An immune dysfunction score for stratification of patients with acute infection based on whole-blood gene expression.

Dysregulated host responses to infection can lead to organ dysfunction and sepsis, causing millions of global deaths each year. To alleviate this burden, improved prognostication and biomarkers of response are urgently needed. We investigated the use of whole-blood transcriptomics for stratification of patients with severe infection by integrating data from 3149 samples from patients with sepsis due to community-acquired pneumonia or fecal peritonitis admitted to intensive care and healthy individuals into a gene expression reference map.

Topical cyclosporine A 1 mg/ml for atopic keratoconjunctivitis: Five-year case series of 99 children and young people.

Purpose: To explore the effects of cyclosporine A (CsA) in the management of atopic keratoconjunctivitis (AKC).

Methods: Open single-group interventional consecutive cohort study (case series) at a single eye care facility in the UK. We reviewed the electronic patient records of 99 children and young people (CYP) aged 3.

Therapeutic Validation of GEF-H1 Using a De Novo Designed Inhibitor in Models of Retinal Disease.

Inflammation and fibrosis are important components of diseases that contribute to the malfunction of epithelia and endothelia. The Rho guanine nucleotide exchange factor (GEF) GEF-H1/ARHGEF-2 is induced in disease and stimulates inflammatory and fibrotic processes, cell migration, and metastasis. Here, we have generated peptide inhibitors to block the function of GEF-H1.

The topical ocular delivery of rapamycin to posterior eye tissues and the suppression of retinal inflammatory disease.

Treatment of posterior eye diseases with intravitreal injections of drugs, while effective, is invasive and associated with side effects such as retinal detachment and endophthalmitis. In this work, we have formulated a model compound, rapamycin (RAP), in nanoparticle-based eye drops and evaluated the delivery of RAP to the posterior eye tissues in a healthy rabbit. We have also studied the formulation in experimental autoimmune uveitis (EAU) mouse model with retinal inflammation.

Experimental Autoimmune Uveitis: An Intraocular Inflammatory Mouse Model.

Experimental Autoimmune Uveitis (EAU) is driven by immune cells responding to self-antigens. Many features of this non-infectious, intraocular inflammatory disease model recapitulate the clinical phenotype of posterior uveitis affecting humans. EAU has been used reliably to study the efficacy of novel inflammatory therapeutics, their mode of action and to further investigate the mechanisms that underpin disease progression of intraocular disorders.

Adhesion Molecule Targeted Therapy for Non-Infectious Uveitis.

Non-infectious uveitis (NIU) is an inflammatory eye disease initiated via CD4 T-cell activation and transmigration, resulting in focal retinal tissue damage and visual acuity disturbance. Cell adhesion molecules (CAMs) are activated during the inflammatory process to facilitate the leukocyte recruitment cascade. Our review focused on CAM-targeted therapies in experimental autoimmune uveitis (EAU) and NIU.

CD4 T-Cell Plasticity in Non-Infectious Retinal Inflammatory Disease.

Non-infectious uveitis (NIU) is a potentially sight-threatening disease. Effector CD4 T cells, especially interferon-γ-(IFNγ) producing Th1 cells and interleukin-17-(IL-17) producing Th17 cells, are the major immunopathogenic cells, as demonstrated by adoptive transfer of disease in a model of experimental autoimmune uveitis (EAU). CD4FoxP3CD25 regulatory T cells (Tregs) were known to suppress function of effector CD4 T cells and contribute to resolution of disease.

Innate and Adaptive Gene Single Nucleotide Polymorphisms Associated With Susceptibility of Severe Inflammatory Complications in Acanthamoeba Keratitis.

Purpose: Over a third of patients with Acanthamoeba keratitis (AK) experience severe inflammatory complications (SICs). This study aimed to determine if some contact lens (CL) wearers with AK were predisposed to SICs due to variations in key immune genes.

Methods: CL wearers with AK who attended Moorfields Eye Hospital were recruited prospectively between April 2013 and October 2014.

