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Blood, 15 August 2002, Vol. 100, No. 4, pp. 1388-1398
IMMUNOBIOLOGY
Genetic analysis of autoantibodies in idiopathic thrombocytopenic
purpura reveals evidence of clonal expansion and somatic
mutation
Jessica H. Roark,
James B. Bussel,
Douglas B. Cines, and
Don L. Siegel
From the Department of Pathology and Laboratory
Medicine, University of Pennsylvania School of Medicine, Philadelphia;
and the Division of Pediatric Hematology/Oncology, Joan and Sanford I. Weill Medical College, Cornell University, New York, NY.
Although idiopathic thrombocytopenic purpura (ITP) is the most
common autoimmune hematologic disorder, little is known about the
associated autoantibodies on a molecular level. Consequently, diagnostic assays and therapy for ITP lack specificity. To avoid technical limitations imposed by B-cell immortalization methods, we
used repertoire cloning (Fab/phage display) to clone platelet autoantibodies and examine the relation between immunoglobulin (Ig)
gene usage, clonality, and antigen specificity. Phage display libraries
were constructed from splenocytes from 2 patients with chronic ITP, and
competitive cell-surface selection was used to isolate several dozen
unique IgG platelet-specific autoantibodies. Platelet-reactive Fabs in
both patients were associated almost exclusively with rearrangements of
a single Ig heavy-chain variable-region gene (VH3-30),
despite an apparent diversity of antigen specificities. Comparative
analysis of platelet-reactive Fab Ig gene rearrangements from each
patient suggested that they evolved from a restricted number of B-cell
clones through somatic mutation with high replacement-to-silent mutation ratios. Although VH3-30-encoded heavy chains were
found with light chains encoded by several different Ig genes,
molecular repairing experiments showed exquisite restriction on the
specific heavy- and light-chain pairings that permitted platelet
reactivity. Together, these data suggest that the development of
platelet-reactive antibodies associated with ITP is driven by an
encounter with diverse platelet antigens through the clonal expansion
of B cells using genetically restricted and highly specific
combinations of heavy- and light-chain gene products. The
extraordinarily high usage of the VH3-30 heavy-chain gene
in these patients has implications for the pathogenesis, diagnosis, and
management of chronic ITP.
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