Biology subjects

Dick, A. D.

Publications and source records attributed to Dick, A. D..

8 recordsLinked to original sources

bioRxiv2026

Inflammatory arthritis disrupts ocular immune privilege by compromising blood-retinal barrier integrity and promoting uveitogenic T cell recruitment

Inflammatory arthritis and uveitis frequently co-exist, yet the mechanisms linking joint and ocular inflammation remain ill-defined. Here, we investigated how inflammatory arthritis influences ocular immune homeostasis using murine models of antigen-induced arthritis and collagen-induced arthritis. Arthritis promoted the accumulation of T cells, myeloid cells, and neutrophils within the vitreoretinal compartment, without progression to overt clinical uveitis. Ocular leukocyte recruitment was dynamically coupled to arthritis activity, resolving with remission of joint inflammation and recurring during arthritic flares. The magnitude of ocular immune perturbation correlated with arthritis severity, being enhanced in IL-27R-deficient mice and markedly reduced in IL-6R-deficient mice. Mechanistically, arthritis increased blood-retinal barrier permeability, demonstrating that systemic inflammation perturbs ocular immune privilege even in the absence of apparent ocular disease. While arthritis alone was insufficient to induce uveitis, it established a permissive ocular microenvironment that selectively enhanced the recruitment of adoptively transferred uveitogenic CD4+ T cells. These findings identify inflammatory arthritis as a systemic driver of subclinical ocular immune dysregulation and reveal a mechanism by which inflammation at a distant site may promote vulnerability to ocular autoimmunity. These data provide a framework for understanding immune dysregulation at the joint-eye axis and highlight cytokine pathways that may be targeted to preserve ocular immune homeostasis.

immunology↗

bioRxiv2025

A pathogenic CD4 T cell phenotype in experimental uveitis shares common features with other immune mediated inflammatory

Murine ocular autoimmunity develops through 3 stages; prodrome, primary peak and secondary regulation. During the prodromal phase, leukocytes accumulate within the retina and vitreous. Using the adoptive transfer model of experimental autoimmune uveitis, we can analyse the disease course by tracking the transferred cells during disease initiation being recruited to the ocular environment throughout peak of disease to secondary regulation. During initiation (the prodrome) of disease pathogenic transferred CD4+ T cells can be detected within the retina as well as an endogenous CD4+ infiltrate and as disease reaches peak, both transferred and endogenous CD4+ T cells can be found in large numbers in the retina. Active clinical disease resolves by day 21 but transferred CD4+ T cells persist within the retina when disease is in a clinically quiescent state. Concurrent transfer of RBP3 specific and OVA specific activated cells induces a similar clinical disease phenotype and time course. Both RBP3 and OVA specific cells are recruited during active clinical disease in equal measure showing that autoantigen specific CD4+ T cells induce susceptibility for recruitment of other activated CD4+ T cells. When analysing the endogenous and transferred CD4+ T cells by RNA sequencing, differences between the two sets of gene signatures highlight genes found in pathogenic T cells in other models, including upregulation of markers associated with cytokine interactions and NK cell mediated cytotoxicity. Due to the persistence of the original transferred population throughout clinical disease, in depth analysis of this population could suggest pathways contributing to ocular autoimmunity.

immunology↗

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↗

bioRxiv2025

Age-Associated Decline in Autophagy Pathways in Retinal Pigment Epithelium and Protective Effects of Topical Trehalose in Light-induced Outer Retinal Degeneration in Mice

Age is a primary risk factor for chronic conditions, including age-related macular degeneration (AMD). Impairments in autophagy processes are implicated in AMD progression, but the extent of autophagys contribution and its therapeutic potential remain ambiguous. This study investigated age-associated transcriptomic changes in autophagy pathways in the retinal pigment epithelium (RPE) and evaluated the protective effects of topical trehalose, an autophagy-enhancing small molecule, against light-induced outer retinal degeneration in mice. Transcriptomic analysis of human RPE/choroid and mouse RPE revealed consistent downregulation of autophagy pathways with age, alongside variable changes as AMD severity progressed. Given the age- and AMD-associated perturbation of autophagy pathways, we examined trehalose treatment in vitro, which enhanced autophagic flux and restored mitochondrial respiratory function in primary murine RPE cells exposed to oxidative stress. In vivo, topical trehalose improved autophagy-lysosome activity in mouse RPE, demonstrated by elevated LC3B turnover and SQSTM1/p62 degradation. Furthermore, trehalose eyedrops protected mice from light-induced damage to the RPE and photoreceptors, preserving outer nuclear layer thickness, RPE morphology, and junctional F-actin organization. Taken together, the data support that age-related decline and severe dysregulation in autophagy contributed to AMD progression. By restoring autophagic flux, topical trehalose demonstrates therapeutic potential to address early autophagy-related pathological changes in AMD.