Immune-Mediated Retinal Vasculitis in Posterior Uveitis and Experimental Models: The Leukotriene (LT)B4-VEGF Axis.

Retinal vascular diseases have distinct, complex and multifactorial pathogeneses yet share several key pathophysiological aspects including inflammation, vascular permeability and neovascularisation. In non-infectious posterior uveitis (NIU), retinal vasculitis involves vessel leakage leading to retinal enlargement, exudation, and macular oedema. Neovascularisation is not a common feature in NIU, however, detection of the major angiogenic factor-vascular endothelial growth factor A (VEGF-A)-in intraocular fluids in animal models of uveitis may be an indication for a role for this cytokine in a highly inflammatory condition.

Small-molecule antagonist of VLA-4 (GW559090) attenuated neuro-inflammation by targeting Th17 cell trafficking across the blood-retinal barrier in experimental autoimmune uveitis.

Background: The integrin VLA-4 (α4β1) plays an important role in leukocyte trafficking. This study investigated the efficacy of a novel topical α4β1 integrin inhibitor (GW559090, GW) in a mouse model for non-infectious posterior uveitis (experimental autoimmune uveitis; EAU) and its effect on intraocular leukocyte subsets.

Methods: Mice (female; B10.

Leukotriene B and Its Receptor in Experimental Autoimmune Uveitis and in Human Retinal Tissues: Clinical Severity and LTB Dependence of Retinal Th17 Cells.

Nomacopan, a drug originally derived from tick saliva, has dual functions of sequestering leukotriene B (LTB) and inhibiting complement component 5 (C5) activation. Nomacopan has been shown to provide therapeutic benefit in experimental autoimmune uveitis (EAU). Longer acting forms of nomacopan were more efficacious in mouse EAU models, and the long-acting variant that inhibited only LTB was at least as effective as the long-acting variant that inhibited both C5 and LTB, preventing structural damage to the retina and a significantly reducing effector T helper 17 cells and inflammatory macrophages.

Functionally distinct IFN-γ IL-17A Th cells in experimental autoimmune uveitis: T-cell heterogeneity, migration, and steroid response.

Immunopathogenic roles for both Th1 (CD4 IFN-γ ) and Th17 (CD4 IL-17A ) cells have been demonstrated in experimental autoimmune uveitis (EAU). However, the role for Th17/Th1 (CD4 T cells co-expressing IFN-γ and IL-17A) cells in EAU is not yet understood. Using interphotoreceptor retinoid-binding protein peptide-induced EAU in mice, we found increased levels of Th17/Th1 cells in EAU retinae (mean 9.

Association study of single nucleotide polymorphisms in IL-10 and IL-17 genes with the severity of microbial keratitis.

Purpose: Exploratory analysis to assess the association of single nucleotide polymorphisms (SNPs) in the interleukin (IL) 10 and IL-17 genes with severity of contact lens keratitis.

Methods: This was a retrospective case control study of 88 contact lens keratitis cases (25 severe) and 185 healthy contact lens wearers recruited from studies conducted at Moorfields Eye Hospital and in Australia-wide during 2003-2005. Buccal swab samples were collected on Whatman FTA cards and mailed by post for DNA extraction and SNP genotyping.

Automated Ocular Surface Image Analysis and Health-Related Quality of Life Utility Tool to Measure Blepharokeratoconjunctivitis Activity in Children.

Purpose: To explore the tolerability of automated conjunctival hyperemia quantification in children with blepharokeratoconjunctivitis (BKC) and its agreement with clinical activity grading and to explore the Children's Health Utility 9D (CHU9D) as a measure of health-related quality of life in children with BKC.

Methods: We enrolled 63 children, 31 with BKC and 32 without ocular surface inflammation, with a median [interquartile range (IQR)] age of 10.6 (7.

Meibography and corneal volume optical coherence tomography to quantify damage to ocular structures in children with blepharokeratoconjunctivitis.

Purpose: To evaluate non-contact infrared meibography and anterior segment optical coherence tomography (AS-OCT) to detect meibomian gland (MG) and corneal changes in children with blepharokeratoconjunctivitis (BKC).

