Bacterial superantigens and inflammatory skin diseases

Bacteria seem to play an important role in the induction and maintenance of inflammatory skin diseases such as psoriasis and atopic dermatitis. Toxins from bacteria including Streptococcus and Staphylococcus aureus, have been shown to function as a new type of allergen termed 'superantigen'. Superantigens bypass the normal control of T-cell activation and activate all T-cell clones bearing certain types of variable chain on the T-cell receptor: this leads to vigorous T-cell activation and cytokine release. These bacterial superantigens may be involved in induction and aggravation of inflammatory skin diseases. Guttate psoriasis is often preceded by a streptococcal throat infection and T cells specific for streptococcal superantigens have been identified in the skin of patients. The skin of patients with atopic dermatitis is often colonized with superantigen-releasing Staph. aureus, and application of a staphylococcal superantigen to human skin induces an eczematoid reaction.     

Role of Bacterial Superantigens in Atopic Dermatitis

The role of staphylococcal superantigens in the pathophysiology of atopic dermatitis (AD) has been the focus of intense interest during the past decade. Although the increased prevalence of Staphylococcus aureus and its bacterial toxins in AD skin is well established, exploitation of the known mechanisms of superantigens in this disease for the development of novel therapies remains an active area of research. With the emergence of multi-drug resistant S. aureus, the need for a better understanding of the pathophysiology of bacterial superantigens in AD has become increasingly important. This review examines the mechanisms of S. aureus colonization and infection, of which the most important are defective skin barrier function, increased S. aureus adherence, and the decreased innate immune responses found in AD skin. The contribution of superantigens to the pathophysiology of AD is then discussed. Important immunologic mechanisms in this context include the role of superantigens in promoting T helper-2 skin inflammation, IgE production, T-regulatory cell subversion, expansion and migration of skin-homing T cells, and IgE anti-superantigen production. Lastly, these findings are discussed with reference to current therapeutic approaches, of which the most important include anti-inflammatory and antimicrobial medications, and future strategies, which are expected to consist of immune-modulators and synthetic antibacterials.     

Superantigens and their association with dermatological inflammatory diseases: facts and hypotheses

Superantigens have been suggested to play an important role in the pathogenesis of several inflammatory skin diseases as well as systemic diseases such as atopic dermatitis, psoriasis, vasculitis, T-cell lymphoma and autoimmune diseases. Infections often precede the onset and relapse of these diseases, and antibiotic treatment with or without additional glucocorticosteroids and immunoglobulins is occasionally successful. Superantigens are microbial proteins that are able to stimulate up to 20% of the naive T-cell population in a non-specific way. They are produced by gram-positive and -negative bacteria as well as by viruses, parasites and yeasts. The importance of the pathogenic role of superantigens is determined by the potency to induce inflammation by extensive cytokine release after T-cell stimulation and/or T-cell-mediated cytotoxicity and, thereby, tissue damage. Furthermore, superantigens may be able to induce autoimmune processes by stimulation of autoreactive T-cells as well as autoantibody production by stimulation of B-cells. Among the diseases associated with superantigens, atopic dermatitis, guttate and chronic plaque psoriasis, as well as Kawasaki disease, are by far the best-characterized. Nevertheless, conflicting results have been obtained and formal proof of a pathogenic role of superantigens in these diseases is still lacking. The aim of this review is to summarize the data on superantigens in terms of their distribution in microorganisms, their interactions with the adaptive immune system and their contribution to skin pathology.     

The keratinocyte as a target for staphylococcal bacterial toxins

Skin infections with Staphylococcus aureus are not only an important cause of morbidity and even mortality, but are thought to serve as initiation and/or persistance factors for numerous inflammatory skin diseases, including psoriasis and atopic dermatitis. One mechanism by which S. aureus can modulate the immune system is through the production of proteins such as superantigenic toxins, Protein A, as well through the cytolytic alpha-toxin. This review serves to discuss the biology of these three types of proteins, with emphasis on their ability to stimulate the production of powerful pro-inflammatory lipid- and protein-derived cytokines in keratinocytes. Characterization of interactions between these proteins and the keratinocyte can provide a better understanding of how bacterial infection modulates inflammatory skin diseases, as well as provide the basis for improved therapies involving antibacterial agents.     

