Small Nuclear Ribonucleoprotein Autoantibody Associated With Blood-Nerve Barrier Breakdown in Guillain-Barré Syndrome

Area of Science:

• Neuroimmunology
• Molecular mechanisms of neurological disorders
• Autoimmune diseases

Background:

• Breakdown of the blood-nerve barrier (BNB) is a hallmark of Guillain-Barré syndrome (GBS).
• The precise molecular mechanisms driving BNB disruption in GBS remain incompletely understood.
• Identifying specific antibodies targeting BNB-endothelial cells is crucial for understanding GBS pathogenesis.

Purpose of the Study:

• To identify antibodies targeting blood-nerve barrier (BNB)-endothelial cells that initiate BNB breakdown in Guillain-Barré syndrome (GBS).
• To elucidate the molecular pathways involved in GBS-associated BNB disruption.
• To investigate the role of U1-small nuclear ribonucleoprotein (U1-snRNP) autoantibodies in GBS.

Main Methods:

• Purification of immunoglobulins G (IgGs) from serum of GBS patients, disease controls, and healthy controls.
• Incubation of human peripheral nerve microvascular endothelial cells (PnMECs) with purified IgGs.
• Evaluation of molecular changes in PnMECs using RNA-sequencing and high-content imaging, including assessment of NF-κB activation and U1-snRNP antibody levels via ELISA.

Main Results:

• GBS-IgGs significantly increased NF-κB nuclear translocation and PnMEC permeability compared to controls.
• RNA-seq identified snRNPs and CXCR5 as key molecules in the NF-κB pathway following GBS-IgG exposure.
• U1-snRNP antibody positivity was found in 36% of GBS patients, and their IgGs showed increased PnMEC permeability and reduced claudin-5 expression in vitro.

Conclusions:

• U1-snRNP autoantibodies are implicated in BNB breakdown in GBS.
• The mechanism involves reduction of U1-snRNP and claudin-5, and activation of NF-κB in BNB-endothelial cells.
• This transient autoantibody response may be triggered by infection in GBS patients.