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Blood, 15 September 2001, Vol. 98, No. 6, pp. 1889-1896
IMMUNOBIOLOGY
Autoreactive CD4+ T-cell clones to
 2-glycoprotein I in patients with antiphospholipid
syndrome: preferential recognition of the major
phospholipid-binding site
Takahide Arai,
Kazue Yoshida,
Junichi Kaburaki,
Hidetoshi Inoko,
Yasuo Ikeda,
Yutaka Kawakami, and
Masataka Kuwana
From the Institute for Advanced Medical Research and
Department of Internal Medicine, Keio University School of Medicine,
Tokyo, Japan; Department of Internal Medicine, Tokyo Electric Power
Company Hospital, Tokyo, Japan; and Division of Molecular Life Science,
Department of Genetic Information, Tokai University School of Medicine,
Isehara, Japan.
Autoreactive CD4+ T cells to
 2-glycoprotein I (2GPI) 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
2GPI-reactive T cells, 14 CD4+ T-cell clones
specific to 2GPI were generated from 3 patients with APS
by repeated stimulation of peripheral blood T cells with recombinant
2GPI. At least 4 distinct T-cell epitopes were
identified, but the majority of the 2GPI-specific T-cell
clones responded to a peptide encompassing amino acid residues 276 to
290 of 2GPI (KVSFFCKNKEKKCSY; single-letter amino acid
codes) that contains the major phospholipid-binding site in the context
of the DRB4*0103 allele. Ten of 12 2GPI-specific T-cell
clones were able to stimulate autologous peripheral blood B cells to
promote anti-2GPI antibody production in the presence of
recombinant 2GPI. T-cell helper activity was exclusively
found in T-cell clones capable of producing interleukin 6 (IL-6). In
vitro anti-2GPI 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-2GPI antibody production in cultures of the T-cell
clone lacking IL-6 expression. These results indicate that
2GPI-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-2GPI 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.
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