Interdigitating reticulum cells in dermatopathic lymphadenitis: freeze-fracture and ultrathin-section morphology

Dermatopathic lymphadenitis is a non-neoplastic lesion found with various chronic skin lesions and associated with hyperplasia of the thymus-dependent (T) areas. These areas consist chiefly of interdigitating reticulum cells (IDC's), which are known to be accessory cells for T-cell-dependent immune reactions. The most characteristic features of IDC's are the bizarre-shaped cell nucleus, numerous cytoplasmic processes, deep cytoplasmic invaginations, and a close topographical relationship to surrounding (T) lymphocytes. The cytoplasmic processes of IDC's do not interdigitate with adjacent lymphocytes, as previously reported in the literature, but show close interdigitations with the processes of neighboring IDC's. With the freeze-fracture technique it can be seen that IDC's exhibit a characteristic distribution of intramembranous particles (IMP). While, for example, macrophages, epithelioid cells and lymphocytes display a clearly greater number of IMP on the P face than on the E face, IDC's show an equally high particle density on both the P face and the E face. The organelle content of IDC's in dermatopathic lymphadenitis varies considerably. Tubular profiles, the Golgi apparatus and vesicles may be increased in number. Birbeck granules are also found in IDC's, but only rarely. Variations in the numbers of the different cytoplasmic organelles may be a reflection of varying degrees of metabolic activity of IDC's.     

Recent developments in the immunology and biology of Malassezia species

Malassezia spp. are members of the normal cutaneous flora, but are also associated with several cutaneous diseases. Recent studies of the interaction of Malassezia spp. with melanocytes, fibroblasts, keratinocytes and dendritic cells have highlighted their potential to modulate the immune response directed against them. In normal skin they may downregulate the inflammatory response, allowing them to live as commensals. In contrast, in atopic/eczema dermatitis syndrome and psoriasis, they may elicit an inflammatory response that contributes to the maintenance of lesions. Future research may define ways to influence this inflammatory cycle and hence to control or prevent exacerbations of these diseases.     

Egg and cows' milk hypersensitivity in exclusively breast fed infants with eczema,and detection of egg protein in breast milk.

Forty nine eczematous infants who were still solely and exclusively breast fed and who had never received anything but breast milk were studied for evidence of sensitisation to foods. Thirty four similar infants without eczema formed a control group. The eczematous infants were divided into three groups according to clinical criteria: (1) definite atopic eczema; (2) possible atopic eczema; (3) atopic eczema unlikely. Twenty three infants showed cutaneous hypersensitivity to foods, usually egg and cows'' milk. Seven of 14 infants in group 1 and nine of 20 in group 2 were sensitised compared with four of 15 in group 3 and three of 34 controls (p less than 0.01). Ovalbumin was detected in breast milk from 14 of 19 mothers tested after ingestion of egg, the concentrations being the same for mothers feeding eczematous and normal infants. Breast fed babies developing eczema may be sensitised by foods eaten by their mothers.     

Genetics of Crohn disease, an archetypal inflammatory barrier disease

Chronic inflammatory disorders such as Crohn disease, atopic eczema, asthma and psoriasis are triggered by hitherto unknown environmental factors that function on the background of some polygenic susceptibility. Recent technological advances have allowed us to unravel the genetic aetiology of these and other complex diseases. Using Crohn disease as an example, we show how the discovery of susceptibility genes furthers our understanding of the underlying disease mechanisms and how it will, ultimately, give rise to new therapeutic developments. The long-term goal of such endeavours is to develop targeted prophylactic strategies. These will probably target the molecular interaction on the mucosal surface between the products of the genome and the microbial metagenome of a patient.     

Eicosanoids in skin inflammation

Eicosanoids play an integral part in homeostatic mechanisms related to skin health and structural integrity. They also mediate inflammatory events developed in response to environmental factors, such as exposure to ultraviolet radiation, and inflammatory and allergic disorders, including psoriasis and atopic dermatitis. This review article discusses biochemical aspects related to cutaneous eicosanoid metabolism, the contribution of these potent autacoids to skin inflammation and related conditions, and considers the importance of nutritional supplementation with bioactives such as omega-3 and omega-6 polyunsaturated fatty acids and plant-derived antioxidants as means of addressing skin health issues.     

