Yael Renert-Yuval

An IL-17–dominant immune profile is shared across the major orphan forms of ichthyosis

Background: The ichthyoses are rare genetic disorders associated with generalized scaling, erythema, and epidermal barrier impairment. Pathogenesis‐based therapy is largely lacking because the underlying molecular basis is poorly understood. Objective: We sought to characterize molecularly cutaneous inflammation and its correlation with clinical and barrier characteristics. Methods: We analyzed biopsy specimens from 21 genotyped patients with ichthyosis (congenital ichthyosiform erythroderma, n = 6; lamellar ichthyosis, n = 7; epidermolytic ichthyosis, n = 5; and Netherton syndrome, n = 3) using immunohistochemistry and RT‐PCR and compared them with specimens from healthy control subjects, patients with atopic dermatitis (AD), and patients with psoriasis. Clinical measures included the Ichthyosis Area Severity Index (IASI), which integrates erythema (IASI‐E) and scaling (IASI‐S); transepidermal water loss; and pruritus. Results: Ichthyosis samples showed increased epidermal hyperplasia (increased thickness and keratin 16 expression) and T‐cell and dendritic cell infiltrates. Increases of general inflammatory (IL‐2), innate (IL‐1&bgr;), and some TH1/interferon (IFN‐&ggr;) markers in patients with ichthyosis were comparable with those in patients with psoriasis or AD. TNF‐&agr; levels in patients with ichthyosis were increased only in those with Netherton syndrome but were much lower than in patients with psoriasis and those with AD. Expression of TH2 cytokines (IL‐13 and IL‐31) was similar to that seen in control subjects. The striking induction of IL‐17–related genes or markers synergistically induced by IL‐17 and TNF‐&agr; (IL‐17A/C, IL‐19, CXCL1, PI3, CCL20, and IL36G; P < .05) in patients with ichthyosis was similar to that seen in patients with psoriasis. IASI and IASI‐E scores strongly correlated with IL‐17A (r = 0.74, P < .001) and IL‐17/TNF–synergistic/additive gene expression. These markers also significantly correlated with transepidermal water loss, suggesting a link between the barrier defect and inflammation in patients with ichthyosis. Conclusion: Our data associate a shared TH17/IL‐23 immune fingerprint with the major orphan forms of ichthyosis and raise the possibility of IL‐17–targeting strategies.

Alterations in B-cell subsets in pediatric patients with early atopic dermatitis

Background B cells undergo maturation and class‐switching in response to antigen exposure and T‐cell help. Early B‐cell differentiation has not been defined in patients with early‐onset atopic dermatitis (AD). Objective We sought to define the frequency of B‐cell subsets associated with progressive B‐cell maturation and IgE class‐switching. Methods We studied 27 children and 34 adults with moderate‐to‐severe AD (mean SCORAD score, 55 and 65, respectively) and age‐matched control subjects (15 children and 27 adults). IgD/CD27 and CD24/CD38 core gating systems and an 11‐color flow cytometric panel were used to determine the frequencies of circulating B‐cell subsets. Serum total and allergen‐specific IgE (sIgE) levels were measured by using ImmunoCAP. Results Compared with adults, children showed T‐cell predominance in the skin. Circulating CD19+CD20+ B‐cell counts were lower in patients with pediatric AD than in control subjects (24% vs 33%, P = .04), whereas CD3+ T‐cell counts were higher (62% vs 52%, P = .05). A decreased B‐cell/T‐cell lymphocyte ratio with age was observed only in pediatric control subjects (r = −0.48, P = .07). In pediatric patients with AD, a positive correlation was observed between B‐cell/T‐cell ratio and nonswitched memory B‐cell counts (r = 0.42, P = .03). Higher frequencies of positive sIgE levels were seen in pediatric patients with AD (P < .0001). Diverse sIgE levels correlated with SCORAD scores and age of pediatric patients with AD (P < .01). Positive correlations were observed between activated B‐cell and memory T‐cell counts (P < .02). In patients with AD, IgE sensitization to most allergens clustered with age, TH1, TH2, total IgE levels, and B‐cell memory subsets. Conclusions Peripheral B and T cells are altered in pediatric patients with early AD, but T cells predominate in skin lesions.

The 'omics' revolution: redefining the understanding and treatment of allergic skin diseases.

Purpose of reviewTo evaluate how the genomic, transcriptomic, and proteomic profiles of allergic skin diseases, like atopic dermatitis and allergic contact dermatitis, contribute to their understanding and promote their therapeutic development. Recent findingsThe ‘-omics’ revolution has facilitated the quantification of inflammatory skin diseases at the molecular level, expanding our understanding of disease pathogenesis. It has also greatly expanded once-limited treatment options and improved the ability to define posttreatment improvements, beyond clinical scores. The findings on the genomic/transcriptomic level are also complemented by proteomic data, contributing to the understanding of the later changes taking place in the final stages of protein formation. Atopic dermatitis is defined as a Th2/Th22 polarized disease with some contributions of Th17 and Th1 pathways. In atopic dermatitis, studies of biologics and small molecules, targeting specific pathways upregulated in atopic dermatitis, seem to provide well tolerated alternatives to conventional immunosuppressive therapies (i.e. corticosteroids and cyclosporine A), particularly for severe patients. Allergic contact dermatitis is defined as having Th1/Th17-centered inflammation, especially with nickel-induced disease, but additional pathways, including Th2 and Th22, are upregulated with other allergens (i.e. fragrance). SummarySupplementing studies of allergic skin diseases with ‘-omics’ approaches are transforming the pathogenic understanding, diagnosis and, perhaps, also the treatment of these diseases.

The spectrum of manifestations in desmoplakin gene (DSP) spectrin repeat 6 domain mutations: Immunophenotyping and response to ustekinumab

Background The immune abnormalities underlying the ichthyoses are poorly understood. Objective To determine the immunophenotype of an ichthyosis resulting from mutations in the spectrin repeat 6 (SR6) domain of desmoplakin gene (DSP) and target therapy on the basis of molecular pathogenesis. Methods Immunophenotyping was performed by using the blood and skin of a girl with SR6 region DSP mutations causing erythroderma/ichthyosis and cardiomyopathy. Results On the basis of the discovery of T helper 1 and T helper 17/interleukin 23 skewing in the skin and T helper 17/interleukin 22 skewing in blood, ustekinumab therapy was initiated. Ustekinumab was also administered to a boy with an SR6 region DSP mutation and ichthyosis without cardiomyopathy. Both children responded despite previous poor responses to immunosuppressants and retinoids. Limitations Small number of patients and immunophenotyping in only 1 patient. Conclusion An understanding of the molecular basis of inflammation in rare cutaneous disorders can lead to targeted therapy, which promises to be more beneficial than broad immunosuppressants.