The Major Orphan Forms of Ichthyosis Are Characterized by Systemic T-Cell Activation and Th-17/Tc-17/Th-22/Tc-22 Polarization in Blood

Abstract

The ichthyoses are rare skin disorders with immune and barrier aberrations. Identifying blood phenotypes may advance targeted therapeutics. We aimed to compare frequencies of skin homing/cutaneous lymphocyte antigen (+) versus systemic/cutaneous lymphocyte antigen (-) "polar" CD4/CD8 and activated T-cell subsets in ichthyosis versus atopic dermatitis, psoriasis, and control blood, with appropriate clinical correlations. Flow cytometry was used to measure IFN-γ, IL-13, IL-9, IL-17, and IL-22 cytokines in CD4/CD8 T cells, with inducible co-stimulator molecule and HLA-DR defining mid- and long-term T-cell activation, respectively. We compared peripheral blood from 47 patients with ichthyosis (congenital ichthyosiform erythroderma, lamellar ichthyosis, epidermolytic ichthyosis, and Netherton syndrome) with 43 patients with atopic dermatitis and 24 patients with psoriasis and 59 age-matched controls. Clinical measures included the ichthyosis severity score, with subsets for erythema and scaling, transepidermal water loss, and pruritus. All ichthyoses had excessive inducible co-stimulator molecule activation (P < 0.001), particularly epidermolytic ichthyosis. Significantly elevated IL-17- (P < 0.05) and IL-22-producing (P < 0.01) T cells characterized ichthyoses, mainly Netherton syndrome and congenital ichthyosiform erythroderma (P < 0.05). Increased T helper 2/cytotoxic T cell 2/T helper 9 (P < 0.05) and similar IFN-γ frequencies (P > 0.1) versus controls were also noted. IL-17/IL-22-producing cells clustered with clinical measures, whereas IFN-γ clustered with age. Our data show peripheral blood IL-17/IL-22 activation across the ichthyoses, correlating with clinical measures. Targeted therapies should dissect the relative contribution of polar cytokines to disease pathogenesis.

Patients with congenital ichthyosis and TGM1 mutations overexpress other ARCI genes in the skin: Part of a barrier repair response?

“…It is well established that the Th17/IL‐23 pathway is induced in psoriasis and a previous study of ARCI patients with TGM1 mutations could link this pathway to ichthyosis severity and inflammation . Furthermore, an increased IL‐17/IL‐22 activation in peripheral blood in patients with lamellar ichthyosis was shown to correlate with clinical variables in a recent study . Indeed, we could confirm increased expression of several of the previously reported IL‐17/TNFα‐regulated genes, namely IL36G/IL1F9, PI3, CCL20, LCN2, DEFB4 and S100A9 , whereas the expression of the cytokines IL17A , IL17C and TNFA was virtually unchanged.…”

“…[32] Furthermore, an increased IL-17/IL-22 activation in peripheral blood in patients with lamellar ichthyosis was shown to correlate with clinical variables in a recent study. [33] Indeed, we could confirm increased expression of several of the previously reported IL-17/TNFα-regulated genes, namely IL36G/IL1F9, PI3, CCL20, LCN2, DEFB4 and S100A9, whereas the expression of the cytokines IL17A, IL17C and TNFA was virtually unchanged.…”

Guidance for assessment of erythroderma in neonates and infants for the pediatric immunologist

“…LEKTI deficiency entails severe disturbances in epidermal homeostasis with marked neonatal erythroderma, debilitating pruritus, recurrent skin infections, and persistent skin inflammation (Figure F). Interestingly, besides high total serum IgE levels, these immunologic processes are characterized by systemic T‐cell activation, Th17/Th22 polarization in peripheral blood samples, and upregulation of Th17‐pathway genes in skin specimens of patients with Netherton syndrome …”

“…tion, Th17/Th22 polarization in peripheral blood samples, and upregulation of Th17-pathway genes in skin specimens of patients with Netherton syndrome 20,21. Consequently, affected neonates regularly develop a failure to thrive and additional systemic sequelae of critical skin barrier impairment.…”

Potential therapeutic targeting of inflammation in epidermolysis bullosa simplex

“…Interestingly, parallel to this work in epidermolysis bullosa, molecular profiling in ichthyoses, including the epidermolytic ichthyoses as a result of keratin 1 and 10 gene pathology, have demonstrated Th17 dominant inflammation that might also be amenable to targeted therapies, with a phase II clinical trial of secukinumab currently underway (https://clinicaltrials.gov/ct2/show/NCT03041038). Although corrective therapies for genodermatoses, including keratinopathies, continue to be developed, an awareness of the potential value of targeting secondary pathology involved in clinical morbidity may lead to significant benefits in terms of amelioration of disease severity and improved patient quality of life.…”