Investigating lymphoid-like structures in the pathogenesis of Multiple Sclerosis

Abstract

Multiple Sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the central nervous system (CNS). Symptoms of MS include focal neurological deficits such as motor weakness or paralysis, sensory alteration or loss, visual disturbances, urinary problems, vestibular symptoms such as dizziness and vertigo, fatigue, depression, and cognitive defects. The median age of diagnosis is 33, striking young adults in the prime of their lives and usually causes permanent disability. The cause of MS is unknown. Epidemiological data suggest combined genetic and environmental factors with a prominent immunological component. Whilst the development of disease-modifying therapies (DMTs) for the relapsing-remitting form of MS (RRMS) has continued at pace, all but two of these drugs have failed in progressive MS trials. Furthermore, it is difficult to predict which patients may get a higher disease burden or when they may develop progressive disease. Progressive MS is characterised by continual accrual of permanent disability, thus, therapies to slow, halt or reverse disease progression are urgently needed. Understanding the immunological differences in different types of MS, and different phases of disease pathogenesis, will support efforts to develop such therapies and better biomarkers for disease prognostication.

A hallmark of progressive MS is accumulating neurodegeneration and cortical demyelination, which are related to the extent of overlying meningeal inflammation. Extensive immune infiltrates, termed lymphoid-like structures (LLS) are observed in many progressive MS cases at post mortem. Cases harbouring LLS exhibit greater parenchymal inflammation, demyelination and a gradient of neurodegeneration, which is greatest in superficial layers of the cortex nearest the pial surface. Importantly, post-mortem studies have shown that the presence of LLS and the relative grade of meningeal lymphoid aggregate correlates with clinical disease severity. Post-mortem cases that have LLS experience earlier transition to progressive MS, become substantially disabled sooner and die following a shorter disease duration and at a younger age. The molecular profiles of LLS are unclear and it is not known whether molecular and immune profiles of LLS are distinct in different CNS compartments that harbour inflammatory cells. This work aims to determine if LLS have distinct molecular and cellular profiles compared to other sites of nested inflammation. Furthermore identification of immune signatures of LLS could be valuable predictors of disease outcome.

These studies identified additional LLS+ cases in an archived post-mortem MS tissue collection (the Dame Ingrid Allen (DIA) tissue collection). Neuropathological characterisation of the DIA cohort found that higher degrees of meningeal inflammation and the presence of LLS were associated with poorer clinical outcomes (earlier time to death and younger age at death) and a trend of greater extent of grey matter demyelination. These studies revealed a novel finding of IGHG3 and IGHG4 as highest expressed genes in LLS. IgG3 and IgG4 profiles were found to be similar across CNS inflammatory compartments. The majority of IgG3 expressing cells in LLS were germinal centre B cells or plasma cells, indicating that LLS could be a potential source of IgG3 in the CNS. Finally, there was a trend of higher IgG3 levels in the cerebrospinal fluid of patients that developed secondary progressive MS. This suggests that distinctions in IgG3 profiles may exist in patients at greater risk of developing progressive MS.

Date of Award	Dec 2023
Original language	English
Awarding Institution	Queen's University Belfast
Sponsors	Northern Ireland Public Health Agency
Supervisor	Denise Fitzgerald (Supervisor), Gavin McDonnell (Supervisor) & Owain W Howell (Supervisor)