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PHYSIOLOGY IN MEDICINE: A SERIES OF ARTICLES LINKING MEDICINE WITH SCIENCE
Physiology in Medicine
Dennis A. Ausiello, MD, Editor; Dale J. Benos, PhD, Deputy Editor; Francois Abboud, MD, Associate Editor;
William Koopman, MD, Associate Editor
Review
Annals of Internal Medicine
Paul Epstein, MD, Series Editor
Following the Molecular Pathways toward an Understanding of the
Pathogenesis of Systemic Sclerosis
Sergio A. Jimenez, MD, and Chris T. Derk, MD
Clinical Principles
Physiologic Principles
Systemic sclerosis is an autoimmune connective tissue
disorder of unknown cause.
The pathogenesis of systemic sclerosis is extremely complex;
at present, no single unifying hypothesis explains all
aspects.
It is clinically heterogeneous, ranging from limited skin
involvement to diffuse skin sclerosis with severe internal
organ involvement.
The Raynaud phenomenon, swelling of the extremities, and
diffuse arthralgias often precede the onset of skin tightness
and induration.
Fundamental abnormalities in at least 3 types of cells are
intimately involved in the development of the clinical and
pathologic manifestations of the disease: 1) fibroblasts; 2)
endothelial cells; and 3) cells of the immune system, in
particular T and B lymphocytes.
Autoantibodies, some with very high specificity, are present
almost universally.
The profound functional alterations in these cells result in the
characteristic triad of pathologic changes: severe and often
progressive cutaneous and visceral fibrosis; obliteration of
the lumen of small arteries and arterioles; and humoral and
cellular immunologic abnormalities, which include the
production of autoantibodies, the chronic mononuclear cell
infiltration of affected tissues, and the dysregulation of
lymphokine and growth factor production.
Mortality and morbidity are substantial and are directly
related to the extent of the fibrotic and microvascular
alterations.
A crucial component in systemic sclerosis pathogenesis is the
persistent and unregulated activation of genes encoding
various collagens and other extracellular matrix proteins.
A better understanding of the pathogenesis of this incurable
disorder will help to design effective therapies in the
future.
Abnormal regulation of transcription of genes encoding
various collagens is responsible for tissue and vascular
fibrosis.
Visceral involvement with fibrosis, microvascular alterations,
and mononuclear cell infiltration of the gastrointestinal
tract, lungs, heart, and kidneys is present to a variable
extent in most patients.
Alterations in the production of cytokines and growth factors,
which are capable of modulating the function of fibroblasts
and other target cells, appear to play a relevant role.
Transforming growth factor-␤ is one of the growth factors
intimately involved in the fibrosis that accompanies
systemic sclerosis.
S
ystemic sclerosis is a disease of unknown origin characterized by excessive deposition of collagen and other
connective tissue macromolecules in skin and multiple internal organs, prominent and often severe alterations in the
microvasculature, and humoral and cellular immunologic
abnormalities (see Glossary). Systemic sclerosis is a complex and heterogeneous disease. Clinical forms range from
limited skin involvement with minimal systemic alterations
(limited cutaneous systemic sclerosis) to forms with diffuse
skin sclerosis and severe internal organ disease (diffuse cutaneous systemic sclerosis) (1), and occasionally a fulminant course (fulminant systemic sclerosis) (2).
The most apparent and almost universal clinical features of systemic sclerosis are related to the progressive
Ann Intern Med. 2004;140:37-50.
For author affiliations, see end of text.
For definition of terms used, see Glossary.
© 2004 American College of Physicians 37
Review
Pathogenesis of Systemic Sclerosis
Glossary
Allele: One of 2 or more different genes containing specific inheritable characteristics that occupy corresponding positions (loci) on paired chromosomes.
Allogenic: Having a different genetic constitution but belonging to the same species.
Apoptosis: Disintegration of cells into membrane-bound particles that are then phagocytosed by other cells.
Calcitonin gene-related peptide: A second product transcribed from the calcitonin gene. It is found in a number of tissues, including the nervous system. It can act as a
vasodilator.
Cellular immunity: Involves the production of lymphocytes by the thymus (T cells) in response to exposure to an antigen.
Codon: A sequence of 3 nucleotides in a strand of DNA that provides the genetic code for a specific amino acid.
COL1A1: Gene encoding the ␣1 chain of type I collagen.
COL1A2: Gene encoding the ␣2 chain of type I collagen.
Connective tissue growth factor (CTGF): Growth factor that plays a critical role in tissue fibrosis as well as angiogenesis, axial development of the musculoskeletal system,
structural organization of connective tissue, and embryo implantation.