The clinician's choice of antibiotics in the treatment of bacterial skin infection

The development of modern antibiotics has vastly improved the therapy of cutaneous bacterial infections, particularly those caused by Staphylococcus aureus . This organism and beta-haemolytic streptococci are the most common cutaneous pathogens. A growing body of evidence suggests that proteins from S. aureus and some strains of streptococci can act as superantigens and cause polyclonal T-cell activation by binding directly to antigen-presenting cells. This process is a likely explanation of Kawasaki's syndrome as well as staphylococcal and streptococcal toxic shock syndrome. Sudden aggravation of atopic dermatitis, contact dermatitis and some cases of psoriasis can be similarly explained. Bacterial toxins can precipitate the staphylococcal scalded skin syndrome. Specific and effective eradication of bacteria and programmes to prevent recurrences are important, particularly in immune suppressed persons. Topical antibiotics used primarily for superficial infections of limited extent and for the prevention of recurrences in carriers of S. aureus should be combined with the use of topical disinfectants. The treatment of selected bacterial skin infections based on clinical examples will be discussed. These include secondarily infected dermatoses, cellulitis and streptococcal carriage in the ano-genital region and staphylococcal folliculitis and nasal carriage.     

Induction of psoriasiform inflammation by a bacterial superantigen in the SCID-hu xenogeneic transplantation model

Psoriasis is a chronic skin disease affecting about 2% of the Caucasian population, characterized by co-existing inflammation and epidermal hyperproliferation. A T-lymphocyte-mediated autoimmune reaction induced by bacterial superantigens might be central in its pathogenesis. To model psoriasiform inflammation, we transplanted clinically uninvolved skin from psoriatic patients onto SCID mice. Repetitive intradermal injections with a bacterial superantigen and simultaneous intraperitoneal injections with the patients' superantigen-stimulated peripheral mononuclear blood cells resulted in an inflammatory reaction exhibiting some of the hallmarks of psoriasis, e.g. epidermal hy-perproliferation, papillomatosis, focal neo-expression of ICAM-1, and an exocytotic T-lymphocytic infiltrate characterized by the expression of the cutaneous lymphocyte-associated antigen. These observations document the potential of superantigens to trigger psoriasiform dermatitis and provide a model to study lymphocyte homing.     

Biologic effects of bacterial superantigens in a xenogeneic transplantation model for psoriasis

Both clinical as well as experimental data support the concept of psoriasis being a T-cell-mediated immune disease possibly triggered by bacterial superantigens. Further analysis of its pathogenesis was facilitated by the generation of a xenogeneic transplantation model in which skin from psoriatic patients is grafted onto SCID mice lacking functional B and T cells. Applying this model it was demonstrated that psoriasis can be triggered by bacterial superantigens; this process depends on the presence of immunocytes. Mutated variants of the respective superantigens exhibiting no measurable affinity to HLA class II molecules can function as competitive inhibitors in vivo.     

Treatment outcomes of secondarily impetiginized pediatric atopic dermatitis lesions and the role of oral antibiotics

Patients with atopic dermatitis (AD) are predisposed to infection with Staphylococcus aureus, which worsens their skin disease; it has been postulated that the lack of antimicrobial peptides due to aberrant allergic inflammation in skin with AD could mediate this enhanced bacterial susceptibility. We sought to characterize the amounts of S. aureus and biological products found in infected AD lesions and whether treatment with topical corticosteroids and oral cephalexin as the only antimicrobial improved outcomes. Fifty-nine children with clinically and S. aureus-positive impetiginized lesions of AD were enrolled in this study. A lesion was graded clinically using the Eczema Area and Severity Index, and wash fluid was obtained from the lesion for quantitative bacterial culture and antibiotic sensitivities and measurement of bacterial products and cytokines. Subjects were re-evaluated 2 weeks after treatment. Improvement in the clinical and inflammatory characteristics of impetiginized lesions were noted, even in the 15% of lesions infected with Methicillin-resistant S. aureus (MRSA). In a subgroup of subjects whose lesions did not contain S. aureus 2 weeks after initiating treatment, beta-defensin levels were higher at both visits than in normal skin. Treatment of uncomplicated impetiginized pediatric AD with topical corticosteroids and cephalexin results in significant clinical improvement, even in subjects infected with MRSA. We propose that the inhibition of abnormal inflammation by the treatment regimen, resulting in the high levels of defensins, is involved in the improvement of AD and that systemic antibiotics do not appear to be necessary in secondary impetiginized AD.     

