Pathological mechanism of secondary-progressive multiples sclerosis and its animal model

Area of Science:

• Immunology
• Neuroscience
• Molecular Biology

Background:

• Acute experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis (MS), is dependent on Th17 cells expressing nuclear factor NR4A2.
• NR4A2 is upregulated in T cells of MS patients.
• Late-onset EAE, independent of NR4A2, involves cytotoxic T-cell-like CD4+ T cells expressing Eomesodermin (Eomes).

Purpose of the Study:

• To investigate the role of NR4A2 and Eomesodermin (Eomes) in EAE pathogenesis.
• To identify pathogenic T cell subsets involved in late-onset EAE.
• To explore potential therapeutic targets for progressive MS.

Main Methods:

• Induction of EAE in wild-type and NR4A2-deficient mice.
• Genetic deletion of Eomes in T cells and in vivo RNA interference.
• Analysis of T cell populations in mouse models and MS patient samples (peripheral blood and cerebrospinal fluid).
• Mechanistic studies involving granzyme B and protease-activated receptor-1.

Main Results:

• Mice lacking NR4A2 in T cells showed reduced Th17-mediated acute EAE symptoms.
• Late-onset EAE, independent of NR4A2, was observed and ameliorated by deleting Eomes in T cells.
• Eomes-expressing CD4+ T cells were identified as pathogenic in late-onset EAE.
• Increased Eomes-expressing CD4+ T cells were found in patients with secondary-progressive MS, not relapsing-remitting MS.
• Granzyme B secretion by Eomes+ CD4+ T cells and its role in neuroinflammation via protease-activated receptor-1 were demonstrated.

Conclusions:

• NR4A2 is crucial for acute EAE, while Eomes-expressing CD4+ T cells mediate late-onset, potentially progressive, disease.
• Eomes-expressing CD4+ T cells and their associated inflammatory pathways represent a potential therapeutic target for neurodegenerative aspects of MS.
• The findings highlight distinct pathogenic mechanisms in different phases of EAE and MS.