Cytokines: Intercellular messenger proteins. Hormone-like products of many different cell types that are usually active within a small radius of the cells producing them.
Dinucleotide: The product of cleaving a polynucleotide (nucleic acid composed of ⱖ2 nucleotides).
Epitope: Any component of an antigen molecule that functions as an antigenic determinant by permitting the recognition and attachment of specific antibodies.
Extracellular matrix: The ground substance occupying the space outside cells in a specific tissue.
Exon: A portion of the DNA that is transcribed to RNA, which is then expressed.
Fibroblasts: Mesenchymal cells responsible for the production of fibrous tissue.
Fibronectin: A cell-binding glycoprotein.
Growth factors: Polypeptides produced by various cells of the body that promote growth and development by directing cell division, maturation, and differentiation and by
mediating maintenance and repair of tissues.
Haplotypes: The genetic constitution of an individual with respect to 1 member of a pair of allele genes.
HLAs: Human leukocyte antigens. The cell surface molecules encoded by genes in the MHC on chromosome 6. These molecules are divided into 2 classes (class I and class II)
on the basis of their structure. Class I and II molecules attach and present antigens to CD8⫹ (cytotoxic and suppressor cells) T cells and CD4⫹ (helper) T cells, respectively.
Humoral immunity: Immunologic system involved in the production of plasma lymphocytes (B cells) in response to antigen exposure with subsequent antibody production.
Intercellular adhesion molecule-1 (ICAM-1): A glycoprotein that is expressed on activated endothelial cells because of stimulation by local production of cytokines, which in
turn causes adherence of leukocytes.
Interferons: A class of small glycoprotein cytokines produced by T cells, fibroblasts, and other cells in response to viral infection and other biological and synthetic stimuli. Their
effects include inducing enzymes, suppressing cell proliferation, inhibiting viral proliferation, enhancing the phagocytic activity of macrophages, and augmenting the
cytotoxic activity of T lymphocytes.
Interleukins: A large family of hormone-like messenger proteins produced by immune cells that act on leukocytes and other cells.
Intron: A portion of DNA that lies between two exons, is transcribed into RNA, but does not appear in mature messenger RNA because the intron is removed and the exons
are spliced together, and so it is not expressed.
Lymphokine: A hormone-like intercellular messenger protein produced by lymphocytes.
Matrix metalloproteinases: A family of protein-hydrolyzing endopeptidases that hydrolyze extracellular proteins, especially collagens and elastin.
MHC: Major histocompatibility complex. The pair of genes on human chromosome 6 that encode the cell surface molecules known as HLAs.
Nucleotide: A combination of a nucleic acid (purine or pyrimidine), 1 sugar (ribose or deoxyribose), and a phosphoric group.
Phenotype: The observable characteristics at the physical, morphologic, or biochemical level of an individual, which are determined by the genetic sequence of the individual.
Platelet-derived growth factor (PDGF): A factor present in platelets that is mitogenic for cells at the site of a wound, causing proliferation of endothelial cells, fibroblasts,
smooth-muscle cells, and glial cells.
Polymerase: Any enzyme catalyzing a polymerization, as of nucleotides to polynucleotides.
Polymorphism: The presence of alleles in a population at a frequency that is higher than expected and that cannot be explained by mutation, suggesting a positive selection
mechanism.
Prostacyclin: A prostanoid produced by endothelial cells that is a potent natural inhibitor of platelet aggregation and a powerful vasodilator.
Protease: Descriptive term for proteolytic enzymes, both endopeptidases and exopeptidases, which hydrolize polypeptide chains.
Sequence homology: The degree of similarity between the nucleotide sequences of strands of DNA.
Smad: A family of messenger/transcription factor proteins that are involved in signal transduction by transforming growth factor-␤.
Topoisomerases: A group of enzymes capable of converting 1 topologic version of DNA into another. They act by catalyzing the breakage and reformation of DNA
phosphodiester linkages.
Transcript: Same as messenger RNA.
Transcription: Transfer of genetic code information from one kind of nucleic acid to another. Commonly used to refer to transfer of genetic information from DNA to RNA.
Transcription factors: Protein factors that interact with promoters and upstream regulatory elements on the DNA of the protein that will be expressed.
Transduction: Transfer of genetic material from one cell to another. Also, transmission of cell surface signals into the nucleus.
Transforming growth factor-␤ (TGF-␤): A regulatory cytokine that has multifunctional properties and can enhance or inhibit many cellular functions, including interfering with
the production of other cytokines and enhancing collagen deposition.
Tumor necrosis factor (TNF): A polypeptide cytokine produced by endotoxin-activated macrophages that has the ability to modulate adipocyte metabolism, lyse tumor cells in
vitro, and induce hemorrhagic necrosis of certain transplantable tumors in vivo.
