High-mobility group box 1 protein (HMGB1) neutralization ameliorates experimental autoimmune encephalomyelitis

• Published in: Journal of autoimmunity Vol. 43; pp. 32 - 43
• Main Authors: Robinson, Andrew P, Caldis, Matthew W, Harp, Christopher T, Goings, Gwendolyn E, Miller, Stephen D
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier Ltd 01.06.2013; Elsevier
• Subjects: Allergy and Immunology; Animals; Antibodies, Neutralizing - administration & dosage; Autoimmune disease; Biological and medical sciences; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - pathology; Central Nervous System - immunology; Central Nervous System - pathology; Cytokines - biosynthesis; EAE; Encephalomyelitis, Autoimmune, Experimental - immunology; Encephalomyelitis, Autoimmune, Experimental - prevention & control; Encephalomyelitis, Autoimmune, Experimental - therapy; Fundamental and applied biological sciences. Psychology; Fundamental immunology; HMGB1; HMGB1 Protein - antagonists & inhibitors; HMGB1 Protein - blood; HMGB1 Protein - immunology; Humans; Innate immunity; Lymphocyte Activation; Medical sciences; Mice; Mice, Inbred C57BL; Multiple Sclerosis - immunology; Multiple Sclerosis - therapy; Multiple sclerosis and variants. Guillain barré syndrome and other inflammatory polyneuropathies. Leukoencephalitis; Neuroimmunomodulation; Neuroinflammation; Neurology; Tolerance; Innate immunity; Autoimmune disease; CNS; HMGB1; experimental autoimmune encephalomyelitis; PLP; CSF; damage-associated molecular pattern; MBP; TLR; myelin oligodendrocyte glycoprotein; peripheral blood mononuclear cells; proteolipid protein; MOG; MS; multiple sclerosis; EAE; Tolerance; Neuroinflammation; myelin basic protein; RAGE; PBMCs; central nervous system; delayed-type hypersensitivity; high-mobility group box 1 protein; cerebrospinal fluid; DTH; toll-like receptor; DAMP; receptor for advanced glycation end-products; Autoimmunity; Immunopathology; Animal model; Nervous system diseases; Multiple sclerosis; HMGB1 Protein; Natural immunity; Experimental allergic encephalomyelitis; Inflammatory disease; Immunology; Central nervous system disease; Neutralization
• ISSN: 0896-8411; 1095-9157
• DOI: 10.1016/j.jaut.2013.02.005

Abstract Multiple sclerosis (MS) is an autoimmune, demyelinating disease and as such, the gold standard of treatment is to selectively suppress the pathogenic autoimmune response without compromising the entire arm of the adaptive immune response. One target of this strategy lying upstream of the pathologic adaptive immune response is the local, innate immune signaling that initiates and drives autoimmunity and sterile injury. High-mobility group box 1 protein (HMGB1) is a ubiquitous nuclear protein that when released from necrotic cells, such as damaged oligodendrocytes in MS lesions, drives pro-inflammatory responses. Here we demonstrate that HMGB1 drives neuroinflammatory responses in experimental autoimmune encephalomyelitis (EAE), a murine model for MS, and that inhibition of HMGB1 signaling ameliorates disease. Specifically i.v. injection of an HMGB1 neutralizing antibody in the C57BL/6 model of chronic EAE or SJL/J model of relapsing-remitting EAE ameliorated clinical disease prophylactically or during ongoing disease, blocked T cell infiltration of the central nervous system, and inhibited systemic CD4+ T cell responses to myelin epitopes. Additionally, lymphocytes from EAE mice restimulated in vitro in the presence of recombinant HMGB1 exhibited increased proliferation and pro-inflammatory cytokine production, an effect that was blocked by anti-HMGB1 antibody. Similarly recombinant HMGB1 promoted proliferation and pro-inflammatory cytokine production of human peripheral blood mononuclear cells stimulated in vitro , and anti-HMGB1 antibody blocked this effect. These findings indicate that HMGB1 contributes to neuroinflammatory responses that drive EAE pathogenesis and that HMGB1 blockade may be a novel means to selectively disrupt the pro-inflammatory loop that drives MS autoimmunity.