AMPAR immunization induces progressive autoimmune encephalitis with autoreactive B cells in the brain

Area of Science:

• Neuroimmunology
• Synaptic Plasticity
• Autoimmune Encephalitis

Background:

• Autoimmune encephalitis targeting AMPA receptors (AMPARs) causes severe neuropsychiatric symptoms by disrupting synaptic signaling.
• The precise cellular autoimmune responses and origin of pathogenic autoantibodies in CNS pathology remain unclear.

Purpose of the Study:

• To investigate the cellular autoimmune responses and autoantibody sources in anti-AMPAR encephalitis.
• To establish a mouse model for studying the pathogenesis of anti-AMPAR encephalitis.

Main Methods:

• Developed a mouse model by immunizing with intact AMPARs in proteoliposomes.
• Analyzed autoantibody production, IgG deposition in the brain, and AMPAR levels.
• Examined the localization and proliferation of AMPAR-ATD-specific B cells, plasma cells, and plasmablasts in the CNS and peripheral tissues.

Main Results:

• Mice developed progressive neuropsychiatric deficits, anti-AMPAR autoantibodies targeting the amino-terminal domain (ATD), and IgG deposition in the brain.
• Reduced AMPAR detection was observed in affected brains.
• AMPAR-ATD-specific plasma cells and plasmablasts accumulated within the brain parenchyma, particularly in AMPAR-expressing areas, while differentiated B cells were less enriched peripherally.

Conclusions:

• Humoral autoimmune responses occurring directly within the CNS are the primary drivers of disease progression in anti-AMPAR encephalitis.
• The brain serves as a key site for the accumulation and activity of pathogenic B cell populations in this condition.