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Is systemic sclerosis an antigen-driven T cell disease.

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Vol. 50, No. 6, June 2004, pp 1721–1733
DOI 10.1002/art.20315
© 2004, American College of Rheumatology
Is Systemic Sclerosis an Antigen-Driven T Cell Disease?
Lazaros I. Sakkas1 and Chris D. Platsoucas2
sion of E-selectin (18–20), TGF␤ (21), and endothelin 1
(22,23). Monocyte activation is also reported, as documented by increased production in the peripheral blood
of superoxide anion (24), IL-6 (25), IL-1, and TGF␤
(26). Other cells that are found to be activated in SSc
include eosinophils (27), mast cells (18), and T cells
(28–31). Disease-associated autoantibodies such as anti–
topoisomerase I (anti–topo I) antibodies (1), and hypergammaglobulinemia in general, have been observed in
patients with SSc, and their production requires both T
and B cells (32). However, the mechanism or mechanisms responsible for the initiation of the disease have
not been identified.
We recently reported the presence of oligoclonal
T cells in skin biopsy specimens from patients with SSc
(33). The only mechanism that can explain these results
is proliferation and clonal expansion of particular clones
of T cells in response to specific antigen(s). These results
bring the role of T cells in the pathogenesis of SSc to the
forefront of the various mechanisms that may contribute
to the pathogenesis of the disease. SSc may be a specific
antigen–driven T cell disease.
Systemic sclerosis (SSc) is a chronic disease characterized by extensive fibrosis, arterial fibrointimal proliferation, and autoantibody production (1). The disease
affects women more often than men and, at least the
extensive form, is relatively rare (2). The etiology of SSc
is unknown, although certain environmental factors that
can cause sclerodermatous changes have been reported
(1). The disease may lead to considerable morbidity and
mortality (3–5), and the available treatment is largely
The pathologic hallmark of SSc is excessive collagen deposition and microvascular injury. However, the
mechanisms that lead to these changes remain largely
unknown. An early skin mononuclear cell infiltrate
consisting primarily of T cells and macrophages has been
identified (6–9). The degree of mononuclear cell infiltration in the skin of patients with SSc has been shown to
correlate well with both the degree and progression of
skin thickening (6). The proportions of dermal mast cells
are also increased (8). In patients with SSc, fibroblast
activation has been documented by the excess production of collagen, fibronectin, and proteoglycans (10),
protooncogene c-myc (1), interleukin-1 (IL-1) (11), and
adhesion molecules such as intercellular adhesion molecule 1 (12). IL-4 production by Th2 type T cells induces
both the production of transforming growth factor ␤
(TGF␤), a fibroblast mitogen (13–15), as well as the
production of collagen by fibroblasts (16,17). Endothelial cell activation is evident, as suggested by the expres-
T cells in SSc
Several lines of evidence suggest that T cells are
important in the pathogenesis of SSc. These are listed in
Table 1 and are discussed here and in subsequent
sections of this review. In sequential skin biopsy specimens from patients with SSc, mononuclear cell infiltrates consisting of T cells and macrophages appear in
the skin early (7,34), before any microscopic evidence of
fibrosis (7). T cells appear in perivascular areas along
with macrophages (Figure 1). T cells with memory
phenotype were also found in lung biopsy specimens
from patients with SSc and lung involvement (36).
Increased numbers of T cells bearing activation
markers, such as IL-2 receptor (IL-2R) (28), HLA–DR,
and CD29 (28–31), and elevated levels of cytokines such
as IL-2 (37–40), IL-4 (37–39), IL-6 (37–39), and IL-17
(41), which indicate T cell activation, were found in the
Supported in part by NIH grant R01-AR-48042.
Lazaros I. Sakkas, MD, PhD: Temple University School of
Medicine, Philadelphia, Pennsylvania, and Thessaly University School
of Medicine, Larisa, Greece; 2Chris D. Platsoucas, PhD: Temple
University School of Medicine, Philadelphia, Pennsylvania.
Address correspondence and reprint requests to Chris D.
Platsoucas, PhD, L. H. Carnell Professor and Chairman, Department
of Microbiology and Immunology, Temple University School of Medicine, 3400 North Broad Street, Philadelphia, PA 19140. E-mail:
Submitted for publication March 26, 2003; accepted in revised
form March 5, 2004.
