TNFR2 limits proinflammatory astrocyte functions during EAE induced by pathogenic DR2b-restricted T cells.

Area of Science:

• Neuroimmunology
• Genetics
• Immunology

Background:

• Multiple sclerosis (MS) is an autoimmune neuroinflammatory disease with unresolved progression mechanisms.
• The HLA-DR2b allele is a major genetic risk factor for MS.
• Tumor Necrosis Factor (TNF) and its receptors (TNFR1, TNFR2) are implicated in MS and its animal model, experimental autoimmune encephalomyelitis (EAE).

Purpose of the Study:

• To investigate the roles of HLA-DR2b and TNFR2 in MS pathogenesis using a transgenic mouse model.
• To elucidate the mechanisms by which TNFR2 influences central nervous system (CNS) pathology, remyelination, and T cell responses in EAE.

Main Methods:

• Generation of transgenic mice expressing human HLA-DR2b and lacking mouse MHC-II and TNFR2 (DR2bΔR2).
• Induction of experimental autoimmune encephalomyelitis (EAE) in DR2bΔR2 mice and control DR2b littermates.
• Analysis of disease progression, T cell differentiation (Th17), astrogliosis, and remyelination.

Main Results:

• DR2bΔR2 mice developed progressive EAE, unlike non-progressive disease in DR2b littermates.
• HLA-DR2b expression promoted Th17 cell development.
• TNFR2 expression was crucial for limiting astrogliosis-induced inflammation and Th17 responses, while promoting remyelination.

Conclusions:

• TNFR2 signaling plays a critical role in ameliorating CNS pathology in EAE by restraining inflammation and promoting remyelination.
• The TNFR2 pathway represents a potential therapeutic target for limiting disease progression in multiple sclerosis.