Encoding a superantigen by Staphylococcus aureus does not affect clinical characteristics of infected atopic dermatitis lesions

Background Bacterial infection with Staphylococcus aureus is a known trigger for the worsening of atopic dermatitis (AD). Staphylococcal superantigens have been theorized to make a potential contribution to this worsening of AD seen with infection. Objectives We sought to assess whether encoding a superantigen by S. aureus affects the inflammatory characteristics of impetiginized AD skin lesions. Methods Fifty‐two children with clinically impetiginized lesions of AD which were positive for S. aureus were enrolled in this study. A lesion was graded clinically using the Eczema Area and Severity Index (EASI), and then wash fluid was obtained from the lesion for quantitative bacterial culture, and measurement of bacterial products lipoteichoic acid and staphylococcal protein A and cytokines. The staphylococcal isolate was tested for antibiotic susceptibilities and the presence of a superantigen. Results Fifty‐four per cent (28 of 52) of the staphylococcal isolates encoded a superantigen. The presence of a superantigen had no significant effect on EASI score, amounts of bacterial products or inflammatory cytokines in the AD lesion. Conclusions These studies suggest that the expression of a superantigen by S. aureus alone does not play an important role in the increased skin inflammation associated with staphylococcal infection in childhood AD.     

Bacteria and the skin: clinical practice and therapy update

Any doctor using antibiotics should be aware of the increasing worldwide problem with multiresistent bacteria, with the majority of hospital-based infections in some countries being caused by these bacteria. Proper use of antibiotics is therefore mandatory for any physician, including for dermatologists, who treat bacterial infections of the skin. Detailed knowledge is needed of when to use topical versus systemic antibiotics, and for how long such treatments should be given. Besides the clinical symptoms of bacterial infections and treatment guidelines, an increased awareness has focused on the possible importance of bacterial toxins, including superantigens, and their contribution to skin inflammation. Rare syndromes such as Kawasaki's syndrome, toxic epidermal necrolysis or staphylococcal scalded skin syndrome, are well-known diseases elicited by specific bacterial toxins. But many observations give indirect support to the notion that bacteriae can augment the immune inflammation seen in common and important diseases such as psoriasis and atopic dermatitis. This supplement provides up-to-date information about skin bacteriology, information on the possible importance of superantigens for chronic skin diseases, and practical guidelines for the use of both topical and systemic antibiotic therapy, together with a review of the dangers following improper use. This information is important for all doctors, including dermatologists.     

Skin bacteriology and the role of Staphylococcus aureus in infection

Many of the staphylococci and coryneforms that inhabit normal human skin do not cause skin disease. Amongst the remainder the mechanisms of pathogenicity vary widely. For Proteus , Pseudomonas and Brevibacterium species proteolysis is a major determinant. The precise role of Corynebacterium minutissimum in erythrasma and the propionibacteria in acne is not known. Staphylococcus aureus , however, produces a wide range of non-specific agents, such as haemolysins and leucocidins as well as highly specific toxins such as the epidermolytic toxins involved in bullous impetigo and scalded skin syndrome. Most of the current attention, however, is devoted to the role of the enterotoxins and toxic shock toxin as superantigens, with emphasis on their role in atopic dermatitis. Molecularly similar toxins in the streptococci play a similar role and may also have a role in the aetiology of psoriasis.     

Psoriasis and inflammatory bowel diseases

Psoriasis and inflammatory bowel diseases (Crohn's disease and ulcerative colitis) are among the immune-mediated inflammatory diseases. This group includes approximately 80 disorders, some of which can at times be associated in a single patient. In psoriasis, Crohn's disease may be observed slightly more frequently, but ulcerative colitis and celiac disease are also an issue. The underlying relations between these disorders comprise: i) genetic data obtained by genome-wide association studies that show the involvement of shared predisposing loci and/or genes, for example, in innate immunity; ii) immunological data: these disorders share inflammation effector mechanisms, particularly the activation pathway of Th17 lymphocytes, which explains the efficacy of anti-TNF antibodies and anti-IL-12/23; and iii) environmental co-factors such as smoking, possibly certain food proteins (gliadin, etc.), and bacterial infections that are probably decisive elements in the genesis of these diseases.     

