Biology subjects

Coupland, S. E.

Publications and source records attributed to Coupland, S. E..

6 recordsLinked to original sources

bioRxiv2025

Tissue resident memory T cells populate the human uveal tract

The current concept is that the eye is an immune privileged site endowed with innate immune regulatory networks to maintain organ function. We now have evidence that resident T cells occupy intraocular tissues. In immune-mediated inflammatory diseases, such as psoriasis and rheumatoid arthritis, tissue resident T cells trigger disease flares in the skin and joints. This suggests resident T cells in the uvea may have similar functions in non-infectious immune-mediated uveitis, a collective term for autoinflammatory and autoimmune diseases of the uveal tract causing intraocular inflammation. Here, we demonstrate by spectral cytometry and immunofluorescence imaging that non-inflamed uveal tissue contains multiple T cell subtypes including CD8+ CD103+ tissue resident memory T (TRM) cells. Using single cell RNA & T cell receptor (TCR) sequencing to profile aqueous humour cells from donors with acute, active uveitis, we identify clonally expanded T cells which are enriched for TRM -associated genes. We further show that in donors with active uveitis, CD8+ CD103+ T cells persist within tissue in the uveal tract. Using bulk RNA sequencing and weighted gene co-expression network analysis (WGCNA) we show that quiescent iris tissue from donors with a history of uveitis are enriched for genes associated with T cell activation and antigen presentation. Finally, we demonstrate that TRM cells persist in the anterior uvea in mice following resolution of experimental autoimmune uveoretinitis (EAU). Our results show that the human eye contains T cells both in health and during active inflammation. Our findings challenge the dogma that the eye is devoid of lymphocytes and supports the concept of resident T cell involvement in the pathogenesis of non-infectious immune-mediated uveitis and as promising targets for therapy. One Sentence SummaryT cells infiltrate aqueous humour during intraocular inflammation and have capacity to migrate into uveal tissue where they remain long-lived.

immunology↗

bioRxiv2024

IL-23 drives uveitis by acting on a novel population of tissue-resident entheseal T cells

Recurrent acute anterior uveitis is a frequent extra-articular manifestation of the axial spondyloarthropathies (AxSpA); chronic inflammatory diseases affecting the spine, enthesis, peripheral joints, skin, and gastrointestinal tract. Pathology in AxSpA has been associated with local tissue-resident populations of interleukin (IL)-23 responsive lymphoid cells. Here we reveal a novel population of ocular T cells defined by CD3+CD4-CD8-{gamma}{delta}TCR+IL-23R+ that reside within the anterior uvea as an ocular entheseal analogue of the mouse eye. Localised cytokine expression demonstrates that uveal IL-23R+ IL-17A-producing cells are both necessary and sufficient to drive uveitis in response to IL-23. This T cell population is also present in humans, occupying extravascular tissues of the anterior uveal compartment. Consistent with the concept of IL-23 as a unifying mediator in AxSpA, we present evidence that IL-23 can also act locally on tissue resident T cells in the anterior compartment of the eye at sites analogous to the enthesis to drive ocular inflammation.

immunology↗

bioRxiv2021

Patient-derived zebrafish xenograft models reveal ferroptosis as a fatal and druggable weakness in metastatic uveal melanoma

Uveal melanoma (UM) is the most common intraocular melanoma, derived from transformed melanocytes of the uvea. Although treatment of primary UM is usually successful, there is a high risk (up to 50%) of liver metastasis with negligible long-term survival. There are currently no reproducible patient-derived animal models that faithfully recapitulate the latter stages of metastatic dissemination of UM, hindering the discovery of curative treatments. To overcome this problem and to accelerate the development of new metastatic UM treatments, we developed a patient-derived zebrafish xenograft (zf-PDX) model, using spheroid cultures generated from metastatic and primary UM tissues. Engrafted UM cells derived from these spheroid cultures give rise to metastatic lesions and recapitulate the molecular features of UMs and their potential drug sensitivity. Importantly, harnessing this versatile model, we reveal a high sensitivity of circulating UM cells to ferroptosis induction in vivo by Erastin and RSL3. Our findings are further corroborated by supportive analysis of patient data implicating ferroptosis as a new, and druggable, target for the treatment of metastatic UM patients, specifically in those with BAP1 loss in the tumor.

cancer biology↗

bioRxiv2020

High Cysteinyl Leukotriene Receptor 1 Expression Correlates with Poor Survival of Uveal Melanoma Patients and Cognate Antagonist Drugs Modulate the Growth, Cancer Secretome, and Metabolism of Uveal Melanoma Cells.

