The role of HMGB1 in the pathogenesis of rheumatic disease.
HMGB1 is a ubiquitous nuclear protein that can be released by any damaged cell or by activated macrophages and certain other cell types. HMGB1 has been successfully therapeutically targeted in multiple preclinical models of infectious and sterile diseases including arthritis. Extracellular HMGB1 mediates inflammation via induction of cytokine and metalloproteinase production and recruitment and activation of dendritic cells needed for priming of naïve T helper type 1 lymphocytes. HMGB1 can bind endogenous molecules such as IL-1beta and nucleosomes and exogenous agents like endotoxin and microbial DNA. These complexes synergistically increase the capacity for activation of adaptive and innate immunity. HMGB1-nucleosome complexes induce autoantibody formation against double-stranded DNA and nucleosomes, which does not occur if HMGB1 is absent. These antibodies are central in the pathogenesis of systemic lupus erythematosus and patients with active disease have both increased HMGB1 and HMGB1-nucleosome levels in circulation. Furthermore, HMGB1 is strongly bipolar charged, enabling cell membrane passage and intracellular transport of complexed molecules including DNA. Rheumatoid arthritis patients have excessive extracellular HMGB1 levels in joints and serum. The HMGB1 release is caused by cytokines, activated complement and hypoxia. The most prominent HMGB1 protein and mRNA expression arthritis is present in pannus regions, where synovial tissue invades articular cartilage and bone. HMGB1 promotes the activity of proteolytic enzymes, and osteoclasts need HMGB1 for functional maturation. Neutralizing HMGB1 therapy in preclinical models of arthritis confers striking protection against structural damage. This review summarizes selected aspects of HMGB1 biology relevant for induction and propagation of some autoimmune conditions.
Andersson
Ulf
U
Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital at Solna, S-171 76 Stockholm, Sweden. Ulf.Andersson@ki.se
Harris
Helena Erlandsson
HE
D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D005110:Extracellular Space / Q000378:metabolism; D024243:HMGB1 Protein / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000473:pathology; D012216:Rheumatic Diseases / Q000209:etiology* / Q000276:immunology / Q000473:pathology / Q000628:therapy
D001323:Autoantibodies; D024243:HMGB1 Protein