Autoantibodies specific to a peptide of β2-glycoprotein I cross-react with TLR4, inducing a proinflammatory phenotype in endothelial cells and monocytes

Blood. 2012 Oct 18;120(16):3360-70. doi: 10.1182/blood-2011-09-378851. Epub 2012 Aug 29.

Abstract

β(2)-glycoprotein I (β(2)GPI) is the major antigenic target for antiphospholipid Abs. Anti-β(2)GPI Abs are a heterogeneous population of Igs targeting all domains of the molecule. Abs specific to β(2)GPI domain I are strongly associated with thrombosis and obstetric complications. In the present study, we sought to understand the possible pathogenic mechanism for this subset of anti-β(2)GPI Abs, investigating their potential cross-reactivity with other self-proteins involved in inflammatory or coagulant events. We compared the amino acid sequence of the β(2)GPI domain I with human proteins in a protein databank and identified a peptide sharing 88% identity with an epitope of human TLR4. A high percentage of patients with antiphospholipid syndrome (41%) and systemic lupus erythematosus (50%) presented serum IgG specific to this peptide. Anti-β(2)GPI peptide Abs binding the TLR4 were able to induce NF-κB activation in HEK293 cells that were stably transfected with the TLR4 gene. Anti-β(2)GPI peptide Abs induced activation of TLR4 and triggered interleukin-1 receptor-associated kinase phosphorylation and NF-κB translocation, promoting VCAM expression on endothelial cells and TNF-α release by monocytes. In conclusion, our observations suggest a novel pathogenic mechanism in the TLR4 stimulation by anti-β(2)GPI peptide Abs that links adaptive immune responses with innate immunity in antiphospholipid syndrome and systemic lupus erythematosus.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Antiphospholipid Syndrome / immunology
  • Antiphospholipid Syndrome / metabolism
  • Antiphospholipid Syndrome / pathology
  • Autoantibodies / blood*
  • Case-Control Studies
  • Chronic Periodontitis / immunology
  • Chronic Periodontitis / metabolism
  • Chronic Periodontitis / pathology
  • Cross Reactions
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Human Umbilical Vein Endothelial Cells / immunology*
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Human Umbilical Vein Endothelial Cells / pathology
  • Humans
  • Inflammation Mediators / metabolism*
  • Lupus Erythematosus, Systemic / immunology
  • Lupus Erythematosus, Systemic / metabolism
  • Lupus Erythematosus, Systemic / pathology
  • Male
  • Middle Aged
  • Monocytes / immunology*
  • Monocytes / metabolism
  • Monocytes / pathology
  • NF-kappa B / metabolism
  • Peptide Fragments / immunology*
  • Protein Transport
  • RNA, Small Interfering / genetics
  • Toll-Like Receptor 4 / antagonists & inhibitors
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / immunology*
  • Tumor Necrosis Factor-alpha / metabolism
  • Young Adult
  • beta 2-Glycoprotein I / immunology*

Substances

  • Autoantibodies
  • Inflammation Mediators
  • NF-kappa B
  • Peptide Fragments
  • RNA, Small Interfering
  • TLR4 protein, human
  • Toll-Like Receptor 4
  • Tumor Necrosis Factor-alpha
  • beta 2-Glycoprotein I