Epidermal barrier in atopic dermatitis

Atopic dermatitis (AD) is a complex disease that affects up to 20% of children and impacts the quality of patients and families in a significant manner. New insights into the pathophysiology of AD point to an important role of structural abnormalities in the epidermis combined with immune dysregulation. Filaggrin (FLG) is synthesized as a large precursor, profilaggrin, and is expressed in the upper layers of the epidermis. FLG plays a critical role in the epidermal barrier, and FLG mutations cause abnormal epidermal function. FLG mutations are strongly associated with early-onset, and persistent severe AD. In addition, FLG deficiency in the epidermis is related to allergic sensitization and asthma. The basic skin care including repair and protection of the skin barrier with proper hydration and topical anti-inflammatory therapy is important to control the severity of skin disease in patients with AD.     

Recent developments in the management of patients with atopic dermatitis

Management of most patients with AD should be directed toward basic therapy--lubricants, moderate potency topical steroids, and antihistamines. Only the severe or unresponsive patient should be considered for management with some of the techniques that have been discussed previously. In part, this is because the addition of extra therapy will substantially decrease long-term compliance, increase the cost of medical care, and produce a dissatisfied patient. There are, however, definite situations in which dietary manipulation, topical and systemic antiseptics, dietary supplementation, and ultraviolet light may be useful. The uses of environmental control, biofeedback, and coal tar were not discussed but may also be useful in certain situations. Finally, all physicians should realize that Herpes simplex infection in patients with AD can be a serious and sometimes life-threatening problem. Rapid, accurate diagnosis is the key to effective management with the newer anti-viral agents.     

Pimecrolimus leads to an apoptosis-induced depletion of T cells but not Langerhans cells in patients with atopic dermatitis

BACKGROUND: Apart from the long-used corticosteroids, topical calcineurin inhibitors (tacrolimus, pimecrolimus) represent novel therapeutic options for the treatment of atopic dermatitis. OBJECTIVE: This study was designed to investigate the pathophysiological target cells and mode of action of pimecrolimus in atopic skin. METHODS: Twenty-two patients were randomly assigned to treatment with pimecrolimus cream 1%, matching vehicle cream, or beta-methasone-17-valerate (BMV) cream 0.1% in a randomized, double-blind, vehicle-controlled, parallel group clinical trial. Treatment was given twice daily for 3 weeks. Cryostat sections of skin biopsies were taken before as well as at selected time points after initiation of therapy. For certain experiments, healthy volunteers were topically treated with the creams described twice a day on 5 consecutive days. Epidermal sheets were prepared from suction blisters. For in vitro experiments, untreated, healthy human skin was obtained from patients undergoing plastic surgery. The effect of pimecrolimus and BMV on Langerhans cells (LCs), inflammatory dendritic epidermal cells, and T cells was investigated by using immunofluorescence and flow-cytometry techniques. RESULTS: While topical BMV treatment depleted LCs in healthy and atopic skin, pimecrolimus did not affect their number. Correlating with the disappearance of inflammatory cells, we observed a depletion of inflammatory dendritic epidermal cells and T cells on pimecrolimus and BMV treatment. Furthermore, we show that pimecrolimus depletes T cells by the induction of apoptosis. CONCLUSION: In summary, our data show that pimecrolimus reduces pathological T cells in atopic dermatitis skin via apoptosis, whereas LCs remain unaffected.     

Cutaneous dendritic cells in allergic inflammation

The skin represents a physical barrier, which is capable of protecting the body from damaging invaders. Moreover, the skin operates as an active immunological organ, harbouring a complex network of dendritic cells (DCs), which serve as a bridge between innate and adaptive immunity. Equipped with specific pattern recognition receptors (PRRs), DCs are able to capture, process and present antigens to naïve T cells in the skin draining lymph nodes, thereby inducing adaptive antigen‐specific immunity. However, the outcome of the immune response is shaped by numerous factors including the DC subtype, maturation state of DCs, composition of PRRs expressed by DCs, type of pathogen as well as factors in the microenvironment. Thus, cutaneous DC subtypes are known to contribute to both, peripheral tolerance and the generation of allergic skin inflammation. Identifying the underlying mechanisms is a challenging task in understanding DC biology. Based on their functional diversity, cutaneous DCs might represent promising therapeutic targets, with the potential of down‐modulating pro‐inflammatory immune responses and inducing tolerogenic pathways, thereby ensuring the maintenance of tissue homeostasis and restoring the balance of dysregulated immune reactions in the context of allergic skin diseases. In this review, we summarize the versatile character of DC subtypes in human skin and highlight their phenotypic characteristics and role in allergic skin inflammation. In addition, we discuss current therapeutic approaches for the management of inflammatory skin diseases such as atopic dermatitis with the main focus on strategies targeting DCs. We point towards potential challenges, benefits, risks and limitations for the treatment of patients.     