Perforin and granzyme B may contribute to skin inflammation in atopic dermatitis and psoriasis

BACKGROUND: Infiltration of the skin by pathogenic T cells is regarded as a key factor in the development of inflammatory skin diseases such as atopic dermatitis (AD) and psoriasis. OBJECTIVES: To investigate whether T cells containing cytotoxic proteins may contribute to the generation of skin inflammation in these skin diseases. METHODS: Skin biopsy specimens were obtained from non-lesional and lesional skin of patients with chronic AD (n = 8) and psoriasis (n = 6), and from non-atopic controls with normal skin (n = 6). Expression of perforin and granzyme B was investigated by immunohistochemistry. RESULTS: A significant enhancement of perforin and granzyme B expression was observed in lesional AD skin as compared with normal skin, non-lesional AD skin and psoriasis. Expression of these cytotoxic proteins was also increased in psoriasis as compared with normal skin and non-lesional psoriatic skin. Immunoreactivity for perforin and granzyme B was mainly found in the cytoplasm of lymphocytic cells located in the perivascular infiltrate. In AD increased numbers of positive cells were also observed focally at sites of spongiosis in the epidermis. Double immunostaining revealed that both CD4+ and CD8+ T cells are capable of expressing perforin and granzyme B. CONCLUSIONS: Our data suggest that cytotoxic CD4+ and CD8+ T cells containing perforin and granzyme B may play an integral part in eliciting cutaneous inflammation in AD.     

Cytokine gene polymorphisms in atopic dermatitis

BACKGROUND: Atopic dermatitis (AD) and psoriasis are genetically determined inflammatory skin disorders characterized by abnormal cytokine production. From association studies there is evidence that functionally relevant cytokine gene polymorphisms contribute to the genetic basis of psoriasis. Association studies in AD have mostly been limited to polymorphisms of T-helper 2-type cytokines, which dominate in acute AD lesions. Unexpectedly, the results of recent genome scans indicate linkage of AD to psoriasis susceptibility loci. Therefore, AD may also be influenced by genes that modulate cutaneous inflammation independently from atopic mechanisms. OBJECTIVES: To investigate further the role of cytokine gene polymorphisms in AD. METHODS: Polymorphisms in the genes encoding tumour necrosis factor-alpha (TNFA-238 G/A, -308 G/A), interleukin (IL)-1beta (IL1B-511 T/C, +3953 T/C), IL-6 (IL6-174 C/G), IL-10 (IL10-1082 A/G) and the IL-1 receptor antagonist (IL1RN intron 2) were investigated in German patients with AD (n = 94) and in healthy nonatopic individuals (n = 214) by polymerase chain reaction-based methods and direct cycle sequencing. RESULTS: No association was found between AD and any of the polymorphisms analysed. This is in contrast to the recently described association between psoriasis and the TNFA-238 and IL1B-511 polymorphisms. CONCLUSIONS: Our data indicate that cytokine gene polymorphisms may act as specific markers of inflammatory skin diseases rather than contribute to a general disposition towards cutaneous inflammation.     

Facing psoriasis and atopic dermatitis: are there more similarities or more differences?

Atopic dermatitis (AD) and psoriasis vulgaris (Pso) represent the most frequent chronic inflammatory skin diseases. It has been assumed for a long time that these diseases have a completely different background. Recent findings about the genetic, epidemiologic and pathophysiologic factors of both diseases have remarkably improved our knowledge about the complex mechanisms underlying AD and Pso. Beyond that, in view of these findings, the question arises, which similarities and differences between AD and Pso exist. In order to address this point, we provide an overview about the current knowledge in the field of AD and Pso.     