Uveal melanoma (UM) is a rare, but often lethal, form of ocular cancer arising from melanocytes within the uveal tract. UM has a high propensity to spread hematogenously to the liver, with up to 50% of patients developing liver metastases. Unfortunately, once liver metastasis occurs, patient prognosis is extremely poor with as few as 8% of patients surviving beyond two years. There are no standard-of-care therapies available for the treatment of metastatic uveal melanoma, hence it is a clinical area of urgent unmet need. Here, the clinical relevance and therapeutic potential of cysteinyl leukotriene receptors (CysLT1 and CysLT2) in UM was evaluated. High expression of CYSLTR1 or CYSLTR2 transcripts is significantly associated with poor disease-free survival and poor overall survival in UM patients. Digital pathology analysis identified high expression of CysLT1 in primary UM is associated with reduced disease-specific survival (p = 0.012) and overall survival (p = 0.011). High CysLT1 expression shows a statistically significant (p = 0.041) correlation with ciliary body involvement, a poor prognostic indicator in UM. Small molecule drugs targeting CysLT1 were vastly superior at exerting anti-cancer phenotypes in UM cell lines and zebrafish xenografts than drugs targeting CysLT2. Quininib, a selective CysLT1 antagonist, significantly inhibits survival (p < 0.0001), long-term proliferation (p < 0.0001), and oxidative phosphorylation (p < 0.001), but not glycolysis, in primary and metastatic UM cell lines. Quininib exerts opposing effects on the secretion of inflammatory markers in primary versus metastatic UM cell lines. Quininib significantly downregulated IL-2 and IL-6 in Mel285 cells (p < 0.05), but significantly upregulated IL-10, IL-1{beta}, IL-2 (p < 0.0001), IL-13, IL-8 (p < 0.001), IL-12p70 and IL-6 (p < 0.05) in OMM2.5 cells. Finally, quininib significantly inhibits tumour growth in orthotopic zebrafish xenograft models of UM. These preclinical data suggest that antagonism of CysLT1, but not CysLT2, may be of therapeutic interest in the treatment of UM.

cancer biology↗

bioRxiv2019

Hepcidin and conventional markers to detect iron deficiency in severely anaemic HIV-infected patients in Malawi.

IntroductionIron deficiency is a treatable cause of severe anaemia in low-and-middle-income-countries (LMIC). Diagnosing it remains challenging as peripheral blood markers poorly reflect bone-marrow iron deficiency (BM-ID), especially in the context of HIV-infection.\n\nMethodsSevere anaemic (haemoglobin [≤]70g/l) HIV-infected adults were recruited at Queen Elizabeth Central Hospital, Blantyre, Malawi. BM-ID was evaluated. Accuracy of blood markers including hepcidin alongside mean corpuscular volume, mean cellular haemoglobin concentration, serum iron, serum ferritin, soluble transferrin receptor (sTfR), sTfR -index, sTfR-ratio to detect BM-ID was valued by ROC area under the curve (AUCROC).\n\nResultsSeventy-three patients were enrolled and 35 (48.0%) had BM-ID. Hepcidin and MCV performed best; AUCROC of 0.593 and 0.545. Other markers performed poorly (ROC<0.5). The AUCROC of hepcidin in males was 0.767 (sensitivity 80%, specificity 78%) and in women 0.490 (sensitivity 60%, specificity 61%).\n\nConclusionBM-ID deficiency was common in severely anaemic HIV-infected patients and is an important and potential treatable contributor to severe anaemia. Hepcidin was the best, though still suboptimal, marker of BM-ID. Hepcidin, which is directly linked to iron absorption, is a very promising marker to guide curative iron supplementation policies in severely anaemic HIV-infected patients.

biochemistry↗

bioRxiv2019

Severe anaemia complicating HIV in Malawi; multiple co-existing aetiologies are associated with high mortality.

BackgroundSevere anaemia is a major cause of morbidity and mortality in HIV-infected adults living in resource-limited countries. Comprehensive data on the aetiology is lacking and needed to improve outcomes.\n\nMethodsHIV-infected adults with severe (haemoglobin [≤]70g/l) or very severe anaemia (haemoglobin [≤]50 g/l) were recruited at Queen Elizabeth Central Hospital, Blantyre, Malawi. Fifteen potential causes of severe anaemia of anaemia and associations with anaemia severity and mortality were explored.\n\nResults199 patients were enrolled: 42.2% had very severe anaemia and 45.7% were on ART. Over two potential causes for anaemia were present in 94% of the patients; including iron deficiency (55.3%), underweight (BMI<20: 49.7%), TB-infection (41.2%) and unsuppressed HIV-infection (viral load >1000 copies/ml) (73.9%). EBV/CMV co-infection (16.5%) was associated with very severe anaemia (OR 2.8 95% CI 1.1-6.9). Overall mortality was high (53%; 100/199) with a median time to death of 16 days. Death was associated with folate deficiency (HR 2.2; 95% CI 1.2-3.8) and end stage renal disease (HR 3.2; 95% CI 1.6-6.2).\n\nConclusionMortality among severely anaemic HIV-infected adults is strikingly high. Clinicians must be aware of the urgent need for a multifactorial approach, including starting or optimising HIV treatment; considering TB treatment, nutritional support and attention to potential renal impairment.

immunology↗