Autoreactive CD4(+) T-cell clones to beta2-glycoprotein I in patients with antiphospholipid syndrome: preferential recognition of the major phospholipid-binding site.
Autoreactive CD4(+) T cells to beta2-glycoprotein I (beta2GPI) that promote antiphospholipid antibody production were recently identified in patients with antiphospholipid syndrome (APS). To further examine antigen recognition profiles and T-cell helper activity in beta2GPI-reactive T cells, 14 CD4(+) T-cell clones specific to beta2GPI were generated from 3 patients with APS by repeated stimulation of peripheral blood T cells with recombinant beta2GPI. At least 4 distinct T-cell epitopes were identified, but the majority of the beta2GPI-specific T-cell clones responded to a peptide encompassing amino acid residues 276 to 290 of beta2GPI (KVSFFCKNKEKKCSY; single-letter amino acid codes) that contains the major phospholipid-binding site in the context of the DRB4*0103 allele. Ten of 12 beta2GPI-specific T-cell clones were able to stimulate autologous peripheral blood B cells to promote anti-beta2GPI antibody production in the presence of recombinant beta2GPI. T-cell helper activity was exclusively found in T-cell clones capable of producing interleukin 6 (IL-6). In vitro anti-beta2GPI antibody production induced by T-cell clones was inhibited by anti-IL-6 or anti-CD40 ligand monoclonal antibody. In addition, exogenous IL-6 augmented anti-beta2GPI antibody production in cultures of the T-cell clone lacking IL-6 expression. These results indicate that beta2GPI-specific CD4(+) T cells in patients with APS preferentially recognize the antigenic peptide containing the major phospholipid-binding site and have the capacity to stimulate B cells to produce anti-beta2GPI antibodies through IL-6 expression and CD40-CD40 ligand engagement. These findings are potentially useful for clarifying the pathogenesis of APS and for developing therapeutic strategies that suppress pathogenic antiphospholipid antibody production in these patients.
Arai
T
T
Institute for Advanced Medical Research and Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
Yoshida
K
K
Kaburaki
J
J
Inoko
H
H
Ikeda
Y
Y
Kawakami
Y
Y
Kuwana
M
M
D000328:Adult; D016736:Antiphospholipid Syndrome / Q000276:immunology*; D001323:Autoantibodies / Q000096:biosynthesis; D001324:Autoantigens / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D015551:Autoimmunity; D001665:Binding Sites; D002478:Cells, Cultured; D002999:Clone Cells; D016207:Cytokines / Q000096:biosynthesis; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D006023:Glycoproteins / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000502:physiology; D008213:Lymphocyte Activation; D010455:Peptides / Q000276:immunology; D010743:Phospholipids / Q000378:metabolism; D017434:Protein Structure, Tertiary; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D053482:beta 2-Glycoprotein I
D001323:Autoantibodies; D001324:Autoantigens; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D006023:Glycoproteins; D015850:Interleukin-6; D010455:Peptides; D010743:Phospholipids; D053482:beta 2-Glycoprotein I