Biology subjects

Fitzgerald, D. C.

Publications and source records attributed to Fitzgerald, D. C..

3 recordsLinked to original sources

bioRxiv2025

Spatial transcriptomics of compartmentalised inflammation in a natural disease multiple sclerosis cohort.

Compartmentalised inflammation is a poorly understood aspect of multiple sclerosis (MS) that is associated with worse outcomes and represents an important therapeutic target. To gain deeper insight into compartmentalised inflammation, we have taken the approach of digital spatial profiling of the whole human transcriptome in areas of perivascular and meningeal inflammation and tertiary lymphoid-like structures (TLS) in MS central nervous system tissue. Critically, we had access to rare archival tissue obtained before the era of disease-modifying therapies, representing a natural history of disease. This analysis has identified differentially expressed genes in TLS compared to meningeal or perivascular inflammation. Pathway analysis highlighted that TLS signalling is dominated by B cell activity including active antibody secretion. Our data demonstrated the diversity of immunoglobulins and the prominence of IgG3- and IgG4-secreting cells in TLS. Intriguingly, pathway analysis suggests TLS may be hubs for viral (re)activation which warrants further investigation. These findings provide insight into the function of TLS in MS disease pathogenesis and reveal unique immune signatures that may support biomarker development to predict which patients harbour TLS in life.

neuroscience↗

bioRxiv2023

Regulatory T cells limit age-associated retinal inflammation and neurodegeneration

Aging is the principal risk factor for retinal degenerative diseases, which are the commonest cause of blindness in the developed countries. These conditions include age-related macular degeneration or diabetic retinopathy. Regulatory T cells play a vital role in immunoregulation of the nervous system by limiting inflammation and tissue damage in health and disease. Because the retina was long-considered an immunoprivileged site, the precise contribution of regulatory T cells in retinal homeostasis and in age-related retinal diseases remains unknown. Our study shows that regulatory T cell elimination leads to retinal pigment epithelium cell dysmorphology, and accumulation of phagocytes in the subretinal space of young and aged mice. However, only aged mice experience retinal neurodegeneration and gliosis. Surprisingly, adoptive transfer of young but not aged regulatory T cells reverse these changes. This study reveals a previously unknown protective role of regulatory T cells in maintaining aged retinal homeostasis.

neuroscience↗

bioRxiv2023

Ageing impairs the regenerative capacity of regulatory T cells in central nervous system remyelination

Myelin regeneration (remyelination) is essential to prevent neurodegeneration in demyelinating diseases such as Multiple Sclerosis, however, its efficiency declines with age. Regulatory T cells (Treg) recently emerged as critical players in tissue regeneration, including remyelination. However, the effect of ageing on Treg-mediated regenerative processes is poorly understood. Here, we show that expansion of aged Treg does not rescue age-associated remyelination impairment due to an intrinsically diminished capacity of aged Treg to promote oligodendrocyte differentiation and myelination. This decline in regenerative Treg functions can be rescued by a young environment. We identified Melanoma Cell Adhesion Molecule 1 (MCAM1) and Integrin alpha 2 (ITGA2) as novel candidates of Treg-mediated oligodendrocyte differentiation that decrease with age. Our findings demonstrate that ageing limits the neuroregenerative capacity of Treg, likely limiting their remyelinating therapeutic potential in aged patients, and describe two novel mechanisms implicated in Treg-driven remyelination that may be targetable to overcome this limitation.

neuroscience↗