Table 1. Evidence of T cell involvement in systemic sclerosis
1. T cells infiltrate skin early, before any evidence of fibrosis
2. Frequency of activated T cells in blood and skin lesions is
3. T cells are Th2 type, producing interleukin-4, which
A. Induces fibroblast collagen production
B. Induces the production of transforming growth factor ␤, a
fibroblast mitogen
4. T cells are necessary for antibody production
5. Graft-versus-host disease, a disease mediated by T cells, has
many similarities to systemic sclerosis
6. Treatments directed against T cells ameliorate systemic sclerosis
7. T cells infiltrating skin lesions contain antigen-driven oligoclonal
T cells
peripheral blood of patients with SSc. Increased protooncogene expression (42) and an increased frequency
of hypoxanthine guanine phosphoribosyltransferase
gene–mutated T cells (43), both of which are suggestive
of T cell activation, were observed in patients with SSc.
Increased levels of soluble IL-2R were also found in
suction blister fluid from the skin of patients with SSc
(44). T cells were found to be necessary for the production of anti–topo I autoantibodies in SSc (32), which,
together with other autoantibodies, is a characteristic
feature of patients with SSc.
Additional evidence for T cell involvement in SSc
comes from the sharing of clinical and pathologic characteristics (45,46), including the serologic profile (47),
between graft-versus-host disease (GVHD) and SSc.
GVHD is mediated by activated T cells and can manifest
as scleroderma-like disease with an increased frequency
of anti–topo I antibodies and an association with particular HLA alleles (47). The various treatment modalities
for patients with SSc have also shed light on the role of
T cells in the pathogenesis of SSc. Treatments directed
against activated T cells, such as cyclosporin A (48,49)
and tacrolimus (49) or depletion of T cells (50), have a
beneficial effect on skin tightness in patients with SSc.
The skin softening that has been observed in certain
patients as a result of the treatment was often associated
with a reduction in the amount of immature (type III)
collagen (51). These treatment approaches against activated T cells were more effective in patients with a short
disease duration, in whom inflammation is more intense
T cell receptors (TCRs) in SSc
It is not known whether T cells in SSc are
activated nonspecifically (i.e., by cytokines or chemokines) or specifically (i.e., by antigens). T cells use their
antigen receptors (TCRs) to recognize, in general, antigenic peptides in association with HLA (classes I and II)
and initiate an immune response. Two different TCRs
have been reported, the ␣/␤ TCR and the ␥/␦ TCR,
which are expressed in a small (usually ⬍10%) proportion of peripheral blood T cells. All 4 TCR chains are
highly polymorphic immunoglobulin-like transmembrane proteins. The variable region of the ␣-chain gene
consists of V␣ and J␣ gene segments, and the variable
Figure 1. Skin lesion in a patient with systemic sclerosis showing the presence of T cells in perivascular areas. Staining was performed using the
avidin–biotin complex immunoperoxidase method and an anti-CD3 monoclonal antibody, as described elsewhere (35). (Original magnification ⫻
100 in A; ⫻ 400 in B.)
region of the ␤-chain gene consists of V␤, D␤, and J␤
segments. Approximately 42 V␣ and at least 65 V␤
functional gene segments (52,53) are grouped into 32 V␣
and 26 V␤ families. Enormous diversity of TCRs is
generated by combinatorial rearrangement of different
VDJ gene segments, imprecise VDJ joining, addition of
template-independent nucleotides (N-region diversity)
at the VDJ junctions, and use of 2 or more D␤ segments.
By analogy to immunoglobulin hypervariable regions,
the corresponding V␣ and V␤ regions are called
complementarity-determining region 1 (CDR1), CDR2,
and CDR3. CDR1 and CDR2 are encoded by V␣ and V␤
gene segments, and CDR3 makes contact with the
peptide (for review, see ref. 54).
The population of T cells comprises a very large
number of different T cell clones, each of which is
defined by the expression of a different TCR. The
maximum theoretical number of different ␤-chain TCR
transcripts has been calculated to be ⬃1012 (54). Although the actual number of ␤-chain TCR transcripts in
the T cell repertoire is very likely considerably smaller,
the possibility of randomly finding multiple identical
copies (ⱖ2) of a single ␤-chain TCR transcript in an
independent sample of T cells is negligible.
