Chromatin interactions in differentiating keratinocytes reveal novel atopic dermatitis– and psoriasis-associated genes

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New perspectives on epidermal barrier dysfunction in atopic dermatitis: gene-environment interactions

Atopic dermatitis (AD) is a multifactorial, chronic inflammatory skin disorder in which genetic mutations and cutaneous hyperreactivity to environmental stimuli play a causative role. Genetic mutations alone might not be enough to cause clinical manifestations of AD, and this review will propose a new perspective on the importance of epidermal barrier dysfunction in genetically predisposed individuals, predisposing them to the harmful effects of environmental agents. The skin barrier is known to be damaged in patients with AD, both in acute eczematous lesions and also in clinically unaffected skin. Skin barrier function can be impaired first by a genetic predisposition to produce increased levels of stratum corneum chymotryptic enzyme. This protease enzyme causes premature breakdown of corneodesmosomes, leading to impairment of the epidermal barrier. The addition of environmental interactions, such as washing with soap and detergents, or long-term application of topical corticosteroids can further increase production of stratum corneum chymotryptic enzyme and impair epidermal barrier function. The epidermal barrier can also be damaged by exogenous proteases from house dust mites and Staphylococcus aureus. One or more of these factors in combination might lead to a defective barrier, thereby increasing the risk of allergen penetration and succeeding inflammatory reaction, thus contributing to exacerbations of this disease.     

Vitamin D in atopic dermatitis,chronic urticaria and allergic contact dermatitis

Vitamin D influences allergen-induced pathways in the innate and adaptive immune system, and its potential immunomodulatory role in allergic skin disorders has been explored. This comprehensive review article provides an overview of the role of vitamin D in three common dermatologic conditions: atopic dermatitis (AD), chronic urticaria, and allergic contact dermatitis (ACD). Whereas the literature regarding vitamin D and AD has resulted in mixed findings, several studies have described an inverse relationship between vitamin D levels and AD severity, and improvement in AD with vitamin D supplementation. Similarly, several studies report an inverse relationship between vitamin D levels and severity of chronic urticaria. Although current research in humans remains limited, an increased likelihood of ACD has been demonstrated in vitamin D-deficient mice. Additional well-designed clinical trials will be necessary to determine whether vitamin D supplementation should be recommended for prevention or adjuvant treatment of these common dermatologic conditions.     

Advances in atopic dermatitis

Atopic dermatitis (AD) results from barrier defects combined with modified immune responses of the innate and the adaptive immune system to exogenous and endogenous factors. Recent research has continued to sort out the complex pathophysiologic puzzle of this frequent skin disease. However, the network of mechanisms leading to the manifestation of AD is far from being completely understood.     

Filaggrin in atopic dermatitis

The recent identification of loss-of-function mutations in the structural protein filaggrin as a widely replicated major risk factor for eczema sheds new light on disease mechanisms in eczema, a disease that had heretofore largely been considered to have a primarily immunologic etiopathogenesis. The filaggrin gene (FLG) mutation findings are consistent with a recently proposed unifying hypothesis that offers a mechanistic understanding of eczema pathogenesis synthesizing a heritable epithelial barrier defect and resultant diminished epidermal defense mechanisms to allergens and microbes, followed by polarized T(H)2 lymphocyte responses with resultant chronic inflammation, including autoimmune mechanisms. Although compelling evidence from genetic studies on FLG implicates perturbed barrier function as a key player in the pathogenesis of eczema in many patients, much is still unknown about the sequence of biologic, physicochemical, and aberrant regulatory events that constitute the transition from an inherited barrier defect to clinical manifestations of inflammatory eczematous lesions and susceptibility to related atopic disorders. The exact contribution of FLG to the wider atopic story, factors modifying FLG expression, and the role of other barrier proteins remain to be delineated. In this review we highlight recent advances in our understanding of the FLG genetics in the cause of eczema and related complex diseases.     

