HMGB1-Neutralizing IgM Antibody Is a Normal Component of Blood Plasma

Area of Science:

• Immunology
• Molecular Biology
• Cell Biology

Background:

• Extracellular high-mobility group box 1 (HMGB1) is a damage-associated molecular pattern.
• While essential for immune defense and tissue repair, elevated HMGB1 levels correlate with inflammatory diseases.

Purpose of the Study:

• To investigate the mechanisms by which healthy individuals regulate extracellular HMGB1 levels.
• To identify endogenous factors that control HMGB1 homeostasis.

Main Methods:

• Plasma analysis in healthy humans and mice.
• Identification and characterization of anti-HMGB1 autoantibodies.
• Investigation of B-1 cell responses to HMGB1 in mice.

Main Results:

• Discovery of an anti-HMGB1 IgM autoantibody in healthy human and mouse plasma.
• This antibody specifically binds to the conserved HMW4 epitope (HMGB1_98-112) and neutralizes HMGB1.
• Extracellular HMGB1 triggers its own neutralizing IgM production by peritoneal B-1 cells via BCR and TLR4 signaling.

Conclusions:

• A novel feedback loop exists where HMGB1 induces its own neutralizing autoantibody.
• This mechanism is crucial for maintaining homeostatic levels of extracellular HMGB1 in healthy individuals.
• Understanding this regulatory pathway offers insights into managing HMGB1-associated inflammatory conditions.