James G Krueger

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.

The Rockefeller University Clinical Scholars (KL2) program 2006–2016

Introduction and Methods The Rockefeller Clinical Scholars (KL2) program began in 1976 and transitioned into a 3-year Master’s degree program in 2006 when Rockefeller joined the National Institute of Health Clinical and Translational Science Award program. The program consists of ∼15 trainees supported by the Clinical and Translational Science Award KL2 award and University funds. It is designed to provide an optimal environment for junior translational investigators to develop team science and leadership skills by designing and performing a human subjects protocol under the supervision of a distinguished senior investigator mentor and a team of content expert educators. This is complemented by a tutorial focused on important translational skills. Results Since 2006, 40 Clinical Scholars have graduated from the programs and gone on to careers in academia (72%), government service (5%), industry (15%), and private medical practice (3%); 2 (5%) remain in training programs; 39/40 remain in translational research careers with 23 National Institute of Health awards totaling

Compléments : Intrinsic atopic dermatitis shows similar T H 2 and higher T H 17 immune activation compared with extrinsic atopic dermatitis

23 million, foundation and philanthropic support of

Iconography : Enhancement of cutaneous immunity during aging by blocking p38 mitogen-activated protein (MAP) kinase–induced inflammation

20.3 million, and foreign government and foundation support of

Iconography : Efficacy and safety of fezakinumab (an IL-22 monoclonal antibody) in adults with moderate-to-severe atopic dermatitis inadequately controlled by conventional treatments: A randomized, double-blind, phase 2a trial

6 million. They have made wide ranging scientific discoveries and have endeavored to translate those discoveries into improved human health. Conclusion The Rockefeller Clinical Scholars (KL2) program provides one model for translational science training.