Early Combined B-Cell Depletion and BTK Inhibition Reduced TLS-like Structures and Relapse in PLP_139-151-Induced EAE

Area of Science:

• Neuroimmunology
• Inflammatory diseases
• Therapeutic strategies

Background:

• B-cell-depleting therapies are effective for multiple sclerosis (MS) but do not prevent relapses in all patients.
• Tertiary lymphoid structures (TLS) are found in progressive MS, but their role in early disease phases is unclear.

Purpose of the Study:

• To investigate the formation and evolution of TLS-like structures in the relapsing-remitting phase of experimental autoimmune encephalomyelitis (EAE).
• To evaluate the efficacy of combined B-cell depletion and Bruton's tyrosine kinase (BTK) inhibition in preventing relapses and resolving TLS-like structures.

Main Methods:

• Utilized the PLP139-151-induced EAE mouse model.
• Administered B-cell depletion, BTK inhibition, or a combination therapy at different disease stages.
• Assessed TLS-like structure formation, B cell and microglia presence, and disease relapse incidence and severity.

Main Results:

• TLS-like structures formed in the subventricular zone during relapse and persisted through remission, containing B cells and activated microglia.
• Neither B-cell depletion nor BTK inhibition alone prevented relapse.
• Early combined therapy abolished TLS-like structures and prevented relapse, while late therapy failed to resolve existing structures but reduced severity.

Conclusions:

• Established TLS-like structures may be treatment-resistant compartments driving MS relapses.
• B cells and microglia are crucial for early TLS formation and sustained inflammation.
• Early combined B-cell depletion and BTK inhibition shows promise for MS treatment, highlighting a potential therapeutic window.