic Dermatitis (AD) that is a chronic skin disorder has been known as Th2 biased nature characterized by high expression of IgE in the serum. In contrast, the chronic skin lesions express IFNgamma and some patients don't show IgE in the serum. Thus, the pathology is also complicated now. OBJECTIVE: We focused on skin scratching that is common feature in the patients. In this study, we investigated in order to determine whether skin scratching regulates immune responses in murine epicutaneous sensitization model. METHODS: The scratched mice on abdominal skin using wire brush were applied with keyhole limpet hemocyanin (KLH) on the skin using occlusive patch. We examined the immune responses including delayed type hypersensitivity (DTH) reaction, antigen-specific serum immunoglobulin formation, and cytokine expressions on the local skin in comparison with mice without scratching. RESULTS: We found that the epicutaneously sensitized mice with KLH on abdominal skin showed Th2 biased immune response including expression of antigen-specific IgE in the serum and IL-13 in the local skin. Surprisingly, scratching on local abdominal skin using wire brush exchanged the immune response from Th2 dominance to Th1, because the mice displayed DTH reaction and significant level of antigen-specific IgG2a and IgG2b but not IgE in the serum. Furthermore, the abdominal skin showed significant level of IFNgamma but not IL-13. CONCLUSION: These data demonstrate that skin scratching switches immune response from Th2 biased response to Th1. This suggests that skin scratching play critical roles as one of exogenous immune modulator. This murine sensitization model may help to understand natures of several allergic disorders including AD.     

Skin diseases and sexually transmitted diseases in HIV‐infected patients on HAART compared to a non‐infected population – results of a retrospective study

Background: The prevalence of skin diseases and sexually transmitted diseases has always played a special role in studying HIV infections, both because of immunosuppression and simultaneous transmission. In the early years of the HIV epidemic, skin diseases were often a pathognomonic sign in heavily immunosuppressed patients. With highly active antiretroviral therapy (HAART), HIV infection has become a treatable chronic disease. For this reason the spectrum as well as the prevalence of skin diseases has changed. Pathognomonic skin diseases have become rare and the wide spectrum today ranges from infectious to iatrogenic skin diseases. Patients and methods: From April to October 2007 166 HIV‐infected patients and 173 patients of a comparison group were surveyed in retrospect by means of a questionnaire about skin diseases and sexually transmitted diseases that appeared over the entire year 2006. Results and conclusions: The study confirmed the shift to a wide variety of mostly trivial skin diseases and away from severe opportunistic skin diseases. HIV‐infected patients today have more numerous skin problems than the non‐infected population and thus need regular dermatologic control examinations.     

Lymphocyte transformation test for diagnosis of isothiazolinone allergy in man.

The lymphocyte transformation test (LTT) has been used for evaluation of in vitro lymphocyte responses in 18 patients with dermatitis and positive patch tests to 200 ppm of a combination of 5-chloro-2-methylisothiazolinone and 28methylisothiazolinone (MCI) in nine patients with dermatitis unrelated to MCI and in seven subjects without skin diseases. Two workers sensitized by occupational exposure to a formulation containing 1,2-benzisothiazolin-3-one (BIT) were also studied. Lymphocytes from nine patch-test-positive patients proliferated vigorously to MCI in vitro. Lymphocytes from the remaining nine patients were not stimulated. Lymphocytes from two BIT-sensitized workers responded to BIT in vitro. The lymphocyte proliferation to isothiazolinones indicates the presence of memory cells in the patients' blood and confirms immunologic reaction to the inducing agent. To establish clinical relevance of LTT results, 12 MCI patch-test-positive patients underwent "use test" with lotion containing 15 ppm MCI. Four of five LTT-positive patients were use-test-positive, whereas seven of seven LTT-negative patients were use-test-negative. LTT-positive and lotion-positive patients responded to 100 ppm or lower concentrations of MCI on patch testing, whereas seven of eight LTT-negative and lotion-negative patients responded to 200 ppm only. In the case of MCI, proliferation was due to the chlorinated component, indicating that this part contains an allergenic epitope. Finally, MCI-specific lymphocyte proliferation was observed only in patients with MCI-positive skin test, but not in nine patients with dermatitis induced by other agents, or in seven subjects without skin diseases. Thus, the lymphocyte transformation test is able to distinguish between irritant and allergic skin responses. It may also be valuable in establishing the clinically relevant patch-test concentration of allergens with irritative properties.     

Dermatitis herpetiformis

The state of our understanding of the pathogenesis of DH relies on the integration of several key characteristics: (1) a high frequency of the HLA antigens HLA-B8, HLA-DR3, and HLA-DQw2, (2) an associated GSE, (3) the resolution of both the skin lesions and gut abnormalities in response to a gluten-free diet, and (4) the presence of granular deposits of IgA in normal and perilesional skin. The role of the HLA class II antigens expressed in patients with DH most likely relates to the afferent or initiating arm of the immune system. The association of the HLA-A1, -B8, -DR3, -DQw2 haplotype with Sjogren's syndrome, chronic hepatitis, Graves' disease, and other presumably immunologically mediated diseases, as well as the evidence that some normal HLA-B8, -DR3 individuals have an abnormal in vitro lymphocyte response to wheat protein and mitogens and have abnormal Fc-IgG receptor-mediated functions, suggests that this HLA haplotype or genes linked closely to it may confer a generalized state of immune susceptibility on its carrier, the exact phenotypic expression of which depends on other genetic or environmental determinants. It also is clear, from the association of DH with GSE and the ability to control the cutaneous manifestations of DH with a gluten-free diet, that the gut disease is a critical factor in the pathogenesis of DH. Several pathogenetic theories about the origin of the cutaneous IgA deposits in DH have been proposed, one of which states that the IgA is produced in the gut mucosa as a response to a dietary antigen or gut epithelial antigen and then cross-reacts with the skin of patients with DH. A second hypothesis is that the IgA produced in the gut binds to an antigen and is deposited in skin as an antigen-antibody complex. Finally, it could be that the gut mucosal abnormality simply allows an unknown antigen access to the central immune system where an IgA antibody is produced that binds to skin. The failure to detect circulating IgA anti-basement membrane zone antibodies in patients with DH suggests that either the structures to which the IgA binds are not present in normal skin without DH, that IgA cannot bind to these structures in vitro, or that the circulating IgA is too scant for detection with conventional methods. Finally, it must be considered that the IgA deposited in DH skin may bind as a result of non-antigen-antibody interactions that cannot be duplicated in vitro.(ABSTRACT TRUNCATED AT 400 WORDS)