T cells may be activated and proliferate in either
a nonspecific manner or in response to a specific antigen. Nonspecific T cell activation and proliferation may
take place in vivo in response to chemokines, cytokines,
or mitogens and would result in a large, heterogeneous,
polyclonal population of T cells that express unique
(different) TCRs when compared with each other. Activation in response to superantigens is also possible and
will also result in polyclonal activation of T cells that will
use a restricted number of V␤ genes and unique CDR3.
In contrast, specific-antigen activation and proliferation
will result in clonal expansion of clones of only those T
cells that recognize this specific antigen through their
TCRs. Such a specific antigen–driven T cell clonal
expansion will be identified by the presence of multiple
identical TCR transcripts, strongly suggesting the presence of monoclonal or oligoclonal populations of T cells.
To determine whether skin biopsy specimens
from patients with SSc contain an antigen-driven oligoclonal population of T cells, we amplified, using the
nonpalindromic polymerase chain reaction (PCR)
method, ␤-chain TCR transcripts from biopsy specimens
of involved skin of patients with SSc (33). The nonpalindromic PCR method was developed in our laboratory
specifically for the amplification of transcripts with an
unknown or variable 5⬘ end, such as the TCRs and
immunoglobulins (55–58). The amplified transcripts
were cloned and sequenced. Sequence analysis revealed
the presence of high proportions of identical ␤-chain
TCR transcripts, ranging from 43% to 90% of those
sequenced, in skin biopsy specimens from 5 patients with
SSc. In 1 patient for whom different skin biopsy specimens were available (obtained at different times [0, 8,
and 13 months earlier] and from 3 different skin regions), identical clonally expanded ␤-chain transcripts
were identified (33).
These results demonstrate the presence of oligoclonal or, in certain cases, monoclonal T cells in biopsy
specimens of involved skin from patients with SSc. It is
very likely that these T cells have undergone specific
antigen–driven proliferation and clonal expansion in
vivo in response to an as yet unidentified antigen. These
results suggest that SSc is an antigen-driven T cell
disease. It remains to be determined whether ␤-chain
TCR transcripts that we have identified in skin biopsy
specimens (33) are expressed on T cells of fetal origin.
Also, it remains to be determined whether these TCR
transcripts recognize self antigen(s) or alloantigen(s).
Identification of these clonally expanded TCR transcripts may facilitate the identification of the antigen(s)
that they recognize. This, in turn, may permit the
development of new therapeutic modalities for the
treatment of SSc.
Similarly, in bronchoalveolar lavage (BAL) fluid
from patients with SSc, restricted TCR junctional region
lengths suggestive of oligoclonal expansion were detected in CD8⫹ T cells (59). Restricted use of TCR V␤
genes was also observed in CD4⫺,CD8⫺ T cells in
patients with SSc (60). Apart from ␣/␤ TCR⫹ T cells,
␥/␦ TCR⫹ T cells were found to display evidence of
activation and oligoclonal expansion. An increased proportion of peripheral blood V␦1 T cells exhibited activation antigens (61), and junctional region lengths were
found to be skewed, which was suggestive of oligoclonal
expansion of ␥/␦ TCR⫹ T cells (62). Non-germline
␦-chain TCR rearrangements have also been reported
(63) and suggest the presence of oligoclonal ␥/␦ TCR⫹
T cells.
Previous studies have shown an association of
particular HLA alleles with SSc (64–74), which supports
the concept that an antigen-driven T cell response is
important in the pathogenesis of SSc. It appears that
HLA associations in SSc may be more involved with
disease susceptibility, because of a substantially stronger
HLA association with autoantibody profiles than with
the disease itself (64–74).
T cell activation and cytokine production in SSc
leading to fibrosis
Activation and proliferation of the relevant T cell
clones in patients with SSc in response to stimulation by
specific SSc antigen(s) (peptide/major histocompatibility
complex [MHC] epitopes) involve ligation of the TCRs
of these T cells with the appropriate peptide/MHC
complexes. In the presence of the appropriate costimulatory signals (75), a productive T cell response will take
place that is characterized by T cell proliferation, cytokine production, and differentiation of precursor T cells
to effector T cells. We propose that this T cell response
is a very significant component in the pathogenesis of
SSc. The production of T cell–derived cytokines is part
of this important process. Among their other functions,
these cytokines are responsible for 1) inducing the
production and regulation of additional cytokines by
other cells of the immune system, 2) inducing the
differentiation of precursor cells of the immune system
to effector cells, and 3) generating, alone or in combination with other mechanisms, pathologic conditions
such as fibrosis. These events are presumed to take place
very early in the pathogenesis of the disease.
