494
Autoimmunity in Scleroderma
topo I–reactive T cells having a strong
helper activity are selectively expanded in
patients with anti-topo I antibody. Also
interestingly, for autoreactive T-cell re-
sponses, antigen forms (native full-length
vs fragmented) and cells of antigen presen-
tation (dendritic cell vs antigen-presenting
cell in PBMC
=
monocytes and B cells)
are critical. The fact that fragmented
recombinant protein strongly induces T-
cell responses suggests cryptic epitopes
(see Chapter 6) recognized by autoreactive
T cells.
4
Scleroderma-associated Nucleolar
Autoantigens
4.1
Fibrillarin
Fibrillarin is a 34 kDa protein that de-
rives its name from its localization to
both the ±brillar center and dense ±b-
rillar component of the nucleolus. It
is associated with U3 and other small
nucleolar RNAs (snoRNAs) required for
rRNA processing. Kasturi et al. showed,
using an immunoblot with recombinant
fragments, that anti±brillarin antibodies
reacted primarily with epitopes present in
the N- (1–80 a.a.) and C- (276–321 a.a.)
domains
of
±brillarin
in
addition
to
a minor epitope at an internal region
(149–229 a.a.).
Autoantibodies against ±brillarin can
also be induced in H-2
s
mice by treat-
ment with mercuric chloride (HgCl
2
).
Immunoprecipitation studies with trun-
cated yeast ±brillarin shows similar recog-
nition
of
a
conserved
conformational
determinant of anti±brillarin responses
in murine HgCl
2
–induced autoimmu-
nity and human scleroderma. However,
the target of the autoantibodies is not a
±brillarin–mercury complex even though
a metal–protein interaction does occur.
Proteolytic cleavage of ±brillarin follow-
ing
xenobiotic-induced
cell
death
can
lead to the generation of novel protein
fragments that obtain more appropriate
immunogenic activity. These studies by
Pollard et al. suggest that cryptic pep-
tides
(see
Chapter 6)
would
serve
as
antigenic determinants for autoreactive
T cells.
4.2
PM/Scl Antigen
A
nuclear/nucleolar
particle
termed
PM/Scl
has been shown to immunopre-
cipitate a complex of 11 to 16 polypeptides
ranging from 20 to 110 kDa. The PM/Scl
complex is the human homologue of
the yeast exosome, which is an RNA-
processing complex. In immunoblotting
studies,
two major
antigenic polypep-
tides have been shown – a 100 kDa anti-
gen (PM/Scl-100) recognized by most
anti-PM/Scl sera and a 75 kDa antigen
(PM/Scl-75) recognized by around half
the sera. According to epitope mapping of
PM/Scl-75 by Alderuccio et al., the major
epitope was estimated to be present within
the C-terminal 160 amino acid residues.
Of eight anti-PM/Scl sera, however, only
two sera react with the cellular 75 kDa
antigen as well as the C-terminal region.
Interestingly, three additional anti-PM/Scl
sera displayed a weaker reactivity with
the entire PM/Scl-75 recombinant protein,
suggesting the existence of another epi-
tope in the N-terminal half. By mapping
studies of PM/Scl-100 with truncated re-
combinant proteins, Bluthner and Bautz
mapped two autoepitopes on the recom-
binant PM/Scl-100: one antigenic domain
between amino acids 153 to 324 recognized
previous page 494 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online next page 496 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online Home Toggle text on/off