38 6 January 2004 Annals of Internal Medicine Volume 140 • Number 1
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Pathogenesis of Systemic Sclerosis
thickening and fibrosis of the skin (3). However, multiple
internal organs are always involved in some degree even
when it is not clinically apparent. The affected skin is tight,
indurated, and firmly bound to the subcutaneous tissue.
Hair follicles and sweat and sebaceous glands atrophy. The
skin over the hands and face is most frequently involved; as
the disease progresses, the sclerotic changes extend and
may affect the entire body. In many cases, the cutaneous
involvement is confined to the digits and the dorsum of the
hands and feet (acrosclerosis), and progression of the
sclerotic process is relatively slow. This form of disease was
previously known as the CREST syndrome (Calcinosis,
long-standing Raynaud phenomenon, Esophageal dysmotility, Sclerodactyly, and Telangiectases) (4). Skin ulcerations, usually localized to fingertips or knuckles, and peculiar pigmentary changes are frequent. Calcinosis is most
commonly found in fingertips and periarticular tissues.
The Raynaud phenomenon is the second most common manifestation of systemic sclerosis and is present in
more than 85% of patients (5). It usually appears simultaneously with other manifestations but may antedate them
by several years. Often, the initial vasoconstriction and
blanching are followed by a dusky cyanosis and are accompanied by paresthesias and numbness. With return of
blood flow, reactive erythema occurs. In some cases, larger
blood vessels are affected and luminal narrowing and occlusion can result in ischemic necrosis.
Musculoskeletal symptoms are often the initial manifestations and may vary from mild polyarthralgias to frank
arthritis (6). Synovitis with a moderate effusion occurs occasionally; however, the synovial fluid is only mildly inflammatory. In more advanced stages, thickening and fibrosis of periarticular tissues result in severe flexion
contractures and distal phalangeal resorption. Muscle involvement can reveal either an inflammatory myopathy or
a more indolent noninflammatory form due to muscle infiltration with fibrotic tissue.
The gastrointestinal tract is the most common internal
organ system involved (7). Esophageal symptoms resulting
from reduced lower esophageal sphincter pressure and dysmotility of the lower two thirds of the esophagus include
reflux, heartburn, and dysphagia to solid foods. In severe
cases, chronic esophagitis can lead to stricture and
odynophagia. Poor gastric emptying and small intestine
involvement may cause abdominal distention, bloating,
nausea, and pain, and, in many instances, bacterial overgrowth with secondary malabsorption, diarrhea, and
weight loss.
Pulmonary involvement has emerged as potentially the
most serious visceral lesion in systemic sclerosis. Because
no reliable ameliorating treatment is available for such involvement, it frequently leads to severe respiratory disability and often death (8). The most prominent symptoms are
tachypnea and exertional dyspnea, secondary to either pulmonary fibrosis or pulmonary hypertension. Many patients
remain asymptomatic despite evidence of fibrotic involvewww.annals.org
Review
ment of the lung parenchyma. In some cases, fulminant
pulmonary hypertension may lead to rapid death (9).
Cardiac involvement is not uncommon (9, 10). Chest
pain, arrhythmias, various degrees of heart block, and myocardiopathy with left ventricular or biventricular failure
may result from myocardial fibrosis. These alterations occur almost exclusively in patients with diffuse systemic sclerosis. Cor pulmonale can develop in patients with pulmonary hypertension. Pericardial involvement is usually
asymptomatic; however, pericardial effusions are found by
echocardiography or autopsy examination in approximately one half of patients.
Until recently, renal disease was the most rapidly fatal
visceral involvement of systemic sclerosis. It is known as
scleroderma renal crisis and is typically characterized by the
abrupt onset of malignant hypertension and rapidly progressive renal insufficiency (11). It is often heralded by
severe headache; visual symptoms from hypertensive retinopathy; seizures and other central nervous system symptoms; or myocardial ischemia, infarction, or left ventricular
failure. Prompt aggressive treatment now can usually reverse this process, which otherwise is fatal.
Functional thyroid abnormalities, including elevated
levels of antithyroid autoantibodies and clinical and subclinical hypothyroidism, are common (12). Impotence
caused by erectile failure may be an early feature of systemic sclerosis (13), and some degree of erectile dysfunction ultimately develops in many affected patients. Patients
may develop the sicca syndrome (keratoconjunctivitis sicca
and xerostomia) caused by fibrosis and lymphocytic infiltration of the salivary and lacrimal glands (14). Unusual
clinical manifestations include urinary bladder involvement, pneumatosis cystoides intestinalis with pneumoperitoneum, trigeminal neuralgia, and hoarseness from vocal
chord involvement.