Based on the type of cytokines that they secrete,
two polar and reciprocal T cell subsets have been
recognized: the Th1 cells that produce proinflammatory
cytokines such as IL-2 and interferon-␥ (IFN␥), and the
Th2 cells that produce antiinflammatory cytokines such
as IL-4 and IL-5 (76–78). In patients with SSc, Th2 cells
are activated and produce large amounts of IL-4, a
profibrotic cytokine. Plasma IL-4 protein levels are
increased in many patients with SSc (37–39,79). We have
demonstrated the presence of increased levels of alternately spliced IL-4 (IL-4␦) transcripts in peripheral
blood mononuclear cells from patients with SSc (39).
Other investigators reported that CD8 T cells from the
BAL fluid of patients with SSc produce predominantly
IL-4, whereas healthy controls produce IFN␥ (80). IL-4
enhances the production of collagen, fibronectin, glycosaminoglycan, and proteoglycan synthesis in vitro
(16,17,81,82). The major IL-4 protein producers are
CD4⫹ T cells (83). Overexpression of the IL-4 gene in
pancreatic Langerhans’ cells in transgenic mice results in
local fibrosis (84). Furthermore, administration of anti–
IL-4 monoclonal antibody prevents GVHD in mice, with
a concomitant decrease in hepatic fibrosis (85), and
markedly reduces hepatic fibrosis in Schistosomainfected mice (86). Finally, IL-4 induces production of
the fibrogenic cytokine TGF␤ (13–15) and enhances
expression of vascular cell adhesion molecule 1 in endothelial cells (87).
In contrast, IFN␥ inhibits collagen synthesis by
fibroblasts in vitro (82,88) and in vivo in mice (89). IFN␥
may also have a favorable effect on patients with SSc
(90–93). The importance of Th1/Th2 cytokines in fibrosis is supported by the finding that MRL/lpr mice lacking
the IFN␥ receptor gene exhibit a syndrome that resembles human SSc (94).
IL-17, a T cell cytokine that can be produced by
both Th1 and Th2 cells (95), is overexpressed in peripheral blood and skin of patients with SSc (41). IL-17
enhances the proliferation of fibroblasts (41), induces
IL-6 production by fibroblasts and endothelial cells (96),
induces IL-1 production, and enhances the expression of
adhesion molecules on endothelial cells (41).
In addition to IL-4, the major fibrogenic cytokine
in SSc is TGF␤. IL-4 promotes the production of TGF␤
(13–15), which is expressed on mononuclear cell infiltrates, endothelial cells, and fibroblasts in the early
stages of skin fibrosis (97,98). There are at least 3 TGF␤
isoforms, TGF␤1, TGF␤2, and TGF␤3. TGF␤, upon
binding to its receptor, activates transcription factors
called Smads, some of which are stimulatory and others
inhibitory (99). SSc skin fibroblasts may produce
amounts of TGF␤ similar to those secreted by normal
skin fibroblasts but express higher levels of TGF␤ receptor type I (TGF␤RI) and TGF␤RII (100,101). TGF␤1
can cause fibroblast activation and hyperplasia and
increased synthesis of collagen and fibronectin
(102,103). Also, it inhibits matrix metalloproteinases
(MMPs) (104). Blockage of TGF␤1 by antibodies abolishes the up-regulated transcription of the collagen gene
(101). TGF␤1 stimulates the production of IL-1 and
platelet-derived growth factor (PDGF) by monocytes
(105) and the production of connective tissue growth
factor (CTGF) by fibroblasts (106).
T cells, monocytes, endothelial cells, and fibroblasts produce IL-6, and it is up-regulated by IL-1 (107),
IL-17 (96), or PDGF (108) in SSc fibroblasts. Elevated
serum levels of IL-6 were observed in patients with SSc
(109). IL-6 induces collagen production by fibroblasts
and promotes Th2 differentiation (110). CTGF is increased in the serum of patients with SSc (111). It is also
expressed during the late sclerotic skin stages of SSc
(112). CTGF is a fibroblast mitogen that increases
collagen production (91) and is produced by fibroblasts
in response to TGF␤ (111–113).
