[6] HMGB1 has been shown to play an important role in helping the RAG endonuclease form a paired complex during V(D)J recombination.

[9] Antibodies that neutralize HMGB1 confer protection against damage and tissue injury during arthritis, colitis, ischemia, sepsis, endotoxemia, and systemic lupus erythematosus.

[citation needed] The mechanism of inflammation and damage consists of binding to toll-like receptor TLR2 and TLR4, which mediates HMGB1-dependent activation of macrophage cytokine release.

[13] HMGB1 released from tumour cells was demonstrated to mediate anti-tumour immune responses by activating toll-like receptor 2 (TLR2) signaling on bone marrow-derived GBM-infiltrating DCs.

HMGB1 can interact with TLR ligands and cytokines, and activates cells through the multiple surface receptors including TLR2, TLR4, and RAGE.

The downstream effect of this signaling is to activate MAPK and NF-κB, and thus cause the production of inflammatory molecules such as cytokines.

In the SCA1 mouse model, over-expression of the HMGB1 protein by means of an introduced virus vector bearing the HMGB1 gene facilitated repair of the mitochondrial DNA damage, ameliorated the neuropathology and the motor defects of the SCA1 mice, and also extended their lifespan.

Recently, a study provided evidence of an association between raised levels of HMGB1 and attention to detail and systemizing in unmedicated children with high-functioning autism spectrum disorder (ASD), suggesting that inflammatory processes mediated by HMGB1 may play a role in the disruption of neurobiological mechanisms regulating cognitive processes in ASD.

[27] However, comprehensive evidence in children is limited, highlighting the need for in-depth research towards understanding possible mechanisms linking HMGB1 with the core features of ASD.