The pathologic changes in systemic sclerosis encompass a spectrum reflecting variable stages of development
and progression of 3 major processes in the affected tissues:
1) severe tissue fibrosis with exaggerated deposition of collagen and other connective tissue components in the extracellular matrix (see Glossary); 2) chronic inflammation, occurring predominantly in the early stages of disease and
characterized by infiltration with mononuclear cells,
mostly of the macrophage and T-cell lineages; and 3) microvascular disease, characterized by intimal proliferation,
concentric subendothelial deposition of collagen and mucinous material, and narrowing and thrombosis of the vessel lumen. Progression of the vascular and fibrotic changes
and a decrease in the inflammatory component lead to
end-stage fibrosis and atrophy of the affected organs.
The histopathologic findings in the skin include
marked thickening of the dermis with massive accumulation of dense collagen, causing epidermal atrophy, flattening of the rete pegs, and replacement of sebaceous and
sweat glands as well as hair follicles. A prominent inflammatory infiltrate is often present at the dermal–adipose
6 January 2004 Annals of Internal Medicine Volume 140 • Number 1 39
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Pathogenesis of Systemic Sclerosis
Figure 1. General overview of the pathogenesis of systemic sclerosis.
The illustrations on the bottom row show examples of, from left to right, the fibrotic process (biopsy of skin), microvascular alterations in pulmonary
arterioles, autoantibodies detected by immunofluorescence, and mononuclear inflammatory cell infiltrates in affected skin.
tissue interphase, especially in early lesions (15, 16). The
small vessels of the lower dermis show fibrous thickening
but no evidence of vasculitis. In the lungs, the architecture
of the alveolocapillary membrane and the parenchymal interstitium are markedly disrupted by fibrosis and severe
mononuclear-cell infiltration. Prominent vascular abnormalities with intimal proliferation causing narrowing or
complete obliteration of small vessels are frequent. The
renal lesions display severe narrowing and obliteration of
the medium-size arterioles because of subintimal accumulation of loose connective tissue and intimal and perivascular fibrosis. The glomeruli frequently appear ischemic,
and there is no evidence of glomerulitis. Severe interstitial,
perivascular, and periglomerular fibrosis may be present in
cases of long duration. Other affected organs display variable degrees of fibrosis, mononuclear-cell infiltration, and
microvascular obliteration and fibrosis.
PATHOGENESIS
The pathogenesis of systemic sclerosis is extremely
complex. At present, no single unifying hypothesis explains
all aspects of its pathogenesis. However, fundamental abnormalities in at least 3 types of cells are intimately involved in the development of the clinical and pathologic
manifestations of the disease: 1) fibroblasts (see Glossary);
2) endothelial cells; and 3) cells of the immune system,
40 6 January 2004 Annals of Internal Medicine Volume 140 • Number 1
particularly T and B lymphocytes. The profound functional alterations in these cells result in the characteristic
triad of pathologic changes in systemic sclerosis: severe and
often progressive cutaneous and visceral fibrosis; obliteration of the lumen of small arteries and arterioles; and humoral and cellular immunologic abnormalities, which include the production of numerous autoantibodies (some
very highly specific for the disease), the chronic mononuclear-cell infiltration of affected tissues, and the dysregulation of lymphokine and growth factor production (see
Glossary). These dysfunctional cellular processes and their
resulting effects on the affected tissues are illustrated in
Figure 1. At present, it is not clear which of these alterations is of primary importance or how they interrelate to
cause the progressive fibrotic process in systemic sclerosis.
However, a crucial component in the pathogenesis of the
disorder is the persistent and unregulated activation of
genes encoding various collagens and other extracellular
matrix proteins in systemic sclerosis fibroblasts. This is the
most important difference between normal fibroblasts,
which promote normal wound healing, and systemic sclerosis fibroblasts, which demonstrate an uncontrolled production and tissue deposition of collagen resulting in
pathologic organ fibrosis. This paper reviews some of the
numerous components of the complex puzzle of systemic
sclerosis pathogenesis, as illustrated in Figure 1, and atwww.annals.org
Pathogenesis of Systemic Sclerosis
tempts to form hypotheses that may provide frameworks
for the development of novel and effective therapies. Because we were not able to provide a comprehensive discussion of the abundant literature published, we refer readers
to recent reviews for a more complete and detailed description.
