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2016 ; 56
(7
): 1763-74
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ADAMTS13 autoantibodies cloned from patients with acquired thrombotic
thrombocytopenic purpura: 1 Structural and functional characterization in vitro
#MMPMID27040144
Ostertag EM
; Kacir S
; Thiboutot M
; Gulendran G
; Zheng XL
; Cines DB
; Siegel DL
Transfusion
2016[Jul]; 56
(7
): 1763-74
PMID27040144
show ga
BACKGROUND: Acquired thrombotic thrombocytopenia purpura (TTP) is a
life-threatening illness caused by autoantibodies that decrease the activity of
ADAMTS13, the von Willebrand factor-cleaving protease. Despite efficacy of plasma
exchange, mortality remains high and relapse is common. Improved therapies may
come from understanding the diversity of pathogenic autoantibodies on a molecular
or genetic level. Cloning comprehensive repertoires of patient autoantibodies can
provide the necessary tools for studying immunobiology of disease and developing
animal models. STUDY DESIGN AND METHODS: Anti-ADAMTS13 antibodies were cloned
from four patients with acquired TTP using phage display and characterized with
respect to genetic origin, inhibition of ADAMTS13 proteolytic activity, and
epitope specificity. Anti-idiotypic antisera raised to a subset of autoantibodies
enabled comparison of their relatedness to each other and to polyclonal
immunoglobulin (Ig)G in patient plasma. RESULTS: Fifty-one unique antibodies were
isolated comprising epitope specificities resembling the diversity found in
circulating patient IgG. Antibodies directed both to the amino terminal domains
and to those requiring the ADAMTS13 cysteine-rich/spacer region for binding
inhibited proteolytic activity, while those solely targeting carboxy-terminal
domains were noninhibitory. Anti-idiotypic antisera raised to a subset of
antibody clones crossreacted with and reduced the inhibitory activity of
polyclonal IgG from a set of unrelated patients. CONCLUSIONS: Anti-ADAMTS13
autoantibodies isolated by repertoire cloning display the diversity of epitope
specificities found in patient plasma and provide tools for developing animal
models of acquired TTP. Shared idiotypes of inhibitory clones with circulating
IgG from multiple patients suggest common features of pathogenic autoantibodies
that could be exploited for developing more targeted therapies.