ODC1 restricts meningeal B cell age-associated-like phenotype and function in multiple sclerosis: A human and...

Area of Science:

• Neuroimmunology
• Cellular Metabolism

Background:

• Meningeal inflammation is a hallmark of multiple sclerosis (MS) and is linked to poorer clinical outcomes.
• Ectopic lymphoid follicles, rich in B cells, are found in the meninges of MS patients and in the experimental autoimmune encephalomyelitis (EAE) model.
• The metabolic needs of meningeal B cells in MS and EAE remain largely unknown.

Purpose of the Study:

• To investigate the role of the arginine/polyamine pathway in meningeal inflammation in MS and EAE.
• To elucidate the function of Ornithine Decarboxylase 1 (ODC1) in regulating meningeal B and T cell responses during autoimmunity.

Main Methods:

• Correlating 7-Tesla MRI brain scans of MS patients with leptomeningeal enhancement and metabolites.
• Analyzing dura meningeal B cells from MOG35-55 induced EAE mice for polyamine metabolism.
• Investigating the effects of ODC1 pharmacological inhibition on meningeal immune cells in EAE.
• Examining the consequences of B cell-specific ODC1 deletion in the MOG1-125 EAE model.

Main Results:

• A correlation was observed between meningeal inflammation and metabolites of the arginine/polyamine pathway in MS patients and EAE mice.
• ODC1 and polyamine metabolism were reduced in meningeal B cells of EAE mice.
• ODC1 inhibition decreased meningeal T cells but increased meningeal B cell proliferation.
• B cell-specific ODC1 deletion led to an expansion of B cells with an age-associated B cell-like phenotype, increased MOG-specific IgG, reduced synaptic density, and worsened EAE disease.

Conclusions:

• Polyamines play a critical, divergent role in modulating B and T cell responses within the meninges during autoimmune conditions like MS.
• ODC1 is a key regulator of meningeal B cell function and impacts overall disease pathology in EAE.