Pregnancy and pregnancy outcome among women with inflammatory skin diseases

BACKGROUND/AIMS: The effect of inflammatory skin diseases on pregnancy has been incompletely characterized. We sought to estimate the incidence of pregnancy and pregnancy outcomes among women with inflammatory skin diseases. METHODS: Cohort study of women with atopic dermatitis (AD), psoriasis, other inflammatory skin diseases, and comparison group, followed for pregnancies and pregnancy outcomes. RESULTS: There were 3,131 pregnancies among 64,773 woman-years (4.8/100) in women with skin diseases, and 2,592 pregnancies among 59,826 woman-years (4.3/100) in the comparison group. The age-standardized incidence of pregnancy was similar to the comparison group [rate ratio (RR) = 1.2, 95% confidence interval (CI) 1.0-1.4 for AD, RR = 1.1, 95% CI 1.0-1.2 for psoriasis, and RR = 1.1, 95% CI 1.0-1.1 for other]. Spontaneous abortion was also similar to the comparison group (RR = 1.2 for AD, 95% CI 1.0-1.4, RR = 1.1, 95% CI 1.0-1.2 for psoriasis, and RR = 1.1, 95% CI 1.0-1.1 for other). CONCLUSIONS: Our results suggest little effect of skin disease on incidence or outcome of pregnancy.     

Superantigen Staphylococcal enterotoxin B induces release of IL-1beta in human epidermis

Lesional skin in patients with inflammatory skin diseases is often colonized with Staphylococcus aureus, which is capable of releasing superantigens. We therefore studied whether application of superantigen on the skin led to release of cytokines, especially IL-1beta. Suction blisters were raised on vehicle- and superantigen-treated skin and IL-1beta protein levels measured in suction blister fluid and supernatant from blister roofs. In all volunteers studied, application of the superantigen Staphylococcal enterotoxin B led to increased release of IL-1beta protein from suction blister roofs (n=7). In contrast, we did not detect any difference in IL-1beta in the blister fluid (n=5). IL-1beta is known as a mediator of inflammation, and the increase in IL-1beta may be involved in the aggravation of inflammatory skin diseases seen following Staphylococcus aureus colonization.     

Increased expression of the aryl hydrocarbon receptor in patients with chronic inflammatory skin diseases

Polychlorinated biphenyls (PCBs) and 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD) are major environmental pollutants, and their effects on the human body critically depend on the aryl hydrocarbon receptor (AhR). The aim of this study was to evaluate the significance of the AhR and its ligands in chronic inflammatory skin diseases such as atopic dermatitis (AD) and psoriasis. Expression of AhR‐related mRNA was increased in lesional skin from patients with AD and psoriasis compared to those of normal skin from healthy controls. The AhR and aryl hydrocarbon receptor nuclear translocator were colocalized in the nuclei of keratinocytes at the lower epidermis of psoriatic lesions, which suggested activation of the AhR pathway. After treatment of normal human epidermal keratinocytes with TCDD or PCBs, IL‐6 and IL‐8 production were increased. The results of this study suggest that AhR is highly expressed in the acute lesional skin of patients with AD and psoriasis, and the AhR pathway is activated especially in psoriasis.     

趋化因子CCL27在常见炎陛皮肤病中的作用

临床常见的炎性皮肤病,如,银屑病、特应性皮炎和接触性皮炎等,其典型特征是T淋巴细胞浸润为主的皮肤炎症。趋化因子CCL27主要由皮肤角质形成细胞产生,其惟一受体是CCRl0。CCL27和CCRl0的相互作用,诱导皮肤记忆T细胞向局部皮肤的聚集,形成并维持了各种炎性皮损,因而已成为药物研究的新靶点。尽管目前尚无真正的临床药物可用,但体外研究和动物实验的良好效果为炎性皮肤病的治疗开启了一扇新的大门。     

骨桥蛋白与皮肤疾病

骨桥蛋白是一种表达于多种组织和细胞的糖蛋白,通过翻译后修饰而在细胞内外存在多种活性形式,可结合不同的受体发生信号转导,介导细胞黏附和迁移、肿瘤侵袭及抗凋亡作用,参与包括Th17在内的Th细胞系的调节.骨桥蛋白能加强机体对分枝杆菌和病毒抗感染能力,且在自身免疫病、银屑病中大量表达,能影响速发性和迟发性变态反应引起的炎症和肉芽肿形成.对骨桥蛋白进行深入研究将为人们治疗相关皮肤病带来新的手段.