Autoimmunity and atopic dermatitis

PURPOSE OF REVIEW: It has been demonstrated that a considerable percentage of patients suffering from atopic dermatitis mount IgE autoantibodies against a broad variety of human proteins. This review summarizes evidence for autoimmune mechanisms in atopic dermatitis and suggests novel pathomechanisms that may be involved in this disease. RECENT FINDINGS: It has been shown that patients suffering from atopic dermatitis exhibit IgE autoreactivity to human proteins. These autoantigens are expressed in a variety of cell and tissue types. Complementary DNAs coding for IgE autoantigens have been identified, cloned and characterized at the molecular level. Using purified recombinant IgE autoantigens, it has been shown in paradigmatic models that IgE autoimmunity may be a pathogenetic mechanism in atopic dermatitis. Moreover, it has been shown that the levels of IgE autoantibodies are associated with severity of disease. SUMMARY: Patients suffering from severe manifestations of atopy mount IgE autoantibodies against a variety of human proteins. The levels of IgE autoantibodies correspond with disease severity. Several mechanisms of IgE autoimmunity may contribute to the pathogenesis of atopic dermatitis.     

Anxiety in allergy and atopic dermatitis

PURPOSE OF REVIEW: Individuals suffering from allergies often exhibit a specific psychological profile characterized by anxiety, depression and emotional excitability. Emotional stress precipitates allergic symptoms not only by heightening anxiety levels but also by dysregulating immune-cell functions. The primary objective of this report is to review recent findings of the relationship between anxiety and hypersensitivity responses in the context of psychoneuroimmunology in allergic individuals, notably patients with atopic dermatitis. RECENT FINDINGS: Atopic subjects with emotional problems develop a vicious cycle between anxiety and clinical symptoms. Acute stresses, which repeatedly and chronically affect patients with atopic dermatitis, raise anxiety in general more preferentially than anxiety at present. This psychological failure enhances Th2-type responses due to dysregulation of the neuroimmune system, leading to worsening of allergic symptoms. Tandospirone, a 5-hydroxytryptamine 1A receptor agonist with anxiolytic and antidepressant effects, attenuates itching through successful control of emotional difficulties. These data suggest the efficacy of administrating drugs with anxiolytic effects as part of the management strategy of stress-associated itching in patients with atopic dermatitis. SUMMARY: Psychological interventions such as periodic monitoring of anxiety levels in the context of immune functions and skin conditions are fundamental in therapy of allergic patients with emotional problems.     

Serum IgE in atopic dermatitis

Serum IgE concentrations were determined according to the radioimmunosorbent technique (RIST, Phadebas) on 116 adult patients with atopic dermatitis of varying severity and activity. Geometric mean IgE levels of patients with atopic dermatitis were significantly higher compared with the mean level of ninety-three non-atopic adult subjects without parasitic infestation. Severity of the atopic dermatitis was highly correlated to the levels of serum IgE. Severe chronic cases with ever-recurrent exacerbations show the most extreme values. In the moderate forms of atopic dermatitis, coexistent bronchial asthma causes a greater increase in the IgE values. Among the mild or abortive forms, higher IgE levels were found in cases with allergic rhinitis than in the cases with‘pure’atopic dermatitis. Other findings in connection with IgE in atopic dermatitis are summarized. The pathogenetic significance of IgE in the cutaneous changes is briefly discussed.     

Genetic investigations in atopic dermatitis

In a population based study of 68 individuals with atopic dermatitis and 94 control individuals it was not possible to demonstrate any significant associations between the disease and gene frequencies of HLA-ABC, ABO, MN, Rhesus, Kell, Duffy, Hp, Gc, Gm, Km/Inv, PGM, AcP, GPT, EsD, GLO, AK, PGD, ADA, and GALT/Gt.     

Tachykinin upregulation in atopic dermatitis

Context: Atopic dermatitis (AD) is a chronic, inflammatory, itching skin disorder, which may worsen due to stress, depression and anxiety. Tachykinins may be involved in inflammation signaling as well as they may have a role in stress, depression and anxiety.

Objective: This study aimed to measure the expression of tachykinin markers, in the skin of patients with AD, and the correlation of these tachykinins with clinical and psychodemographic parameters.

Materials and methods: Twenty-eight adult patients with AD were investigated regarding tachykinin expression in skin biopsies, using an immunohistochemical technique. The patients were characterized with clinical and psychodemographic parameters.

Results: The number of substance P and neurokinin (NK)A positive nerve fibers, as well as NKA positive mononuclear dermal cells, was increased in lesional compared to non-lesional skin. Interestingly, the depression score and the number of dermal NK-1 receptor (R) positive cells in lesional as well as in non-lesional skin showed a correlation.

Conclusion: These findings indicate an upregulation of the tachykinergic system in the inflamed skin of AD.