Influence of weather and climate on subjective symptom intensity in atopic eczema

The frequent clinical observation that the course of atopic eczema, a skin disease involving a disturbed cutaneous barrier function, is influenced by climate and weather motivated us to analyse these relationships biometrically. In the Swiss high-mountain area of Davos the intensity of itching experienced by patients with atopic eczema was evaluated and compared to 15 single meteorological variables recorded daily during an entire 7-year observation period. By means of univariate analyses and multiple regressions, itch intensity was found to be correlated with some meteorological variables. A clear-cut inverse correlation exists with air temperature (coefficient of correlation: –0.235, P<0.001), but the effects of water vapour pressure, air pressure and hours of sunshine are less pronounced. The results show that itching in atopic eczema is significantly dependent on meteorological conditions. The data suggest that, in patients with atopic eczema, a certain range of thermo-hygric atmospheric conditions with a balance of heat and water loss on the skin surface is essential for the skin to feel comfortable. Received: 9 August 1999 / Revised: 10 July 2000 / Accepted: 11 July 2000     

Interdigitating reticulum cells in the popliteal lymph node of the rat

Summary Electronmicroscopic and cytochemical studies were performed to localize interdigitating reticulum cells (IDC) in the popliteal lymph node of the rat.The morphological features of the IDC of the rat correspond to those described for other species, but also show similarities to normal macrophages in the rat. This is considered to be an argument in favour of the common origin of IDC's and macrophages.Ultrahistochemical studies with horseradish peroxidase (HRP) reveal no phagocytotic capacity of IDC's. After perfusion fixation containing ruthenium red (RR) the surface coat stains heavily: RR is also found deep in the membrane invaginations of the IDC, indicating the presence of polyanionic sialoglyco-proteins. The post-capillary-venules (PVC) are very permeable to both HRP and RR.The phosphotungstic acid-chromic acid stain (PTA-CrA) also reveals glycoproteins in the surface coat; these glycoproteins are susceptible to -neuraminidase, whereas glycoproteins in the Golgi complexes, lysosomes and in the vesicular complexes of IDC are not. The glycoproteins of the latter are susceptible to 0.1 N NaOH. These findings indicate that IDC produce different kinds of glycoprotein, one of which may be secreted and act as a factor for stimulating peripheral T-lymphocytes.Intimate contact between IDC's and PCV's could be observed. It is therefore conceivable that IDC's play an important role in the homing of T-lymphocytes.     

Combined oral and nasal beclomethasone diproprionate in children with atopic eczema: a randomised controlled trial.

In a double blind, placebo controlled, crossover trial in 26 children with severe atopic eczema those receiving four weeks'' treatment with combined oral plus nasal beclomethasone diproprionate improved significantly more than those receiving placebo. No adverse effects were observed, but 24 hour urinary cortisol excretion was slightly reduced. This combination may provide effective treatment in refractory atopic eczema with relatively little of the danger associated with systemic administration of prednisolone and other traditional corticosteroids.     

Respiratory infections in the first year of life in children at risk of developing atopy.

Ninety-two infants, each of whom had one parent with asthma or hay fever, were followed up from birth to age of 1 year and 72 to the age of three years. During the first year of life respiratory symptoms, eczema, and respiratory viral infections were all reported. Within the first year 24 babies developed eczema; 28 had a wheal of 1 mm in diameter or more on prick skin testing with cutaneous allergens. Forty-three children had one or both of these characteristics and formed an atopic subgroup; by the same criteria, 49 children were non-atopic. The number of respiratory infections in the two groups was not significantly different; similar viruses were isolated from both groups. These viruses were associated with both upper and lower respiratory tract infections. Wheezing was a clinical feature in 12 children during lower respiratory tract infections. Of these babies six were atopic in the first year of life. Of the six non-atopic babies, one had eczema in the second year and five children developed raised total serum IgE values within the 3 years.     

Topical ‘dual-soft’ glucocorticoid receptor agonist for dermatology

Steroidal glucocorticoids (GR agonists) have been widely used for the topical treatment of skin disorders, including atopic dermatitis. They are a very effective therapy, but they are associated with both unwanted local effects in the skin (skin thinning/atrophy) and systemic side effects. These effects can limit the long-term utility of potent steroids.Here we report on a topically delivered non-steroidal GR agonist, that has the potential to deliver high efficacy in the skin, but due to rapid metabolism in the blood & liver (“dual-soft”) it should have greater systemic safety than existing treatments. In addition, compared to less selective steroidal GR agonists, the new non-steroidal Selective Glucocorticoid Agonists (SEGRAs) have the potential to avoid the skin atrophy observed with existing topical steroids.Due to its potential for reduced skin atrophy and low systemic exposure, LEO 134310 (17) may be suitable for long term topical treatment of skin diseases such as atopic dermatitis and psoriasis.     

