Regulation of Dendritic cell function by the ocular microenvironment

The ocular microenvironment is immunosuppressive in animal models of antigen presenting cell function. My hypothesis was that in humans the normal ocular microenvironment maintains an immature dendritic cell (DC) phenotype, whereas in intraocular inflammation (uveitis) this regulation fails, permitting full DC maturation leading to the production and recruitment of pathogenic effector T cells to the eye. Using an in vitro model of DC function, I observed that non-inflammatory aqueous humour (AqH) inhibited DC maturation, with reduced MHC and CD86 expression, and reduced capacity to induce proliferation of allogeneic T cells, an effect which was cortisol and TGFβ2 dependent. In contrast, exposure to uveitis AqH generated a distinct DC profile with IFNγ dependent elevation of MHC class I, but reduced MHC class II and CD86 expression and impaired induction of T cell proliferation. Exposure to uveitis AqH from patients on topical glucocorticoid treatment caused additional suppression of CD86. Characterisation of ex vivo myeloid DC from patients with uveitis supported the findings of the in vitro model, with AqH-derived myeloid DC showing elevated MHC, but reduced CD86 expression. In summary human AqH is shown to be a powerful inhibitor of DC maturation, retaining this regulatory role during uveitis

Building trust in real-world data: lessons from INSIGHT, the UK's health data research hub for eye health and oculomics

PURPOSE OF REVIEW: In this review, we consider the challenges of creating a trusted resource for real-world data in ophthalmology, based on our experience of establishing INSIGHT, the UK's Health Data Research Hub for Eye Health and Oculomics. RECENT FINDINGS: The INSIGHT Health Data Research Hub maximizes the benefits and impact of historical, patient-level UK National Health Service (NHS) electronic health record data, including images, through making it research-ready including curation and anonymisation. It is built around a shared 'north star' of enabling research for patient benefit. INSIGHT has worked to establish patient and public trust in the concept and delivery of INSIGHT, with efficient and robust governance processes that support safe and secure access to data for researchers. By linking to systemic data, there is an opportunity for discovery of novel ophthalmic biomarkers of systemic diseases ('oculomics'). Datasets that provide a representation of the whole population are an important tool to address the increasingly recognized threat of health data poverty. SUMMARY: Enabling efficient, safe access to routinely collected clinical data is a substantial undertaking, especially when this includes imaging modalities, but provides an exceptional resource for research. Research and innovation built on inclusive real-world data is an important tool in ensuring that discoveries and technologies of the future may not only favour selected groups, but also work for all patients

Pharmacotherapy for uveitis: current management and emerging therapy.

Uveitis, a group of conditions characterized by intraocular inflammation, is a major cause of sight loss in the working population. Most uveitis seen in Western countries is noninfectious and appears to be autoimmune or autoinflammatory in nature, requiring treatment with immunosuppressive and/or anti-inflammatory drugs. In this educational review, we outline the ideal characteristics of drugs for uveitis and review the data to support the use of current and emerging therapies in this context. It is crucial that we continue to develop new therapies for use in uveitis that aim to suppress disease activity, prevent accumulation of damage, and preserve visual function for patients with the minimum possible side effects

Distinct Types of Fibrocyte Can Differentiate from Mononuclear Cells in the Presence and Absence of Serum

Background: Ageing, immunity and stresstolerance are inherent characteristics of all organisms. In animals, these traits are regulated, at least in part, by forkhead transcription factors in response to upstream signals from the Insulin/Insulin–like growth factor signalling (IIS) pathway. In the nematode Caenorhabditis elegans, these phenotypes are molecularly linked such that activation of the forkhead transcription factor DAF-16 both extends lifespan and simultaneously increases immunity and stress resistance. It is known that lifespan varies significantly among the Caenorhabditis species but, although DAF-16 signalling is highly conserved, it is unclear whether this phenotypic linkage occurs in other species. Here we investigate this phenotypic covariance by comparing longevity, stress resistance and immunity in four Caenorhabditis species. Methodology/Principal Findings: We show using phenotypic analysis of DAF-16 influenced phenotypes that among four closely related Caenorhabditis nematodes, the gonochoristic species (Caenorhabditis remanei and Caenorhabditis brenneri) have diverged significantly with a longer lifespan, improved stress resistance and higher immunity than the hermaphroditic species (C. elegans and Caenorhabditis briggsae). Interestingly, we also observe significant differences in expression levels between the daf-16 homologues in these species using Real-Time PCR, which positively correlate with the observed phenotypes. Finally, we provide additional evidence in support of a role for DAF-16 in regulating phenotypic coupling by using a combination of wildtype isolates, constitutively active daf-16 mutants and bioinformatic analysis. Conclusions: The gonochoristic species display a significantly longer lifespan (p<0.0001) and more robust immune and stress response (p<0.0001, thermal stress; p<0.01, heavy metal stress; p<0.0001, pathogenic stress) than the hermaphroditic species. Our data suggests that divergence in DAF-16 mediated phenotypes may underlie many of the differences observed between these four species of Caenorhabditis nematodes. These findings are further supported by the correlative higher daf-16 expression levels among the gonochoristic species and significantly higher lifespan, immunity and stress tolerance in the constitutively active daf-16 hermaphroditic mutants