It is our opinion that antigen-driven T cell activation and clonal expansion in SSc is the primary event
in the pathogenesis of the disease, and that it is mediated
at large through T cell–derived cytokines. These cytokines are produced either directly by activated T cells, or
their expression is regulated directly or indirectly by T
cells and/or T cell–derived cytokines. In addition, certain
other cytokines are produced and/or regulated mostly by
other cell types (non–T cells) and appear to be secondary to the antigen-driven T cell activation and proliferation. These other cytokines are found in SSc lesions or
in the serum of patients with SSc, as the result of the
chronic inflammation that has been initiated and is
propagated by the antigen-driven T cells (which is the
primary event in the pathogenesis of the disease). Certain of these other cytokines are discussed below.
IL-1 produced by monocytes, B cells, T cells, and
SSc fibroblasts participates in mononuclear cell chemotaxis. It enhances collagen synthesis by fibroblasts either
directly or through fibroblast production of IL-6 and
PDGF (107). However, IL-1 in synovial fibroblasts stimulates the release of MMPs (114).
PDGF is produced by platelets, macrophages,
fibroblasts, and endothelial cells. It is increased in SSc
Figure 2. Schematic paradigm of T cell involvement in fibrosis of
systemic sclerosis. T cells produce interleukin-4 (IL-4), which promotes fibroblast collagen production and macrophage (Mo) production of transforming growth factor ␤ (TGF␤), which in turn induces
fibroblast collagen synthesis and proliferation. TGF␤ also induces
connective tissue growth factor (CTGF) production by fibroblasts. T
cells also produce IL-17, which promotes macrophage production of
tumor necrosis factor ␣ (TNF␣) and IL-1. IL-1 in turn induces
fibroblast production of collagen, IL-6, and platelet-derived growth
factor (PDGF). IL-17 and TNF␣ on endothelial cells (EC) promote
the recruitment of inflammatory cells into perivascular areas. MMP ⫽
matrix metalloproteinase.
Figure 3. Simplified diagram of T cell involvement in microvascular
injury in systemic sclerosis. Activated T cells produce IL-4 and IL-17.
IL-4 in the blood vessel wall induces fibrosis and causes fibroblast
hyperplasia through the production of TGF␤. IL-17 stimulates endothelial cell production of adhesion molecules IL-1 and IL-6 through
induction of TNF␣. Endothelial cell activation contributes to inflammatory cell influx into the perivascular areas. See Figure 2 for
(97) and can be up-regulated in endothelial cells by
complement activation (115) or hypoxia (116). PDGF is
a fibroblast mitogen and stimulates collagen synthesis
(102). Induction of fibroblast collagen production by
TGF␤ may be mediated through up-regulation of PDGF
receptors (97). PDGF can also promote IL-6 production
by fibroblasts (108). Elevated serum levels of monocyte
chemoattractant protein 1, macrophage inflammatory
protein 1 (117), and tumor necrosis factor ␣ (TNF␣)
(118) were also found in SSc. These molecules participate in mononuclear cell chemotaxis to SSc lesions.
Endothelin-1, produced by endothelial cells in patients
with SSc, is a potent vasoconstrictor and can induce
collagen synthesis and inhibit MMP expression (119).
Activated T cells and the cytokines that they
produce are sufficient to explain all 3 main characteristics of SSc, as follows:
1) Generation of fibrosis, which is illustrated in
Figure 2. As previously discussed, IL-4 is produced by
CD4⫹ T cells (16,17,80–83) and promotes the production of collagen by fibroblasts (16,17) and the production
of TGF␤ by monocyte/macrophages (13–15). TGF␤ also
induces fibroblasts to proliferate and produce collagen
(13–15) and to produce CTGF (111–113). CTGF also
significantly increases the synthesis of collagen and
fibronectin and promotes substantial matrix remodeling
of fibroblast-populated 3-dimensional collagen lattices
(113). In addition, T lymphocytes produce IL-17, which
induces TNF␣ and IL-1 production by monocyte/macro-
Figure 4. Paradigm of likely T cell interactions with B cells. T cells are
necessary for anti–topoisomerase I (anti–topo I) autoantibody production and very likely for the production of other antibodies (abs).
Antiendothelial cell and antifibroblast antibodies appear to induce
IL-1 production after binding to the respective cells. See Figure 2 for
other definitions.
phages (26,41,96). IL-1 induces production of collagen,
IL-6, and PDGF by fibroblasts and endothelial cells (96).