pathology↗

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↗

bioRxiv2023

Replenishing Age-Related Decline of IRAK-M Expression in Retinal Pigment Epithelium Attenuates Outer Retinal Degeneration

Unchecked, chronic inflammation is a constitutive component of age-related diseases, including age-related macular degeneration (AMD). Here we identified interleukin-1 receptor-associated kinase (IRAK)-M as a key immunoregulator in retinal pigment epithelium (RPE) that declines with age. Rare genetic variants of IRAK-M increased the likelihood of AMD. IRAK-M expression in RPE declined with age or oxidative stress and was further reduced in AMD. IRAK-M-deficient mice exhibited increased incidence of outer retinal degeneration at earlier ages, which was further exacerbated by oxidative stressors. The absence of IRAK-M disrupted RPE cell homeostasis, including compromised mitochondrial function, cellular senescence, and aberrant cytokine production. IRAK-M overexpression protected RPE cells against oxidative or immune stressors. Subretinal delivery of AAV-expressing IRAK-M rescued light-induced outer retinal degeneration in wild-type mice and attenuated age-related spontaneous retinal degeneration in IRAK-M- deficient mice. Our data support that replenishment of IRAK-M expression may redress dysregulated pro-inflammatory processes in AMD, thereby treating degeneration. One Sentence SummaryIRAK-M is a protective molecule and promising therapeutic target for macular degeneration

immunology↗

bioRxiv2021

Interleukin-33 regulates metabolic reprogramming of the retinal pigment epithelium in response to immune stressors.

It remains unresolved how retinal pigment epithelial (RPE) cell metabolism is regulated following immune activation to maintain retinal homeostasis and retinal function. We exposed RPE to several stress signals, particularly toll-like receptor stimulation, and uncovered an ability of RPE to adapt their metabolic preference on aerobic glycolysis or oxidative glucose metabolism in response to different immune stimuli. We have identified interleukin-33 (IL-33) as a key metabolic checkpoint that antagonises the Warburg effect to ensure the functional stability of the RPE. The identification of IL-33 as a key regulator of mitochondrial metabolism suggests roles for the cytokine that go beyond its extracellular "alarmin" activities. IL-33 exerts control over mitochondrial respiration in RPE by facilitating oxidative pyruvate catabolism. We have also revealed that in the absence of IL-33, mitochondrial function declines and resultant bioenergetic switching is aligned with altered mitochondrial morphology. Our data not only sheds new light in the molecular pathway of activation of mitochondrial respiration in RPE in response to immune stressors, but also uncovers a novel role of nuclear intrinsic IL-33 as a metabolic checkpoint regulator.

immunology↗

bioRxiv2019

Intravenous indocyanine green dye is insufficient for robust immune cell labelling in the human retina

It is not currently possible to reliably visualise and track immune cells in the human central nervous system or eye. Previous work demonstrated that indocyanine green (ICG) dye could label immune cells and be imaged after a delay during disease in the mouse retina. We report a pilot study investigating if ICG can similarly label immune cells within the human retina. Twelve adult participants receiving ICG angiography as part of routine standard of care were recruited. Baseline retinal images were obtained prior to ICG administration then repeated over a period ranging from 2 hours to 9 days. Matched peripheral blood samples, in addition to human and mouse macrophage cultures as controls, were analysed by flow cytometry. Differences between the delayed near infrared ICG imaging and 488 nm autofluorescence was observed across pathologies, likely arising from the retinal pigment epithelium (RPE). Only one subject demonstrated ICG signal on peripheral blood myeloid cells and only three distinct cell-sized signals appeared over time within the retina of three participants. No significant increase in immune cell activation markers were detected after ICG administration. ICG accumulated in the endosomes of macrophage cultures and was detectable above a minimum concentration, suggesting cell labelling is possible. ICG can label RPE and may be used as an additional biomarker for cell health across a range of retinal disorders. Standard clinical doses of intravenous ICG do not lead to robust immune cell labelling in human blood or retina and further optimisation in dose and route are required.

immunology↗