Autoimmunity in Scleroderma
495
by all anti-PM/Scl–positive sera, another
domain between amino acids 492 to 703
recognized by the minority of sera. Ge
et al. identiFed three antigenic regions;
156 to 312, 507 to 749, and 750 to 882.
Using synthetic peptides, Bluthner et al.
demonstrated that a cluster of epitopes
is located between amino acids 166 and
245 and that the second cluster is lo-
cated between 672 and 866. Among them,
a major epitope is located between 231
and 245, which is suggested to form a lo-
cal
α
-helical secondary structure. Recently,
anti-PM/Scl antibodies are shown to rec-
ognize also other components in human
exosome.
5
Molecular Mimicry and Scleroderma
Autoantigens
Production of some autoantibodies has
been considered to be caused by cross-
reactivity between viral or bacterial protein
and autoantigen, which were named
molec-
ular mimicry
. The concept of molecular
mimicry was Frst tested in an exper-
imental animal model of autoimmune
encephalomyelitis in 1985, and since that
time, substantial evidence has accumu-
lated such that it has become the favored
mechanism for causing some autoim-
mune diseases. If the Frst reaction was
initiated by a foreign stimulus, the major
epitope would have a similar antigenic-
ity to the true antigen as a reminiscence
of the primary immunization. However,
recent epitope-mapping studies indicate
that none other than the antigen molecule
itself is a trigger molecule as for autoim-
munity in systemic autoimmune diseases.
Maul et al. reported that the sequence
spanning 741 to 746 in the C-terminal
region of topo I matches a sequence
present in mammalian retroviral p30
gag
core nucleoprotein. However, antibodies
reacting to the sequence are shown to
be rare in anti-topo I autoantibodies,
and topo I fragments containing this se-
quence were rarely recognized by periph-
eral blood T cells from anti-topo I–positive
patients.
Because the two autoepitopes of CENP-
A have been restricted to small peptide
regions, its possible molecular mimicry
was explored. A variety of autoantibodies
has been described in hepatitis B and C
for ages and we found that major epi-
topes of CENP-A, peptides A and B, are
homologous to the core antigens of hep-
atitis B virus (HBV) and hepatitis C virus
(HCV). Especially, the HCV core antigen
contains a sequence similar to peptide B
and the PRRRS sequence that repeats in
peptide A. However, the corresponding
regions of viruses were not generally rec-
ognized by HBV- or HCV-infected sera
according to the previous epitope-mapping
studies of hepatitis patients. Detailed map-
ping studies by Mahler et al. showed
that the CENP-A major epitope motif
(GPXRX) was present in Epstein–Barr
nuclear antigen 1. However, the gradual
development of ACA in a patient from
an antihistone response was not mediated
by the molecular mimicry mechanism re-
sulting from an anti-Epstein–Barr virus
response.
6
Apoptosis and Scleroderma Autoantigens
A lot of evidence suggests the involve-
ment of biochemical events activated dur-
ing apoptosis (programmed cell death),
such as caspase activation in the gener-
ation of particular autoantigens targeted
in systemic autoimmune diseases. Selec-
tive substrate phosphorylation/association
to splicing factors has been seen to be
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