IL-17 also induces the expression of IL-1 and adhesion
molecules on endothelial cells (41).
2) Microvascular fibrointimal proliferation,
which is illustrated in Figure 3. Activated T cells produce
IL-4 (16,17,80–83) and IL-17 (41). IL-4 induces fibrosis
(16,17) and causes fibroblast hyperplasia by enhancing
TGF␤ production (13–15). TGF␤ induces fibroblasts to
proliferate and secrete collagen (13–15) and also to
produce CTGF (111–113) (see above). IL-17 induces the
expression on endothelial cells of adhesion molecules,
IL-1, and IL-6. Activation of adhesion molecules of the
endothelial cell layer allows inflammatory mononuclear
cells to cross the endothelial cell layer into the perivascular space, thereby propagating the disease.
3) Autoantibody production, which is shown diagrammatically in Figure 4. A substantial number of
autoantibodies have been detected in the serum of
patients with SSc (for review, see refs. 1 and 120) and
include anti–topo I (32,68), anticentromere (121), antifibrillarin, and anti–RNA polymerases I, II, and III
(1,120). Production of antiendothelial (122) and antifibroblast antibodies (123) has also been reported. The
latter antibodies appear to induce IL-1 production after
binding to the respective cells. In addition to B cells, T
cells also are required for anti–topo I autoantibody
production (32) and very likely for the production of the
other autoantibodies.
Other diseases with a predominance of Th2 immune response include helminthic diseases and allergic
diseases. Helminthic diseases, such as Schistosoma infection, are characterized by intense local fibrosis (86).
However, allergic diseases may lack overt fibrosis. One
explanation may be that allergen-reactive Th2 cells in
individuals who are atopic may be present in the circulation temporarily during seasonal allergen exposure
(77). Nevertheless, airway fibrosis beneath the subepithelial basement membrane still occurs in human atopic
asthma as well as in a murine model of atopic asthma
(124). It should be noted that the Th1/Th2 immune
response pattern is an oversimplification, and that a
local cytokine field is a summation of the cytokine fields
produced by a variety of individual cells (125). In
individuals who are atopic, a local field may be derived
from many basophils, which are not present in SSc.
Putative T cell antigens in SSc
Several lines of evidence suggest that the activation of T cells in SSc is antigen driven, yet the antigen or
antigens that drive this T cell clonal expansion (33) are
not known. However, several putative SSc antigens have
emerged, including the following:
HLA of fetal or maternal origin. The presence of
small proportions (usually ⬍5%) of fetal cells in the
peripheral blood and the skin of women with SSc who
were previously pregnant has been well documented
(126–133). Additionally, small proportions of maternal
cells have been identified in the peripheral blood of
women with SSc who were not previously pregnant or in
men with SSc (131,133). The presence of fetal cells or
maternal cells in these patients with SSc is believed to be
the result of microchimerism (126–133), which may
persist in both patients with SSc and normal donors
(130,131,133). These fetal or maternal cells belong to a
number of different hemopoietic cell lineages (126–
133). The sources of the HLA-disparate cells in both
men and women may include cells from the fetus (only
women who have been pregnant), cells from the mother,
cells from a twin sibling, cells from a blood transfusion,
or cells from a transplant (the last 4 may be the source
of engraftment in both men and women). The mechanisms of engraftment in microchimerism are not fully
understood, and it is not known whether regulatory cells
that induce/regulate tolerance of the microchimerism
are involved. Interestingly, the genotype HLA–
DQA1*0501, which is associated with SSc (69), has been
found to be associated with the persistence of microchimerism in women with SSc (70). Other investigators
were unable to demonstrate such an association (134).
However, not all investigators reported increased microchimerism in SSc (135,136).
It has been proposed that SSc in previously
pregnant women is caused by chronic fetal anti-maternal
GVHD that is manifested as SSc; this may be designated
as maternal SSc (126–133). In other words, SSc in
previously pregnant women is initiated by activation of T
cells of fetal origin in response to maternal antigens or
unknown antigenic stimuli, or because of breaking of the
tolerance (129–133) that controls microchimerism (the
coexistence of maternal and fetal cells), resulting in
induction of chronic fetal anti-maternal GVHD (126–
133). In a similar manner, T cells of maternal origin may
be activated in response to offspring antigens or to
unknown antigenic stimuli, or because of breaking of
tolerance (127–135), resulting in induction of chronic
maternal anti-offspring GVHD, which is manifested as
SSc in women who have not been previously pregnant or
in men; this may be designated as offspring SSc. Therefore, alloantigens may be putative SSc antigens with an
alloresponse of fetal T cells to maternal alloantigens or
of maternal T cells to offspring alloantigens possibly
responsible for the initiation of SSc. This concept is
consistent with the clinical and pathologic characteristics
(45,46) and the serologic profile (47) that are shared
between patients with GVHD and patients with SSc,
including fibrosis, microvascular fibrointimal proliferation, and production of autoantibodies (47). However,
additional studies are needed to prove this concept.
