Keratinocyte EGF signalling dominates in atopic dermatitis lesions: A comparative RNAseq analysis

Atopic dermatitis (AD) remains a highly heterogenous disorder with a multifactorial aetiology. Whilst keratinocytes are known to play a fundamental role in AD, their contribution to the overall immune landscape in moderate‐to‐severe AD is still poorly understood. In order to design new therapeutics, further investigation is needed into common disease pathways at the molecular level. We used publicly available whole‐tissue RNAseq data (4 studies) and single‐cell RNAseq keratinocyte data to identify genes/pathways that are involved in keratinocyte responses in AD and after dupilumab treatment. Transcripts present in both keratinocytes (single‐cell) and whole‐tissue, referred to as the keratinocyte‐enriched lesional skin (KELS) genes, were analysed using functional/pathway analysis. Following statistical testing, 2049 genes (16.8%) were differentially expressed in KELS. Enrichment analyses predicted increases in not only type‐1/type‐2 immune signalling and chemoattraction, but also in EGF‐dominated growth factor signalling. We identified complex crosstalk between keratinocytes and immune cells involving a dominant EGF family signature which converges on keratinocytes with potential immunomodulatory and chemotaxis‐promoting consequences. Although keratinocytes express the IL4R, we observed no change in EGF signalling in KELS after three‐month treatment with dupilumab, indicating that this pathway is not modulated by dupilumab immunotherapy. EGF family signalling is significantly dysregulated in AD lesions but is not associated with keratinocyte proliferation. EGF signalling pathways in AD require further study

Factors determining parents' perception of their child's risk of life-threatening food-induced anaphylaxis

Background: Although food allergy is known to be associated with increased disease burden, factors shaping parents' perception of their child's risk of future severe or fatal anaphylaxis are poorly understood. Objective: This study aimed to evaluate factors associated with parents' perceived risk of food-induced anaphylaxis.Methods: A questionnaire-based survey of 202 parents was conducted in a single specialist centre outpatient clinic treating children with food allergies. Parents' perceived risk of their child experiencing further food-induced anaphylaxis was assessed using a validated Food Allergy Independent Measure. Demographic data, as well as parents' anxiety, and depression scores were assessed using Hospital Anxiety and Depression Score. Results: Nineteen percent of parents felt their child had a moderate to high chance of dying from food-induced anaphylaxis. Lack of a university education, higher anxiety score and particularly possession of an epinephrine auto-injector (relative risk 9.9 (3.3 - 30)) were key factors associated with heightened risk perception. Caring for a child with multiple food allergies was the main factor associated with parents feeling less able to manage future reactions (relative risk 9.5 (1.7 - 53)). Parents' risk perception of fatal anaphylaxis correlated with anxiety and mood scores. Conclusion: Parents' education, affect and possessing an epinephrine auto-injector were associated with a heightened perceived risk of future anaphylaxis. Clinicians should consider not only the child's needs, but also providing counselling for parents, particularly those possessing auto-injectors. Parents of children with multiple food allergies may need additional education and training to help them cope with future reactions. <br/

Regional risk of tuberculosis and viral hepatitis with tumor necrosis factor-alpha inhibitor treatment: A systematic review

Background: TNFα inhibitors are regularly used to treat autoimmune diseases. Tuberculosis (TB) and viral hepatitis B are considered potential infectious complications, and screening and surveillance are therefore recommended. Current guidelines do not take into account regional differences in endemicity of these infections.Methods: A systematic literature review of TB and viral hepatitis in patients receiving TNFα-inhibitors was performed, searching in PubMed, Embase, MEDLINE and Web of Science databases. Studies were selected against predefined eligibility criteria and assessed using the Newcastle-Ottawa scale. The number of TB and viral hepatitis cases/1,000 TNFα-inhibitor patients were evaluated, and regional variation compared.Results: 105 observational studies involving over 140,000 patients were included. Overall, 1% of patients developed TB or viral hepatitis B. TB cases/1,000 TNFα-inhibitor patients were 4-fold higher in Asia, Africa, and South America than in Europe, North America, and Australasia where only 0%–0.4% of patients developed TB. Hepatitis B cases/1,000 patients were over 15-fold higher in countries with high prevalence (China, Taiwan, South Korea, Thailand) compared with low prevalence (p &lt; 0.00001) where only 0.4% of patients developed hepatitis B. Only three of 143 patients developed viral hepatitis C, and there was insufficient data to allow regional sub-analysis.Conclusion: TB and viral hepatitis B infections in patients treated with TNFα inhibitors are largely confined to countries with high prevalence of these infections. As only 1/2,500 patients in low prevalence countries treated with TNFα inhibitors develop TB or viral hepatitis B, we suggest an individualized, risk-based approach, rather than universal screening for all patients

Defective Leukocyte Adhesion and Chemotaxis Contributes to Combined Immunodeficiency in Humans with Autosomal Recessive MST1 Deficiency.

