Identification of Neutralizing Anti-HMGB1 IgM Autoantibody and Its B Cell Producers

Abstract Extracellular High Mobility Group Box 1 (HMGB1) is a prototypic damage-associated molecular pattern (DAMP). While a homeostatic level of extracellular HMGB1 may be beneficial for immune defense, tissue repair and tissue regeneration, excessive HMGB1 is linked to chronic inflammation and inflammatory diseases. This prompts an intriguing question: How does a healthy body control the level of extracellular HMGB1? Here we have identified, in the plasma of both healthy humans and healthy mice, an anti-HMGB1 IgM autoantibody that neutralizes extracellular HMGB1 via binding specifically to a 100% conserved epitope, namely HMW4 (HMGB1 98–112). In mice, this anti-HMGB1 IgM (i.e., anti-HMW4 IgM) is produced by peritoneal B-1 cells, and concomitant triggering of their B cell receptor and toll-like receptor 4 by extracellular HMGB1 stimulates the production of anti-HMW4 IgM. The ability of extracellular HMGB1 to induce its own neutralizing antibody suggests a feedback loop limiting the level of this DAMP in a healthy body. Currently, our studies are ongoing to identify and characterize the human counterpart B cells that produce the anti-HMGB1 IgM, by first amplifying HMW4-reactive B cells from human peripheral blood mononuclear cells (PBMCs) in NSG recipient mice, in the presence of B cell-stimulating adjuvants (such as B cell mitogens). These studies serve as the prelude to exploring human anti-HMGB1 IgM down the road for treating patients with inflammatory diseases and provide insight pertaining to the role and regulation of other DAMP molecules.