Scaletti et al reported that 39 of 202 T cell clones
derived from skin biopsy specimens or peripheral blood
from 3 women with SSc, and 11 of 312 T cell clones
derived from the peripheral blood of 3 healthy women,
proliferated in response to maternal MHC antigens
(137). All 6 women had a male offspring. In situ
hybridization studies using appropriate fluorescence
probes specific for the Y chromosome revealed that 7 of
the maternal MHC-responding T cell clones obtained
from the patients with SSc and 1 of the T cell clones
obtained from healthy donors exhibited the Y chromosome, demonstrating that these T cell clones are indeed
derived from the male offspring. The T cell clones
derived from male offspring T cells of women with SSc
were of the Th2 type and produced, in response to
maternal MHC antigens, substantially higher levels of
IL-4 than did all of the remaining T cell clones derived
from the same women. In the remaining T cell clones,
the Y chromosome was not detectable, although they
responded by proliferation to maternal or allogeneic
MHC antigens (137). These results demonstrate that
male offspring T cells that are present in small proportions in the skin or in the peripheral blood of women
with SSc are able to respond, under appropriate conditions, to maternal MHC antigens and produce Th2
cytokines (137). The long-term presence of these male
offspring T cells in women with SSc supports the notion
that long-term microchimerism, manifested as chronic
GVHD, may play an important role in the pathogenesis
of SSc (137).
DNA topo I and other autoantigens. DNA topo I
elicits both autoantibody responses (32,68) and cellular
responses in patients with SSc (137–139). Collaboration
of T and B cells is required for autoantibody responses
to DNA topoisomerase (32). Anti–topo I antibodies are
characteristic of the diffuse type of SSc (1,120). The
possibility that an autoantigen elicits both an autoantibody response and a cellular response is supported by
the findings of a substantially stronger HLA association
with autoantibody profiles than with the disease itself
(64–68,140). Kuwana et al reported that HLA–DQ and
DR genes together control the anti–topo I antibody
response in patients with SSc (68). In that study, all
patients with anti–topo I antibody response were HLA–
DQB1*0601 positive or DQB1*0301 positive, whereas
these alleles were found in only 44% of the anti–topo I
antibody–negative patients (P ⬍ 0.00001) and in 58% of
the healthy control subjects (P ⬍ 0.00001).
Peripheral blood mononuclear cells from 25 of 26
patients (96%) with SSc who had anti–topo I antibody
exhibited substantial T cell proliferative responses to
human recombinant topo I (138). These responses were
evident after only 3 days in culture with topo I. In
contrast, only 4 of 10 patients (40%) with SSc who were
anti–topo I antibody negative, and 13 of 21 normal
donors (62%) exhibited such a proliferative response
(138). These responses required a 7-day incubation in
culture with topo I. All patients with SSc and normal
donors who were positive for either DRB1*1501,2
(DR15), DRB1* 1101,3,4 (DR11), or DRB1*07 (DR7)
exhibited T cell proliferative responses to topo I. This
response was mediated by CD4⫹ T cells, required
antigen-presenting T cells, and was restricted by
HLA–DR and to some extent by HLA–DQ. Limiting
dilution analysis was used to estimate the frequency of T
cell responses to topo I, which was found to be in the
range 1/9,277–1/24,853 (138).
T cells specific for DNA topo I in patients with
SSc used highly restricted CDR3 regions of the ␤-chain
TCR transcripts (139). However, identical CDR3 se-
quences were used by DNA topo I–specific T cells
derived from normal donors (139). In another study,
substantial differences were not found in the phenotypic
and functional properties of topo I–reactive T cells from
a patient with SSc and her healthy identical twin (141).