Identification of a novel proinflammatory human skin-homing Vγ9Vδ2 T cell subset with a potential role in psoriasis

γδ T cells mediate rapid tissue responses in murine skin and participate in cutaneous immune regulation including protection against cancer. The role of human γδ cells in cutaneous homeostasis and pathology is characterized poorly. In this study, we show in vivo evidence that human blood contains a distinct subset of proinflammatory cutaneous lymphocyte Ag and CCR6-positive Vγ9Vδ2 T cells, which is rapidly recruited into perturbed human skin. Vγ9Vδ2 T cells produced an array of proinflammatory mediators including IL-17A and activated keratinocytes in a TNF-α- and IFN-γ-dependent manner. Examination of the common inflammatory skin disease psoriasis revealed a striking reduction of circulating Vγ9Vδ2 T cells in psoriasis patients compared with healthy controls and atopic dermatitis patients. Decreased numbers of circulating Vγ9Vδ2 T cells normalized after successful treatment with psoriasis-targeted therapy. Taken together with the increased presence of Vγ9Vδ2 T cells in psoriatic skin, these data indicate redistribution of Vγ9Vδ2 T cells from the blood to the skin compartment in psoriasis. In summary, we report a novel human proinflammatory γδ T cell involved in skin immune surveillance with immediate response characteristics and with potential clinical relevance in inflammatory skin disease.     

Genetically programmed differences in epidermal host defense between psoriasis and atopic dermatitis patients

In the past decades, chronic inflammatory diseases such as psoriasis, atopic dermatitis, asthma, Crohn's disease and celiac disease were generally regarded as immune-mediated conditions involving activated T-cells and proinflammatory cytokines produced by these cells. This paradigm has recently been challenged by the finding that mutations and polymorphisms in epithelium-expressed genes involved in physical barrier function or innate immunity, are risk factors of these conditions. We used a functional genomics approach to analyze cultured keratinocytes from patients with psoriasis or atopic dermatitis and healthy controls. First passage primary cells derived from non-lesional skin were stimulated with pro-inflammatory cytokines, and expression of a panel of 55 genes associated with epidermal differentiation and cutaneous inflammation was measured by quantitative PCR. A subset of these genes was analyzed at the protein level. Using cluster analysis and multivariate analysis of variance we identified groups of genes that were differentially expressed, and could, depending on the stimulus, provide a disease-specific gene expression signature. We found particularly large differences in expression levels of innate immunity genes between keratinocytes from psoriasis patients and atopic dermatitis patients. Our findings indicate that cell-autonomous differences exist between cultured keratinocytes of psoriasis and atopic dermatitis patients, which we interpret to be genetically determined. We hypothesize that polymorphisms of innate immunity genes both with signaling and effector functions are coadapted, each with balancing advantages and disadvantages. In the case of psoriasis, high expression levels of antimicrobial proteins genes putatively confer increased protection against microbial infection, but the biological cost could be a beneficial system gone awry, leading to overt inflammatory disease.     

Recent findings on genes associated with inflammatory disease

Inflammatory diseases encompass a variety of medical conditions. In this chapter, autoimmune diseases and allergic disorders will be our focus. The autoimmune diseases include organ-specific autoimmunities, such as type I diabetes mellitus and autoimmune thyroiditis (AITD), and organ non-specific disorders such as systemic lupus erythematosus (SLE). All of them seem to share aspects of aberrant immunologic tolerance toward self-antigens. Asthma and atopic diathesis are among the allergies. Crohn disease and SLE are relatively rare with a prevalence of 10-50 per 100,000, and rheumatoid arthritis (RA), psoriasis, AITD and asthma are commoner with a prevalence of 500 per 100,000 or much higher. The difference among ethnic groups is not prominent for rheumatoid arthritis, psoriasis, AITD or asthma, but Crohn disease and SLE affect some ethnic populations more than others. Although all of these disorders have some environmental component, asthma and atopy seem most affected by environmental factors, as is suggested by the significant increase in their incidence over the last several decades with changes in various environmental factors, especially in developed countries. Over the last 10 years, multiple linkage studies revealed many disease-linked loci throughout the genome with various consistencies. As implicated by some pathophysiological studies of inflammatory immune system related disorders, certain loci are involved in multiple disorders. In the following sections, reports on the identification of disease-associated genes or markers will be summarized for individual diseases (cytotoxic T lymphocyte-associated 4 (CTLA4), CARD15, DLG5, SLC22A4/A5, programmed cell death 1 (PDCD1), RUNX1, SLC9A3R1/NAT9, PADI4, ADAM33, DPP10, PHF11 and GPRA), followed by a discussion of the genes that have been implicated in multiple disorders.     

