492
Autoimmunity in Scleroderma
have been found in humans. They are
closely related and contain two functionally
important and conserved domains: N-
terminal chromo and C-terminal chromo
shadow domains. Three human homo-
logues HP1
HS
α
,HP
1
HS
β
,an
dHP
1
HS
γ
are targeted by ‘‘antichromo antibodies’’
in a subset of ACAs. Interestingly, an-
tichromo antibodies are always associated
with ACAs. Furuta et al. reported that 20%
of ACA-positive sera also had antichromo
antibodies that targeted p23 (HP1
HS
γ
)and
p25 (a mixture of HP1
HS
α
and HP1
HS
β
).
HP1
HS
α
, which has 191 amino acids,
was used for epitope mapping with im-
munoblotting. Regions 1 (16–43) and 2
(106–191) were found to be important for
autoepitopes and in the two conserved
regions:
chromodomain
(13–78)
and
chromo shadow domain (114–179). Since
HP1
HS
α
localizes in the inner centromeric
region of mitotic chromosomes and an-
tichromo antibodies are exclusively found
in ACAs, ACA is likely to recognize macu-
lomolecular antigenic complexes. Interest-
ingly, some ACA-positive sera were found
to develop antichromo antibodies after a
long period. This phenomenon implies
‘‘epitope spreading,’’ which means that the
epitope is spreading to another molecule
or to domains of the same molecule.
Another autoantigen targeted by a mi-
nor subset of ACA has been characterized
by ACA-positive patients. This antigen,
p27, has 199 amino acids with a pre-
dicted molecular weight of 22 kDa and
was nomenclatured ‘‘SSSCA1’’ (
S
j¨ogren
s
yndrome/
sc
leroderma
a
utoantigen
1).
Many charged residues (17 acidic and
12 basic) are present in the N-terminal
region (7–83 a.a.) and two short Pro-
rich stretches are present in the remain-
ing region (113–122 and 138–145 a.a.).
So far, it is not known whether p27
is
a
structural component
such
as
a
centromere-associated protein; however,
the exclusive association between anti-
bodies against p27 and the centromere
is suggestive of a biological interaction
between these antigenic molecules. Inter-
estingly, Zhou et al. showed that p27 as
well as CENP-B, ±brillarin, and RNA poly-
merase II was overexpressed in ±broblasts
from scleroderma patients.
3
Topoisomerase I
3.1
Autoimmunity against Topoisomerase I
In the eukaryotic cell, the topological
status of DNA is modulated by DNA
topoisomerases. Topo I causes a single-
strand break, which can allow the two
sections of DNA helix on either side of
the nick to rotate freely relative to each
other. This enzyme plays important roles
in chromatin organization, DNA replica-
tion, recombination, and transcription. It
localizes in the nucleoplasm, nucleolus,
and nucleolar organizing regions, giving
IIF staining patterns of speckled nucleolar
and densely speckled nucleoplasmic dec-
oration (Fig. 1b). Racial differences in the
prevalence and autoepitopes of anti-topo
I antibodies are noted. Immunoglobu-
lin isotypes are IgG, IgA, and IgM, and
their frequencies are IgG
>
=
IgA
À
IgM.
Isotypesw
itchw
ithpers
istenceofIgGex
-
pression in longitudinal studies and the
presence of all four IgG anti-topo I sub-
classes suggest chronic B-cell stimulation
by antigen-driven mechanism.
3.2
B-cell Epitope
Topo I, a 105 kDa polypeptide, has 4 major
domains: the N-terminal domain (1–200
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