These results suggest that these topo I T cell clones are
members of the normal T cell repertoire. This T cell
response is restricted by class II MHC alleles and is not
associated with the presence or absence of SSc or the
presence of anti–topo I antibody. The anti–topo I antibody and the cellular responses may be autoimmune in
nature and may take place in patients with SSc because
of the extensive dysregulation of the immune system
caused by the disease. If such is the case, this would
decrease the likelihood that topo I is a putative antigen
responsible for the initiation of SSc.
Other putative autoantigens that elicit autoantibody responses in patients with SSc include fibrillarin
(142), centromere (121), RNA polymerases I, II, and III
(1,120), and other nucleolar autoantigens (143). Antifibrillarin antibodies are found in 33% of men with SSc
and in 14% of women with SSc and are associated with
the HLA–DQB1*0604 and DRB1*1302 haplotypes
(142). Antibodies to CENP-E, a centromere kinesin-like
protein, are found mostly in a rather infrequent form of
SSc known as the CREST syndrome (calcinosis,
Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, telangiectasias), and their presence is associated
with the HLA–DQB1*05 alleles (121). Certain HLA–
DRB1 (DRB1*0101,*0405, and *01302) or DQB1
(DQB1*0501) alleles were found to be associated with
high serum anticentromere titers (140).
Cytomegalovirus (CMV). CMV has been suggested as the cause of SSc, because increased levels of
anti-CMV antibodies were found in patients with SSc,
and extensive similarities in the pathology between
CMV vasculopathy and SSc vascular changes have been
demonstrated (144–146). A molecular mimicry has been
identified between a peptide sequence of the UL70
protein of CMV (DDGYF) and topo I (residues 122–
126) (145,146). Molecular mimicry is defined as the
sharing of common epitopes between microorganisms
(such as viruses) and host proteins (for review, see ref.
147). T cells that recognize viral determinants may
recognize, by molecular mimicry, host determinants that
are shared with the virus, even long after the virus is no
longer present. This may result in the development of
autoimmune disease. Molecular mimicry may play an
important role in the pathogenesis of SSc.
Retroviruses. Retroviruses have been long suspected as putative antigens in SSc (148). An increased
frequency of cancer in first-degree relatives of patients
with SSc (149) could be attributed to environmental
factors such as retroviruses. A molecular mimicry (complete identity of 6 sequential amino acid residues) has
been identified between topo I and retroviral protein
p30gag of type C mammalian retroviruses (150).
T cells in animal models of SSc
The tight-skin (TSK) mouse is perhaps the best
animal model for SSc. In the TSK mouse, Th2 T cells
infiltrate skin lesions and produce IL-4 (151). In this
animal model, fibrosis can be prevented by null mutation
of the IL-4 gene (151), by anti–IL-4 treatment (152), or
by introduction of an IL-12–encoding plasmid (153). In
vivo administration of intravenous immunoglobulin decreased splenocyte secretion of IL-4 and TGF␤ and
abrogated fibrosis (154). T cells infiltrating skin lesions
use restricted TCR V␤ gene segments (155). However,
cutaneous thickening can still occur in TSK mice that are
T cell and B cell deficient (156). In a mouse model of
SSc induced by local injections of bleomycin, TGF␤1
was detected early in skin lesions (157).
Concluding remarks and future perspectives
Current evidence suggests that T cells, B cells,
macrophages, fibroblasts, endothelial cells, eosinophils,
and mast cells are activated in SSc. The presence of
monoclonal/oligoclonal expansions of T cells infiltrating
the skin lesions of patients with SSc (33) strongly
suggests that these T cells have undergone in situ
antigen-driven proliferation and clonal expansion in
response to an as yet unidentified antigen(s). This
antigen may be a self antigen or an alloantigen. In other
words, antigen-driven T cell activation in SSc is a
primary event and is not secondary to the nonspecific
action of cytokines secreted by other cell types. These
findings suggest that T cells are very important in the
pathogenesis of the disease and make T cells targets of
immunotherapy and other treatment modalities in SSc.
A new therapy may be redirection of T cell cytokines
toward Th1. Redirection of cytokines produced by activated T cells toward Th1 has been tried in experimental
systems, with success (13–15,84,91,158,159). Administration of IFN␥ to patients with idiopathic pulmonary
fibrosis has led to increased survival and downregulation of TGF␤ (160). In addition, identification of
the antigen(s) that elicit T cell responses in SSc may
permit the development of new therapeutic approaches
for the treatment of this disease.
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