HMGB1, an innate alarmin, in the pathogenesis of type 1 diabetes

Int J Clin Exp Pathol. 2009 Sep 8;3(1):24-38.

Abstract

HMGB1, an evolutionarily conserved chromosomal protein, was recently re-discovered to act as a "danger signal" (alarmin) to alert the innate immune system for the initiation of host defense or tissue repair. Extracellular HMGB1 can be either passively released from damaged/necrotic cells or secreted by activated immune cells. Upon stimulation, dendritic cells (DCs), macrophages and natural killer (NK) cells secrete high levels of HMGB1 into the intercellular milieu. HMGB1 is potent to target DCs, macrophages, neutrophils and CD4(+) T cells. It also upregulates the expression of BCL-XL by which it may prevent the elimination of activated immune cells. As a result, HMGB1 has been suggested to be implicated in the pathogenesis of autoimmune disorders such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and experimental allergic encephalomyelitis (EAE). Given the similarities of autoimmune response against beta cell self-antigens in type 1 diabetes (T1D), in this view we will discuss the possible implications of HMGB1 in T1D pathogenesis. Specifically, we will summarize and update the advancement of HMGB1 in the pathogenesis of autoimmune initiation and progression during T1D development, as well as islet allograft rejection of diabetic patients after islet transplantation. Elucidation of the role for HMGB1 in T1D pathogenesis would not only enhance the understanding of disease etiology, but also have the potential to shed new insight into the development of therapeutic strategies for prevention or intervention of this disorder.

Keywords: HMGB1; innate alarmin; pathogenesis type 1 diabetes; review.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Dendritic Cells / immunology
  • Dendritic Cells / pathology
  • Diabetes Mellitus, Type 1 / etiology*
  • Diabetes Mellitus, Type 1 / metabolism
  • Diabetes Mellitus, Type 1 / pathology
  • Disease Progression
  • Graft Rejection / immunology
  • Graft Rejection / pathology
  • HMGB1 Protein / physiology*
  • Humans
  • Immunity, Innate / physiology*
  • Islets of Langerhans Transplantation / immunology
  • Islets of Langerhans Transplantation / pathology
  • Killer Cells, Natural / immunology
  • Killer Cells, Natural / pathology
  • Macrophages / immunology
  • Macrophages / pathology
  • Molecular Sequence Data
  • Transplantation, Autologous
  • Up-Regulation
  • bcl-X Protein / metabolism

Substances

  • BCL2L1 protein, human
  • HMGB1 Protein
  • bcl-X Protein