Chemotaxis of human neutrophils and eosinophils towards leukotriene B4 and its 20-w-oxidation products in vitro

Peripheral blood neutrophils and eosinophils from 70 patients and controls were studied for their in vitro chemotactic and chemokinetic responses towards synthetic leukotriene B4 (LTB4), 20-OH-LTB4 and 20-COOH-LTB4. All three factors induced chemotaxis and chemokinesis of cells. 20-OH-LTB4 was always less and 20-COOH-LTB4 even less active than the parent compound. Cells from patients with atopic eczema and T cell lymphoma moved less than cells from normal controls or from patients with psoriasis. In the presence of LTB4, 20-OH-LTB4 and buffer alone, more eosinophils than neutrophils moved to the lower side of the filter, while this did not occur with platelet activating factor as chemoattractant. Studies of neutrophil and eosinophil chemotaxis in the presence of LTB4 should therefore always take into account a high variability of the quantitative response which is donor and disease dependent.     

Atopic dermatitis: insights from linkage overlap and disease co-morbidity

Atopic dermatitis (AD) is a strongly heritable, chronic relapsing dermatosis that frequently co-occurs with other atopic phenotypes including asthma and allergic rhinitis (the so-called atopic triad disorders). However, despite high levels of co-morbidity, relatively low levels of genomic co-incidence have been observed between atopic triad disorders. Conversely, current mapping data have revealed a striking pattern of co-localisation between AD disease loci and those mapped using another chronic dermatological disease - psoriasis. In this review, we examine the evidence for co-localisation between AD and a range of atopic, infectious, inflammatory and autoimmune diseases, and consider the implications of these data for the AD disease concept and future research in the field.     

Neurotrophins act as neuroendocrine regulators of skin homeostasis in health and disease.

Neurotrophins regulate cutaneous innervation, act as growth and motility factors on structural skin cells such as keratinocytes and fibroblasts, modulate cutaneous immune function and even serve as stress mediators in skin biology. The multilayered neurotrophin interaction with skin biology through high affinity specific tyrosinekinase receptors and the Janus-faced p75 receptor, which depending on ligand and co-receptor expression can serve as a low-affinity pan-neurotrophin receptor or a high affinity proneurotrophin receptor, guaranties this neuroendocrine peptide family a central position in the control of skin homeostasis in health and disease. It is a challenging task for future research efforts to integrate our knowledge on differential neurotrophin expression patterns and signaling pathways into complex concepts of neuroendocrine tissue remodeling and pathogenetic processes. In addition, we need to improve our understanding of the role of neurotrophin processing enzymes, associated co-receptors and intracellular adaptor molecules in specific cutaneous cell populations to design precise interaction tools for research and treatment. Such tools will allow us to utilize this ancient growth factor family in the management of neurotrophin responsive pathogenetic pathways and cutaneous diseases such as neurogenic inflammation, peripheral nerve degeneration, wound healing, atopic dermatitis or psoriasis.     

Mast cells and their degranulation in the Tsk mouse model of scleroderma

The Tsk mouse is a genetically transmitted example of cutaneous fibrosis which has been compared with human scleroderma. During a systematic histopathological study of the Tsk mouse, both an increased number and an increased proportion of degranulated mast cells were observed. The consistent association of mast cells and fibrosis in scleroderma, graft-vs-host reactions (GVHR), and now the Tsk mouse raises the question of a pathogenetic role for mast cells in fibrotic disorders in general.     

Cell-penetrating peptides as antifungals towards Malassezia sympodialis

Aim: To determine whether different antimicrobial peptides (AMPs) and cell‐penetrating peptides (CPPs) are able to inhibit the growth of the commensal yeast Malassezia sympodialis, which can act as a trigger factor in different skin disorders, such as atopic eczema (AE), seborrhoeic eczema (SE) and dandruff. Methods and results: The antifungal activity of 21 different AMPs and CPPs was investigated by microdilution assay and plate counting to determine the number of colony forming units. Five CPPs and one AMP showed fungicidal activity at submicromolar concentrations. Importantly, no membrane damage on human keratinocytes was detected after peptide treatment. Conclusions: Several CPPs, while being nontoxic to mammalian cells, possess growth inhibitory activity on the very stringent yeast M. sympodialis. Significance and impact of study: Our findings that five CPPs and one AMP that are harmless towards mammalian cells act as antifungal agents against M. sympodialis opens up the possibility to use these in the treatment for AE, SE and dandruff. To our knowledge, this is the first time peptides have been identified as antifungal agents against M. sympodialis. Further studies to elucidate the mechanism are warranted.