Autoimmunity in Scleroderma
497
(1) most antibodies do not preferentially
recognize cleaved forms, (2) most autoepi-
topes are the functional sites of antigens,
and (3) cleavage sites are not associated
with the major epitope region (Tables 1
and 2), although we cannot speculate on
conformational change induced by cryptic
peptides. Although the preferential au-
toantibodies against Granzyme B-cleaved
CENP-C in scleroderma patients with is-
chemic digital loss were recently shown,
the theory that Granzyme B-generated
fragments serve as a source of T-cell
antigenic determinants is more relevant
a
ss
h
ow
ni
nt
h
es
t
u
d
yo
ft
o
p
oI(
s
e
e
Chapter 3.3).
Investigations of early-involvement le-
sions in scleroderma suggest that apop-
tosis of endothelial cells, possibly caused
by cytotoxic antiendothelial cell antibod-
ies, may occur before the inFltration
of lymphocytes. Although a direct role
for the antibodies inducing apoptosis
in
vivo
remains to be elucidated, the re-
cent report by Lunardi et al. showed that
antibodies in scleroderma patients, re-
acting with the human cytomegalovirus
late protein UL94, cause apoptosis of en-
dothelial cells through speciFc interaction
with the cell-surface integrin–NAG-2 pro-
tein complex. Other than protein cleavage
described above, recent studies showed
that, in the case of infection of herpes
simplex virus type 1, viral immediate-
early protein ICP0 induced degradation of
CENP-A and CENP-C by a proteasome-
dependent manner. This is one of the
cases in which viral infection can in-
duce an altered autoantigen. In order
to
clarify
the
pathogenesis
of
sclero-
derma, further studies especially to reveal
mechanisms of exposure of a cryptic epi-
tope and its reactive T-cell activation are
needed.
See also
Antigen Presenting Cells
(APCs).
Bibliography
Books and Reviews
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and
Related
Disorders
in
Adults
and
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Oxford Textbook
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, Oxford University Press,
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Primary Literature
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cod
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a
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en
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Association
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antinuclear
and
antinucleolar
antibodies
in
progressive
