Specific and Polyfunctional T Cell Response Against N-Methyl-d-aspartate Receptor in an Autoantibody-Mediated...

Area of Science:

• Neuroimmunology
• Autoimmune Diseases

Background:

• Anti-N-methyl-d-aspartate receptor (NMDAR) autoimmune encephalitis (NMDAR AE) presents with severe psychiatric and neurological symptoms.
• The role of antibodies against the GluN1 subunit is known, but T helper cell involvement in B cell response generation remains unclear.
• A mouse model of NMDAR AE was previously established using GluN1 peptide immunization, exhibiting anxiety and spatial memory deficits.

Purpose of the Study:

• To investigate the role of T helper cells in the pathogenesis of NMDAR AE.
• To explore the mechanisms of T and B cell crosstalk in generating pathogenic anti-GluN1 antibodies.

Main Methods:

• Development of a B-cell-mediated mouse model of NMDAR AE.
• Identification of anti-GluN1-specific CD4+ and CD8+ T cells in spleen and meninges.
• Proteomic analysis of meninges from affected mice.

Main Results:

• Polyfunctional T helper cells and CD8+ T cells were identified in the spleen and meninges.
• Evidence suggests T and B cell crosstalk is crucial for producing pathogenic anti-GluN1 antibodies.
• Proteomic analysis revealed enrichment of B cell activation and cytokine signaling pathways in AE meninges.

Conclusions:

• This research provides the first evidence for T helper cell contribution to NMDAR AE pathology.
• Findings open possibilities for developing novel tolerogenic therapies to manage NMDAR AE relapses.