Evidence-based practice in Behçet’s disease : identifying areas of unmet need for 2014

BACKGROUND: Behçet’s Disease (BD) is characterized by a relapsing-remitting course, with symptoms of varying severity across almost all organ systems. There is a diverse array of therapeutic options with no universally accepted treatment regime, and it is thus important that clinical practice is evidence-based. We reviewed all currently available literature describing management of BD, and investigated whether evidence-based practice is possible for all disease manifestations, and assessed the range of therapeutic options tested. METHODS: We conducted an internet search of all literature describing management of BD up to August 2013, including pharmacological and non-pharmacological interventions. We recorded treatment options investigated and disease manifestations reported as primary and secondary study outcomes. Quality of data was assessed according to the Scottish Intercollegiate Guideline Network (SIGN) hierarchy of evidence. RESULTS: Whilst there is much literature describing treatment of ocular and mucocutaneous disease, there is little to guide management of rheumatoid, cardiovascular and neurological disease. This broadly reflects the prevalence of disease manifestations of BD, but not the severity. Biologic therapies are the most commonly investigated intervention. The proportion of SIGN-1 graded studies is declining, and there are no SIGN-1 graded studies investigating neurological or gastrointestinal manifestations of BD. CONCLUSIONS: This is the first study to investigate trends in published literature for management of BD over time. It identifies neurological, cardiovascular and gastro-intestinal disease as particular areas of unmet need and suggests that overall quality of evidence is declining. Future research should be designed to address these areas of insufficiency to facilitate evidence-based practice in BD

Role of Dendritic Cell Subsets in Immunity and Their Contribution to Non-infectious Uveitis

Dendritic cells (DCs) are a heterogeneous population. Murine DCs consist of conventional DCs (cDCs) and plasmacytoid DCs (pDCs). In human, the analogous populations are myeloid DCs (mDCs) and pDCs. Though distinct in phenotypes and functions, studies have shown that these DC subsets may interact or ‘crosstalk’ during immune responses. For example, cDCs may facilitate pDC maturation, while pDCs may enhance antigen presentation of cDCs in certain pathogenic conditions or even take on a cDC phenotype themselves. The role of DCs in non-infectious uveitis has been studied primarily in the experimental autoimmune uveitis mouse model and to a more limited extent in patients. Recent evidence shows that the number, phenotype and function of DC subsets are altered in this disease. We provide an overview of selected recent developments of pDCs and cDCs/mDCs, with special attention to their interaction and the dual roles of DC subsets in non-infectious uveitis

Detection of branch retinal artery occlusions in Susac’s syndrome

BACKGROUND: We report an interesting case of asymptomatic retinal involvement in an encephalopathic patient enabling early identification of Susac’s syndrome. CASE PRESENTATION: A 39-year-old Caucasian lady with hearing loss and encephalopathy was referred for ophthalmic assessment, including screening for branch retinal artery occlusions characteristic of Susac’s syndrome. Clinical features included severe headaches, right-sided hypoacusis, dysphasia and poor memory. Routine blood tests were normal. MRI brain showed numerous hyperintense lesions mainly in corpus callosum. Although she was visually asymptomatic, dilated funduscopy detected bilateral multiple peripheral branch retinal artery occlusions which were confirmed on fluorescein angiography. She was subsequently started on intravenous steroids and pulsed cyclophosphamide which improved her symptoms within 48 hours. Full recovery was made with no new arterial occlusions on four months follow-up. CONCLUSION: The case further establishes the crucial role of a detailed ophthalmic examination supported by fluorescein angiography in the assessment of these patients, who are at risk of being misdiagnosed and undertreated

Association of sildenafil use with age-related macular degeneration:a retrospective cohort study

Objective: Despite significant advances in clinical care and understanding of the underlying pathophysiology, age-related macular degeneration (AMD)—a major cause of global blindness—lacks effective treatment to prevent the irreversible degeneration of photoreceptors leading to central vision loss. Limited studies suggest phosphodiesterase type 5 (PDE5) inhibitors, such as sildenafil, may prevent AMD by increasing retinal blood flow. This study explores the potential association between sildenafil use and AMD risk in men with erectile dysfunction using UK data. Methods and analysis: Using the UK’s IQVIA Medical Research Data, the study analysed 31 575 men prescribed sildenafil for erectile dysfunction and no AMD history from 2007 to 2015, matched with a comparator group of 62 155 non-sildenafil users in a 1:2 ratio, over a median follow-up of approximately three years. Results: The primary outcome was the incidence of AMD in the two groups. The study found no significant difference in AMD incidence between the sildenafil users and the non-users, with an adjusted hazard ratio (HR) of 0.99 (95% CI 0.84 to 1.16), after accounting for confounders such as age, ethnicity, Townsend deprivation quintile, body mass index category, and diagnosis of hypertension and type 2 diabetes. Conclusion: The study results indicated no significant association between sildenafil use and AMD prevention in UK men with erectile dysfunction, suggesting sildenafil’s protective effect on AMD is likely insignificant