Transforming Growth Factor-β1 Regulates the Expression of the High-Affinity Receptor for IgE on CD34+ Stem Cell-Derived CD1a+ Dendritic Cells In Vitro

It has been reported that monocytes, Langerhans cells (LC) and other dendritic cells (DC) express the high-affinity receptor for IgE (FcεRI) in patients with atopic diseases. These cells may be instrumental in the control of the immune response and the allergic inflammation. In this context, transforming growth factor beta 1 (TGF-β1) has been highlighted as a key cytokine involved in the mechanisms aimed to orchestrate tolerance and has been suggested as a candidate gene in atopic diseases. In this report, we investigate the putative role of TGF-β1 in the regulation of FcεRI on cord blood CD34+ stem cell-derived CD1a+ DC (CD34-derived CD1a+ DC). Kinetic experiments show that FcεRI spontaneously appears on the surface of CD1a+ DC, but decreases when exogenous TGF-β1 is added at high doses (10 ng per mL) or when endogenous TGF-β1 is neutralized in the culture conditions. In contrast, low-dose TGF-β1 (0.5 ng per mL) stabilizes surface FcεRI expression on DC. Increasing TGF-β1 concentrations leads to the generation of LC-like DC showing an augmentation in stimulatory capacity towards allogeneic T cells. In view of these data, a picture emerges that FcεRI+ on DC is finely modified by the TGF-β1 concentration in the microenvironment and could be of primary relevance in the context of atopic diseases

Gamma-Interferon Promotes the Release of IgE-Binding Factors (Soluble CD23) by Human Epidermal Langerhans Cells

In a previous study, we have demonstrated that human epidermal Langerhans cells (LC) are induced to express FcεR2/CD23 by stimulation with IL-4 and/or IFN-γ. In this study, using LC-enriched and LC-depleted epidermal cell (EC) cultures, we have shown that stimulation with IL-4 and/or IFN-γ not only led to FcεR2/CD23 expression on normal human LC but also to the release of significant amounts of IgE-BF (soluble CD23). Furthermore, stimulation with IL-4 was more effective in induction of FcεR2/CD23 on LC when compared to IFN-γ, which, in contrast, strongly promoted the release of IgE-BF. These results indicate that FcεR2/CD23-positive LC represent a potential source of IgE-BF and that, as is observed in monocytes or U937 cells, IFN-γ and IL-4 differently regulate the FcεR2/CD23 expression and release on LC

A detailed look at the European Medicines Agency's recommendations for use of Janus kinase inhibitors in patients with atopic dermatitis

Background Oral Janus kinase inhibitors (JAKi) have been approved for the treatment of several chronic inflammatory conditions, including rheumatoid arthritis (RA) and atopic dermatitis (AD). Prompted by new evidence, the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) recently reassessed the benefit–risk balance of oral JAKi. The PRAC recommended that oral JAKi should be used only if no suitable alternatives are available in patients ≥65 years of age, or who have a history of atherosclerotic cardiovascular (CV) disease, other CV risk factors (e.g. history of long-term smoking) or have malignancy risk factors, and used with caution in patients at risk of pulmonary embolism or deep vein thrombosis. The European Commission's final decision was issued in March 2023. Objectives Our goal was to highlight the PRAC recommendations, especially in the context of oral JAKi use in AD. Methods Authors summarized the PRAC recommendations, the new clinical evidence on oral JAKi safety and key differences between patients with RA and AD. Results Risk of developing adverse events of special interest (e.g. cardiovascular events, malignancy) is higher in patients with RA than in patients with AD, because of the higher prevalence of the underlying risk factors. Conclusions The benefit–risk profile of JAKi approved for AD remains favourable, including use as first-line systemic therapy for patients with AD <65 years of age and without CV or malignancy risk factors

Evidence for a Pathophysiological Role of Keratinocyte-Derived Type III Interferon (IFNλ) in Cutaneous Lupus Erythematosus

Type I IFNs (IFNα/β) have been shown to have a central role in the pathophysiology of lupus erythematosus (LE). The recently discovered type III IFNs (IFNλ1/IL29, IFNλ2/IL28a, IFNλ3/IL28b) share several functional similarities with type I IFNs, particularly in antiviral immunity. As IFNλs act primarily on epithelial cells, we investigated whether type III IFNs might also have a role in the pathogenesis of cutaneous LE (CLE). Our investigations demonstrate that IFNλ and the IFNλ receptor were strongly expressed in the epidermis of CLE skin lesions and related autoimmune diseases (lichen planus and dermatomyositis). Significantly enhanced IFNλ1 could be measured in the serum of CLE patients with active skin lesions. Functional analyses revealed that human keratinocytes are able to produce high levels of IFNλ1 but only low amounts of IFNα/β/γ in response to immunostimulatory nuclear acids, suggesting that IFNλ is a major IFN produced by these cells. Exposure of human keratinocytes to IFNλ1 induced the expression of several proinflammatory cytokines, including CXCL9 (CXC-motiv ligand 9), which drive the recruitment of immune cells and are associated with the formation of CLE skin lesions. Our results provide evidence for a role of type III IFNs in not only antiviral immunity but also autoimmune diseases of the skin

