Immunosenescence in multiple sclerosis: innate immunity as a possible therapeutic target

Abstract

Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating and neurodegenerative disease of the central nervous system (CNS). Although the aetiology remains unknown, ageing is a significant factor influencing the course of the disease. The debut of MS at an older age is associated with increased risk of presenting a primary progressive form, earlier conversion to the secondary progressive form and greater disability accumulation. However, there are no effective therapy options available that can stop disability accumulation in patients with progressive forms of the disease. Emerging data suggest that there is a premature ageing of the immune system, known as immunosenescence, in many autoimmune diseases, including MS. In addition, it is known that the progressive phase of MS is characterised by a compartmentalised immune response in the CNS, which suggests that the innate immunity could play a key role in the progressive forms of the disease. Herein, we characterised the impact of ageing on the immunopathogenesis of the well-established experimental model of MS, myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE). Clinical outcome of EAE was more severe with age, probably as a result of the more inflammatory and neurodegenerative environment found in the CNS. Underneath mechanisms revealed that the age-related peripheral immune response was mainly driven by adaptive immunity. This immune response was characterised by a shift in naïve/memory T cell ratio, a pro-inflammatory helper T (Th)1 skewed response, an increase in highly suppressive regulatory T (Treg) cells, immune checkpoint inhibitors and the capacity of B cells to present antigens. Concerning age-related changes in the innate immunity, most relevant changes included a decrease in natural killer (NK) cell maturation and cytotoxicity but enhanced degranulation. Splenocyte proliferative capacity was not altered, although cytokine production was enhanced after MOG stimulation. The transcriptomic analysis of the peripheral immune response reflected less pathways, protein interactions and transcription factors promoted with age in EAE. Considering that the innate immunity could play a key role in the chronic phase of the disease, we tested two different treatments targeting the innate immunity as potential therapies for elderly MS patients, specifically the inhibition of interleukin (IL)-1[Beta] and IL-6 signalling. Treatment with IL-1 receptor antagonist (IL-1Ra) did not improve the clinical outcome of either age, whereas treatment with anti-IL-6 antibody was able to promote the peripheral immunosuppressive response and slightly ameliorate the age-related clinical outcome. Taken together, in the present study we have conducted an exhaustive characterisation of the impact of ageing in the immune system in the context of EAE. Our results led to the identification of an age-associated transcriptomic profile and possible therapeutic targets in the early and late immune response, which contributes to a better understanding of the immunopathogenesis underlying progressive forms in elderly MS patients.

Date of Award	31 Oct 2023
Original language	English
Supervisor	Herena Eixarch Ahufinger (Director) & Carmen Espejo Ruiz (Director)