Analysis of regulatory mechanisms for HMGB1 secretion and signal transduction and their clinical significance

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We isolated high mobility group (HMG) nonhisitone chromosomal proteins 1 and 2 (HMGB1/HMGB2) as target antigens of anti-neutrophil cytoplasmic antibody, and have been analyzing the roles of those autoantibodies as well as the autoantigens.In this study, we found that the major B-cell epitope of a monoclonal anti-HMGB1 antibody, FBH7, is a combinatorial structure which is constructed by amino acid residue 52-56, ant that this portion is different between neutrophil-derived and lymphocyte-derived HMGB1 (J.Biochem.136;155,2004). We also analyzed the HMGB1 epitopes that were recognized by serum antibodies derived from patients with various autoimmune diseases : rheumatic diseases, inflammatory bowel diseases, and autoimmune liver diseases. Although we have not completed the epitope mapping, data obtained so far indicate that some sera recognize the similar epitope.The T-cell epitope of HMGB1 was investigated by measuring the affinity to bind to HLA-A2.1. We revealed that the 9-mer of HMGB1 12-20 showed the similar affinity as a well-known CTL epitope, p17-WT. These results suggest that HMGB1 may induce CTL restricted to HLA-A2.1.We also established a novel fatal mouse model, in which 90% of the hepatic blood flow was blocked by a surgical procedure. All mice died 60 hr after the ligation with a median survival time of 30 hr. These mice showed an elevated level of serum HMG1, and the survival rate increased by a simultaneous i.p.injection of monoclonal anti-HMG1 antibody (J.Surg.Res.124:59,2005). Taken together, these data indicates that HMG1 protein may play an important role in a certain fatal condition, and that the intervention of serum HMG1 levels may serve as a new strategy for such a critical state. For that purpose, we started to establish a biological membrane that can absorb HMGB1 effectively.