Beta2-glycoprotein I: antiphospholipid syndrome and T-cell reactivity

Thromb Res. 2004;114(5-6):347-55. doi: 10.1016/j.thromres.2004.06.029.

Abstract

There is increasing evidence showing that recurrent thrombosis and intrauterine fetal loss in antiphospholipid syndrome (APS) are attributable to antiphospholipid (aPL) antibodies. We have recently identified autoreactive CD4+ T cells to beta2-glycoprotein I (beta2GPI) that promote production of pathogenic antiphospholipid antibodies. beta2GPI-specific CD4+ T cells preferentially recognize the antigenic peptide containing the major phospholipid (PL)-binding site in the context of DR53. T-cell helper activity that stimulates B cells to produce IgG anti-beta2GPI antibodies is mediated through IL-6 and CD40-CD154 interaction. beta2GPI-specific T cells respond to reduced beta2GPI and recombinant beta2GPI fragments produced in a bacterial expression system but not to native beta2GPI, indicating that the epitopes recognized by beta2GPI-specific T cells are 'cryptic' determinants, which are generated at a subthreshold level by the processing of native beta2GPI under normal circumstances. Although beta2GPI-specific T cells are detected in both APS patients and healthy individuals, these autoreactive T cells are activated in vivo in APS patients but not in healthy individuals. These findings indicate activation of beta2GPI-specific T cells and subsequent production of pathogenic anti-beta2GPI antibodies can be induced by the exposure of such T cells to cryptic peptides of beta2GPI efficiently presented by functional antigen-presenting cells (APC). Delineating the mechanisms that induce the efficient processing and presentation of cryptic determinants of beta2GPI as a consequence of antigen processing would clarify the etiology that initiates the autoantibody response in APS.

Publication types

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

MeSH terms

  • Amino Acid Motifs
  • Antibodies, Antiphospholipid / chemistry
  • Antigen Presentation
  • Antiphospholipid Syndrome / metabolism*
  • Antiphospholipid Syndrome / pathology
  • Autoantibodies / chemistry
  • Binding Sites
  • CD4-Positive T-Lymphocytes / metabolism
  • CD40 Antigens / biosynthesis
  • CD40 Ligand / biosynthesis
  • Glycoproteins / metabolism
  • Glycoproteins / physiology*
  • HLA-DR Antigens / chemistry
  • HLA-DRB4 Chains
  • Humans
  • Interleukin-6 / metabolism
  • Lupus Erythematosus, Systemic / metabolism
  • Models, Biological
  • Peptides / chemistry
  • beta 2-Glycoprotein I

Substances

  • Antibodies, Antiphospholipid
  • Autoantibodies
  • CD40 Antigens
  • Glycoproteins
  • HLA-DR Antigens
  • HLA-DR53
  • HLA-DRB4 Chains
  • Interleukin-6
  • Peptides
  • beta 2-Glycoprotein I
  • CD40 Ligand