Disease Aggravation With Age in an Experimental Model of Multiple Sclerosis: Role of Immunosenescence

Abstract

Adaptive immunity; Experimental autoimmune encephalomyelitis; Neurodegeneration

Immunitat adaptativa; Encefalomielitis autoimmune experimental; Neurodegeneració

Inmunidad adaptativa; Encefalomielitis autoinmune experimental; Neurodegeneración

The onset of multiple sclerosis (MS) in older individuals correlates with a higher risk of developing primary progressive MS, faster progression to secondary progressive MS, and increased disability accumulation. This phenomenon can be related to age-related changes in the immune system: with age, the immune system undergoes a process called immunosenescence, characterized by a decline in the function of both the innate and adaptive immune responses. This decline can lead to a decreased ability to control inflammation and repair damaged tissue. Additionally, older individuals often experience a shift toward a more pro-inflammatory state, known as inflammaging, which can exacerbate the progression of neurodegenerative diseases like MS. Therefore, age-related alterations in the immune system could be responsible for the difference in the phenotype of MS observed in older and younger patients. In this study, we investigated the effects of age on the immunopathogenesis of experimental autoimmune encephalomyelitis (EAE). Our findings indicate that EAE is more severe in aged mice due to a more inflammatory and neurodegenerative environment in the central nervous system. Age-related changes predominantly affect adaptive immunity, characterized by altered T cell ratios, a pro-inflammatory Th1 response, increased regulatory T cells, exhaustion of T cells, altered B cell antigen presentation, and reduced NK cell maturation and cytotoxicity. Transcriptomic analysis reveals that fewer pathways and transcription factors are activated with age in EAE. These findings allow us to identify potential therapeutic targets specific to elderly MS patients and work on their development in the future.

This work was supported by the Fondo de Investigaciónes Sanitarias, Instituto de Salud Carlos III, and co-funded by the European Union (European Regional Development Fund/European Social Fund), “A way to build Europe”, under Grant PI18/01146 and the “Agència de Gestió d'Ajuts Universitaris i de Recerca” (AGAUR; Generalitat de Catalunya) under Grant 2021SGR782.