Role of vitamin D in the pathogenesis and treatment of atopic dermatitis

Atopic dermatitis (AD) is a highly prevalent allergic skin disease that affects children worldwide. Epidemiological, clinical and basic immunological studies have suggested an association between vitamin D (VD) deficiency and the development of AD and other allergic diseases. Low levels of VD, a pleiotropic hormone that has widespread effects on the immune system and skin integrity, appear to be inversely correlated with AD severity, and VD deficiency at birth is associated with higher risk of developing AD. Recent randomized trials have reported inconsistent, but still promising, results on whether VD supplementation may improve AD severity. The apparent differences are likely due to small samples, different regimens and different patient populations. The mechanisms underlying this potential improvement in AD severity remain under investigation.     

Association of HLA-DRB1 genetic variants with the persistence of atopic dermatitis

Atopic dermatitis (AD) is a waxing and waning illness of childhood that is likely caused by interactions between an altered skin barrier and immune dysregulation. The goal of our study was to evaluate the association of DRB1 genetic variants and the persistence of AD using whole exome sequencing and high resolution typing. DRB1 was interrogated based on previous reports that utilized high throughput techniques. We evaluated an ongoing nation-wide long-term cohort of children with AD in which patients are asked every 6 months about their medication use and their AD symptoms. In total, 87 African-American and 50 European-American children were evaluated. Genetic association analysis was performed using a software tool focusing on amino acid variable positions shared by HLA-DRB1 alleles covering the antigen presenting domain. Amino acid variations at position 9 (pocket 9), position 26, and position 78 (pocket 4) were marginally associated with the prevalence of AD. However, the odds ratio was 0.30 (0.14, 0.68; p = 0.003) for residue 78, 0.27 (0.10, 0.69; p = 0.006) for residue 26 and not significant for residue 9 with respect to the persistence of AD. In conclusion, amino acid variations at peptide-binding pockets of HLA-DRB1 were associated with the persistence of AD in African-American children.     

Distinctive role of donor strain immature dendritic cells in the creation of allograft tolerance

Dendritic cells (DCs) are pivotal antigen-presenting cells and serve a unique role in initiating immunity. To test the hypothesis that pre-immunization of recipient with certain DC subsets of donor origin can influence graft outcome, we have studied the effects of immunization with allogeneic CD4(+)CD8(-)CD11c(+) dendritic cell (CD4(+)DC) and CD4(-)CD8(+)CD11c(+) dendritic cell (CD8(+)DC) on the allograft response. Although both immature CD4(+)DC and CD8(+)DC subsets from DBA/2 were able to prime naive allogeneic C57BL/6 (B6) T cells in mixed lymphocyte reaction (MLR), CD8(+)DC exerted more vigorous alloimmune responses than CD4(+)DC did. Also, CD4(+)DC-driven allogeneic T cell response was attenuated more significantly by anti-CD154 mAb than CD8(+)DC-driven response. Consistent with the MLR results, combined pre-treatment with CD4(+)DC, but not CD8(+)DC, plus anti-CD154 mAb produced donor strain-specific long-term graft survival and induced tolerance while treatment with CD8(+)DC plus anti-CD154 mAb created minimal prolongation of allograft survival in a pancreas islet transplant model (DBA/2-->B6). The beneficial effects exerted by CD4(+)DC and anti-CD154 mAb pre-treatment were correlated with T(h)1 to T(h)2 immune deviation and with the amplified donor-specific suppressive capacity by recipient CD4(+)CD25(+) T cells. These findings highlight the capacity of CD4(+)DC to modulate alloimmune responses, and suggest therapeutic approaches for the induction of donor-specific tolerance.     

Interplay between barrier epithelial cells and dendritic cells in allergic sensitization through the lung and the skin

The prevalence of asthma is increasing over the years and it has become obvious that a thorough understanding of mechanisms leading to Th2 sensitization and to asthma is urgently needed to provide better ways to treat the disease. This articles reviews the different players involved in the initiation of allergic reactions in the lung and in the skin, and highlights the importance of a crosstalk between antigen-presenting dendritic cells and structural cell-derived signals in this process. Our increasing understanding of these mechanisms indicates that structural cells, such as airway epithelial cells and skin keratinocytes, need to be considered as more than a simple physical barrier since they are very upstream of the entire Th2 cascade and therefore might represent crucial targets for new therapies.     

IgE on Langerhans cells in the skin of patients with atopic dermatitis and birch allergy

Epidermal cell suspensions from the skin of seven patients with atopic dermatitis (AD) and seven healthy non-atopic controls were investigated for the presence of surface HLA-DR and CD1 antigen, and IgE using indirect and double-staining immunofluorescence techniques. Fifty-seven percent of all CDI + and 68% of all HLA-DR + cells from the patients demonstrated IgE on their surface, indicating that Langerhans cells (Lc) in AD may be a heterogeneous population with regard to surface characteristics. No IgE + cells were found in the epidermal cell suspensions from the healthy non-atopic controls. An attempt lo demonstrate birch pollen antigen on the surface of Lc from the same patients all strongly allergic to birch pollen, using indirect immunofluorescence techniques, was unsuccessful, also after in vitro incubation of the Lc with high concentration of the birch antigen.