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
Black, C.M., Denton, C.P. (1998) Scleroderma
and
Related
Disorders
in
Adults
and
Children, in: Maddison, P.J., Isenberg, D.A.,
Woo, P., Glass, D.N. (Eds.)
Oxford Textbook
of Rheumatology
, Oxford University Press,
Oxford, pp. 1217–1247.
Harvey, G.R., McHugh, N.J. (1999) Serologic
abnormalities in systemic sclerosis,
Curr.
Opin. Rheumatol.
11
, 495–502.
Pollard, K.M. (2002) Cell death, autoantigen
cleavage, and autoimmunity,
Arthritis Rheum.
46
, 1699–1702.
Rosen, A., Casciola-Rosen, L. (1999) Autoanti-
gens as substrates for apoptotic proteases:
implications for the pathogenesis of systemic
autoimmune disease,
Cell Death Differ.
6
,
6–12.
RothFeld, N.±. (1996) Autoantibodies to Sclero-
derma-associated Antigens, in: Venrooij, W.J.,
Maini, R.N. (Eds.)
Manual of Biological Markers
of Disease
, Kluwer, Dordrecht, C5.1, pp. 1–7.
Verheijen, R.
(1992)
B-cell
epitopes
of
scleroderma-speciFc autoantigens,
Mol. Biol.
Rep.
16
, 183–189.
von Muhlen, C.A., Tan, E.M. (1995) Autoanti-
bodies in the diagnosis of systemic rheumatic
diseases,
Semin. Arthritis Rheum.
24
, 323–358.
Wucherpfennig, K.W. (2001) Mechanisms for
the induction of autoimmunity by infectious
agents,
J. Clin. Invest.
108
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Primary Literature
Alderuccio, ±., Chan, E.K.L., Tan, E.M. (1991)
Molecular characterization of an autoantigen
of PM-Scl in the polymyositis/scleroderma
overlap syndrome: a unique and complete
hum
ancDNAen
cod
inganapp
a
r
en
t75
-kD
acidic protein of the nucleolar complex,
J. Exp.
Med.
173
, 941–952.
Bernstein, R.M.,
Steigerwald, J.C.,
Tan, E.M.
(1982)
Association
of
antinuclear
and
antinucleolar
antibodies
in
progressive
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