PURPOSE: To investigate the clinical and functional aspects of MST1 (STK4) deficiency in a profoundly CD4-lymphopenic kindred with a novel homozygous nonsense mutation in STK4. Although recent studies have described the cellular effects of murine Mst1 deficiency, the phenotype of MST1-deficient human lymphocytes has yet to be fully explored. Patient lymphocytes were therefore investigated in the context of current knowledge of murine Mst1 deficiency. METHODS: Genetic etiology was identified by whole exome sequencing of genomic DNA from two siblings, combined with linkage analysis in the wider family. MST1 protein expression was assessed by immunoblotting. The ability of patient lymphocytes to adhere to ICAM-1 under flow conditions was measured, and transwell assays were used to assess chemotaxis. Chemokine receptor expression was examined by flow cytometry and receptor signalling by immunoblotting. RESULTS: A homozygous nonsense mutation in STK4 (c.442C > T, p.Arg148Stop) was found in the patients, leading to a lack of MST1 protein expression. Patient leukocytes exhibited deficient chemotaxis after stimulation with CXCL11, despite preserved expression of CXCR3. Patient lymphocytes were also unable to bind effectively to immobilised ICAM-1 under flow conditions, in keeping with a failure to develop high affinity binding. CONCLUSION: The observed abnormalities of adhesion and migration imply a profound trafficking defect among human MST1-deficient lymphocytes. By analogy with murine Mst1 deficiency and other defects of leucocyte trafficking, this is likely to contribute to immunodeficiency by impairing key aspects of T-cell development and function such as positive selection in the thymus, thymic egress and immune synapse formation in the periphery.This is thepublished version. It first appeared at http://link.springer.com/article/10.1007%2Fs10875-016-0232-2

Very early onset IBD-associated IL-18opathy treated with an anti-IL-18 antibody 1

Background/Objectives: The etiology of inflammatory bowel disease (IBD), particularly when occurring early 8 in childhood, is diverse and patient focused treatment is required where standard therapy is ineffective. Materials and 9 Methods: Clinical case report of a child with Very-Early Onset IBD (VEOIBD) and evidence of high serum IL-18 10 responding to anti-IL-18 immunotherapy. Detailed cytokine profiling was performed by ELISA and multiplex assay 11 flow cytometry. Results: A four-year-old girl with recalcitrant VEOIBD from six weeks old due to an IL-18opathy, 12 characterized by high blood IL-18 concentration, responded to therapy with a novel neutralizing anti-IL-18 antibody 13 (GSK1070806). After two years of hospitalization, the child’s systemic inflammation and extensive upper and lower 14 gastrointestinal mucosal ulceration remitted with this cytokine inhibitor, allowing discontinuation of total parenteral 15 nutrition and resumption of normal oral intake and daily activities. After 18 months on regular GSK1070806, the patient 16 remains in disease remission. Conclusions: VEOIBD can be associated with evidence of an underlying IL18opathy and 17 respond to anti-IL-18 antibody therapy. IL-18 should be measured in patients with IBD unresponsive to conventional 18 treatments and if elevated, anti-IL-18 antibody therapy considered as a potential therapy

Clinical features that identify children with primary immunodeficiency diseases

BACKGROUND: The 10 warning signs of primary immunodeficiency diseases (PID) have been promoted by various organizations in Europe and the United States to predict PID. However, the ability of these warning signs to identify children with PID has not been rigorously tested. OBJECTIVE: The main goal of this study was to determine the effectiveness of these 10 warning signs in predicting defined PID among children who presented to 2 tertiary pediatric immunodeficiency centers in the north of England. METHODS: A retrospective survey of 563 children who presented to 2 pediatric immunodeficiency centers was undertaken. The clinical records of 430 patients with a defined PID and 133 patients for whom detailed investigations failed to establish a specific PID were reviewed. RESULTS: Overall, 96% of the children with PID were referred by hospital clinicians. The strongest identifiers of PID were a family history of immunodeficiency disease in addition to use of intravenous antibiotics for sepsis in children with neutrophil PID and failure to thrive in children with T-lymphocyte PID. With these 3 signs, 96% of patients with neutrophil and complement deficiencies and 89% of children with T-lymphocyte immunodeficiencies could be identified correctly. Family history was the only warning sign that identified children with B-lymphocyte PID. CONCLUSIONS: PID awareness initiatives should be targeted at hospital pediatricians and families with a history of PID rather than the general public. Our results provide the general pediatrician with a simple refinement of 10 warning signs for identifying children with underlying immunodeficiency diseases. </jats:sec