Antiprotons at Solar Maximum

New measurements with good statistics will make it possible to observe the time variation of cosmic antiprotons at 1 AU through the approaching peak of solar activity. We report a new computation of the interstellar antiproton spectrum expected from collisions between cosmic protons and the interstellar gas. This spectrum is then used as input to a steady-state drift model of solar modulation, in order to provide predictions for the antiproton spectrum as well as the antiproton/proton ratio at 1 AU. Our model predicts a surprisingly large, rapid increase in the antiproton/proton ratio through the next solar maximum, followed by a large excursion in the ratio during the following decade.New measurements with good statistics will make it possible to observe the time variation of cosmic antiprotons at 1 AU through the approaching peak of solar activity. We report a new computation of the interstellar antiproton spectrum expected from collisions between cosmic protons and the interstellar gas. This spectrum is then used as input to a steady-state drift model of solar modulation, in order to provide predictions for the antiproton spectrum as well as the antiproton/proton ratio at 1 AU. Our model predicts a surprisingly large, rapid increase in the antiproton/proton ratio through the next solar maximum, followed by a large excursion in the ratio during the following decade

Implications of fluctuations in the distribution functions of interstellar pick‐up ions for the scattering of low rigidity particles

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/95235/1/grl9864.pd

IL‐13, periostin and dipeptidyl‐peptidase‐4 reveal endotype‐phenotype associations in atopic dermatitis

Background: The heterogeneous (endo)phenotypes of atopic dermatitis (AD) require precision medicine. Currently, systemic therapy is recommended to patients with an Eczema Area and Severity Index (EASI) ≥ 16. Previous studies have demonstrated an improved treatment response to the anti‐interleukin (IL)‐13 antibody tralokinumab in AD subgroups with elevated levels of the IL‐13‐related biomarkers dipeptidyl‐peptidase (DPP)‐4 and periostin. Methods: Herein, 373 AD patients aged ≥12 years were stratified by IL‐13$^{high}$, periostin$^{high}$ and DPP‐4$^{high}$ endotypes using cross‐sectional data from the ProRaD cohort Bonn. “High” was defined as >80th quantile of 47 non‐atopic controls. We analyzed endotype‐phenotype associations using machine‐learning gradient boosting compared to logistic regression. Results: Atopic dermatitis severity and eosinophils correlated with IL‐13 and periostin levels. Correlations of IL‐13 with EASI were stronger in patients with increased (rs = 0.482) than with normal (rs = 0.342) periostin levels. We identified eosinophilia >6% and an EASI range of 5.5–17 dependent on the biomarker combination to be associated with increasing probabilities of biomarker$^{high}$ endotypes. Also patients with mild‐to‐low‐moderate severity (EASI < 16) featured increased biomarkers (IL‐13$^{high}$: 41%, periostin$^{high}$: 48.4%, DPP‐4$^{high}$: 22.3%). Herthoge sign (adjusted Odds Ratio (aOR) = 1.89, 95% Confidence Interval (CI) [1.14–3.14]) and maternal allergic rhinitis (aOR = 2.79–4.47) increased the probability of an IL‐13$^{high}$‐endotype, “dirty neck” (aOR = 2.83 [1.32–6.07]), orbital darkening (aOR = 2.43 [1.08–5.50]), keratosis pilaris (aOR = 2.21 [1.1–4.42]) and perleche (aOR = 3.44 [1.72–6.86]) of a DPP‐4$^{high}$‐endotype. Conclusions: A substantial proportion of patients with EASI < 16 featured high biomarker levels suggesting systemic impact of skin inflammation already below the current cut‐off for systemic therapy. Our findings facilitate the identification of patients with distinct endotypes potentially linked to response to IL‐13‐targeted therapy

Atopic dermatitis: a need to define the disease activity

INTRODUCTION : Atopic dermatitis (AD) is one of the most frequent inflammatory skin diseases characterized by flares and remissions of eczematous lesions and intense itching. Mild disease is the most common severity presentation, nevertheless it is estimated that 20–30% of patients suffer from moderate-to-severe AD. Until recently, there was an unmet need for long-term disease control in these more severe patients. The emergence of new systemic therapies has led to significant clinical improvement for many patients. Therefore, during the long-term management of AD, it is important to properly characterize the severity of the disease in order to allow optimal and individual therapeutic decisions. However, the terminology used needs to be clearly defined. [...