Methods: We acquired infrared meibography images of upper and lower lids and AS-OCT corneal scans. One masked observer graded meiboscore, full/partial MG dropout, and measured total corneal volume and differential corneal volume per quadrant and central corneal thickness (CCT).

Management of ocular allergy.

The treatment and management of ocular allergy (OA) remain a major concern for different specialties, including allergists, ophthalmologists, primary care physicians, rhinologists, pediatricians, dermatologists, clinical immunologists, and pharmacists. We performed a systematic review of all relevant publications in MEDLINE, Scopus, and Web Science including systematic reviews and meta-analysis. Publications were considered relevant if they addressed treatments, or management strategies of OA.

A Review of the Cytokine IL-17 in Ocular Surface and Corneal Disease.

To investigate the role of interleukin-17 in ocular surface and corneal disease. Ocular surface and corneal disease is a leading cause of blindness and is an ongoing challenge for the public health sector to implement effective therapies. The majority of cells in corneal lesions are derived primarily from neutrophils that induce inflammatory events that lead to tissue damage.

Clinical Remission of Sight-Threatening Non-Infectious Uveitis Is Characterized by an Upregulation of Peripheral T-Regulatory Cell Polarized Towards T-bet and TIGIT.

Background: Non-infectious uveitis can cause chronic relapsing and remitting ocular inflammation, which may require high dose systemic immunosuppression to prevent severe sight loss. It has been classically described as an autoimmune disease, mediated by pro-inflammatory Th1 and Th17 T-cell subsets. Studies suggest that natural immunosuppressive CD4CD25FoxP3 T-regulatory cells (Tregs) are involved in resolution of inflammation and may be involved in the maintenance of clinical remission.

Severity, therapeutic, and activity tear biomarkers in dry eye disease: An analysis from a phase III clinical trial.

Purpose: To evaluate the effect of 0.1%-fluorometholone (FML) on tear inflammatory molecule levels after 22-days treatment in dry eye disease (DED) patients exposed to an adverse controlled environment (ACE), identifying different biomarkers.

Methods: Analysis of a double-masked randomized clinical trial.

Tear Cytokine Levels in Contact Lens Wearers With Acanthamoeba Keratitis.

Purpose: To determine differences in key tear film cytokines between mild and severe cases of acanthamoeba keratitis (AK) and control contact lens (CL) wearers.

Methods: This was a prospective study of CL wearers with AK attending Moorfields Eye Hospital and control CL wearers from the Institute of Optometry, London. Basal tear specimens were collected by 10-μL capillary tubes (BLAUBRAND intraMark, Wertheim, Germany), and tear protein levels were measured with a multiplex magnetic bead array (Luminex 100; Luminex Corporation, Austin, TX) for cytokines interleukin (IL)-1β, IL-6, IL-8, IL-10, IL-17A, IL-17E, IL-17F, IL-22, and interferon gamma and with enzyme-linked immunosorbent assay (Abcam, Cambridge, United Kingdom) for CXCL2.

Diagnostic tools in ocular allergy.

Ocular allergy (OA) includes a group of common and less frequent hypersensitivity disorders frequently misdiagnosed and not properly managed. The diagnosis of OA is usually based on clinical history and signs and symptoms, with the support of in vivo and in vitro tests when identification of the specific allergen is required. To date, no specific test is available for the diagnosis of the whole spectrum of the different forms of OA.

Pharmacological Inhibition of Bromodomain Proteins Suppresses Retinal Inflammatory Disease and Downregulates Retinal Th17 Cells.

Experimental autoimmune uveitis (EAU), in which CD4 Th1 and/or Th17 cells are immunopathogenic, mimics various clinical features of noninfectious uveitis in humans. The impact of bromodomain extraterminal (BET) inhibitors on Th17 cell function was studied in a mouse model of EAU in vivo and in mouse and human Th17 cells in vitro. Two BET inhibitors (GSK151 and JQ1) were able to ameliorate the progression of inflammation in EAU and in mouse CD4 T cells in vitro, downregulating levels of Th17 cells.