496
Autoimmunity in Scleroderma
a crucial event for production of some
autoantibodies. During apoptosis, for ex-
ample, the lupus autoantigens cluster and
become concentrated in the surface blebs
of apoptotic cells where several of these
molecules are speciFcally cleaved by pro-
teases of the interleukin 1
β
–converting
enzyme family. Lymphocytes are educated
not to react against immunodominant epi-
topes of autoantigens and consequently au-
toantibodies are not produced. However,
the fragmentation of speciFc autoantigens
as a result of apoptosis can generate cryp-
tic epitopes, which may break tolerance to
autoantigens.
Casciola-Rosen et al. demonstrated that
scleroderma autoantigens (topo I, the large
subunit of RNA polymerase II, NOR-90)
are fragmented in the presence of reac-
tive oxygen species (ROS) and speciFc
metals, such as copper and iron. They
propose that the autoantibody production
in scleroderma is induced and driven by
cycles of ischemia/reperfusion generating
ROS. The observation that scleroderma au-
toantigens are enriched in nucleoli should
be noted since they colocalize with sites
of high-afFnity metal binding. ±ibrillarin
can also be fragmented and can acquire
high immunogenicity during apoptosis
induced by administration of mercury (see
Chapter 4.1).
Although a number of autoantigens
have been shown to be cleaved by cas-
pases during apoptosis, susceptibility to
cleavage by caspases is not considered to
be a general feature of autoantigens due
to the reasons that (1) caspases during
all forms of apoptosis produce identical
fragments of autoantigens and (2) several
autoantigens (e.g. CENP-B, Fbrillarin) can-
not be cleaved by caspase. Casciola-Rosen
et al. found that several autoantigens are
exclusively or preferentially cleaved by
Granzyme B, which is a serine protease
found in the cytoplasmic granules of cy-
totoxic T lymphocytes and natural killer
cells, and induces apoptosis in target cells
during granule exocytosis–induced cyto-
toxicity. The function of Granzyme B is
achieved partly by catalyzing the cleav-
age and activation of several caspases,
as well as through caspase-independent
pathways. Also, for scleroderma autoanti-
gens, cleavage by Granzyme B is strongly
predictive as shown in Table 2. B-cell epi-
topes of these antigens are believed not to
be hidden in the intact molecule because
Tab. 2
Scleroderma autoantigens cleaved by granzyme B.
Autoantigens
Cleavage site
Topoisomerase I
IEAD
15
-F
a
Fibrillarin
VGPD
184
-G
a
PM/Scl-100
b
VEQD
252
-M
CENP-B
b
VDSD
457
-E
CENP-C
ITQD
452
-E
c
,VGHD
607
-E
c
,LESD
621
-E
c
,LSPD
775
-T
c
,LDND
804
-E
c
,VGQD
888
-I
c
PM/Scl-75
LEND
188
-Q
c
,LEPD
321
-K
c
p27 (SSSCA1)
LDSD
79
-V
c
a
Cleaved sites are experimentally defned by Casciola-Rosen et al.
b
Cleavage by Granzyme B was confrmed by Casciola-Rosen et al.
c
Possible cleaved sites according to the consensus sequences.
As ±or CENP-A and HP1
HS
α,β,γ
, no consensus sequences are ±ound.
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