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Blood, Vol. 94 No. 1 (July 1), 1999:
pp. 208-215
Complexes of Heparin and Platelet Factor 4 Specifically Stimulate T
Cells From Patients With Heparin-Induced Thrombocytopenia/Thrombosis
S. Bacsi,
R. De Palma,
G.P. Visentin,
J. Gorski, and
R.H. Aster
From The Blood Research Institute, The Blood Center of
Southeastern Wisconsin; the Departments of Cell Biology, and
Medicine and Pathology, Medical College of Wisconsin, Milwaukee,
WI; and the Fondazione Salvatore Maugeri, Laboratorio di Medicina
Sperimentale, Pavia, Italy.
Heparin-induced thrombocytopenia with thrombosis (HITT) is
associated with antibodies specific for complexes consisting of heparin
and platelet factor 4 (PF4). Studies in individual patients with HITT
have demonstrated immunoglobulin (Ig) class switching from IgM to the
IgG or IgA isotypes. This transition is thought to require helper T
cells, but no studies of the cellular or molecular basis of this
process have yet been reported. To characterize T-cell involvement in
HITT, peripheral blood mononuclear cells (PBMC) from two patients with
classical HITT obtained shortly after the acute episode were
restimulated with heparin:PF4 complexes, PF4 alone, heparin alone, and
medium alone in the presence of autologous antigen-presenting cells
(APC). Responding T cells were then examined using the technique of
"spectratyping," in which sequences encoding CDR3 domains of
individual V beta (BV) families are amplified and separated by gel
electrophoresis. After 14 days in culture with antigen (heparin:PF4
complexes), but not after culture with PF4, heparin, or medium alone,
patient cells, but not cells from normal subjects, preferentially
expressed T-cell receptor (TCR)-containing  chains of the BV 5.1 family. Nucleotide sequencing of BV 5.1 TCR CDR3 showed that each
patient had a personal repertoire, but also shared a tetrapeptide motif
(PGTG). These findings provide evidence that the humoral immune
response associated with HITT is driven by helper T cells that
presumably recognize peptides derived from PF4. Identification of a
common -chain CDR3 motif in responding T cells from each of two
patients suggests that a limited number of helper TCRs may be used to
mount an antibody response to heparin:PF4 complexes. TCR spectratyping
appears to offer a new way to examine the molecular basis of pathologic
immune responses and may be useful in further studies of HITT and other immune-mediated hematologic disorders.
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