Possible Causative Agents
The cause of systemic sclerosis has remained elusive
despite intense investigations. Although the disease is not
inherited in a classical Mendelian pattern, there is strong
evidence that genetic factors contribute to its development
and clinical manifestations, as discussed in more detail
shortly. However, it has become apparent that environmental agents play a crucial and more important role than
genetic influences. One study reported a remarkably low
concordance in the development of systemic sclerosis
among homozygous twins, indicating that the heritability
component of the disease was very low and that the most
important factor was of an environmental or acquired origin (17). Many infectious, chemical, and physical agents
have been postulated as being involved in the cause of the
disease. The hypothesis that infectious agents may cause
systemic sclerosis has been studied extensively. Some researchers have suggested that the production of specific
autoantibodies in systemic sclerosis is the result of an antigen-driven response caused by “molecular mimicry.” The
concept of “molecular mimicry” proposes that antibodies
against self-antigens are produced because these antigens
contain epitopes (see Glossary) that share structural similarities with viral or bacterial proteins. In the immunopathogenesis of systemic sclerosis, herpesviruses, retroviruses, and human cytomegalovirus infections, among
others, have been suggested as possible causative agents.
Evidence supporting the role of retroviruses includes the
demonstration of sequence homologies (see Glossary) between certain retroviral proteins and the topoisomerase I
antigen (see Glossary), which is the target of anti–Scl-70
antibodies in patients with systemic sclerosis (18). In addition, it has been shown that the induced expression of
retroviral proteins in normal human dermal fibroblasts results in the acquisition of a systemic sclerosis–like phenotype (see Glossary) in the production of extracellular matrix proteins (18). Furthermore, antibodies to retroviral
proteins have been detected in serum specimens from patients with systemic sclerosis (19). Another hypothesis has
suggested that human cytomegalovirus may be involved in
the initial events of systemic sclerosis. This hypothesis is
supported by the observations of a higher prevalence of IgA
antihuman cytomegalovirus antibodies in patients with systemic sclerosis, which are capable of inducing apoptosis
(see Glossary) in human endothelial cells; the increased
prevalence of anticytomegalovirus IgA antibodies in patients positive for Scl-70 autoantibodies; and the severe
fibroproliferative vascular changes and the increased occurrence of antinuclear antibodies with an immunofluoreswww.annals.org
Review
cence pattern similar to that present in serum specimens
from patients with systemic sclerosis in human cytomegalovirus infections (20, 21). Despite intensive study, however, there is no definitive evidence to conclude that systemic sclerosis has a viral origin.
Environmental agents have also been implicated in the
development of systemic sclerosis (22, 23). Silica and metal
dust exposure had been shown in case studies to be related
to systemic sclerosis (22–24), although some studies have
failed to confirm an association. On the other hand, organic solvent exposure may eventually be proven to be an
important environmental factor in triggering this disease.
Indeed, persons exposed to vinyl chloride have an increased
risk for skin thickening, the Raynaud phenomenon, and
digital ulcers (23), and recent epidemiologic studies have
found a higher frequency of organic solvent exposure in
patients with systemic sclerosis than in normal controls
(24). Several other environmental exposures have been associated with the development of systemic sclerosis, including certain pesticides, hair dyes, and fuel-derived or industrial fumes (22, 23).
Role of Genetic Factors
The contribution of genetic factors in the development and expression of systemic sclerosis is strongly supported by the observation of familial clustering of the disease, the high frequency of autoimmune disorders and
autoantibodies in family members of patients with systemic
sclerosis, differences in prevalence and clinical manifestations among different ethnic groups, and the increased
prevalence of certain HLAs and MHC alleles (see Glossary)
among different ethnic groups and among patients with
different clinical subsets of the disease or with different
patterns of autoantibodies (25). Strong evidence indicates
that genetic factors largely determine the production of
specific autoantibodies in systemic sclerosis. Although the
concordance of systemic sclerosis among identical twins is
only 4.2% and is not significantly different from the concordance of disease in dizygotic twins (5.9%), the concordance for the presence of specific autoantibodies is substantially higher (17). These observations indicate that
inherited genetic factors are important for the production
of autoantibodies but are not sufficient for development of
disease.
Prevalence of the disease varies by geographic region
and by ethnic background; the prevalence in the United
States is 242 to 286 cases per million persons in the population. However, in Native American persons of the
Choctaw tribe in Oklahoma, one of the best-studied
groups for the role of genetic factors in systemic sclerosis,
the prevalence is 469 cases per million persons in the population (26). The differences of MHC and HLA allele expression are evident when comparing the different haplotypes (see Glossary) identified as being linked to disease
expression, in particular to the pattern of autoantibody
response, among ethnic groups (27). Disease expression
6 January 2004 Annals of Internal Medicine Volume 140 • Number 1 41
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Pathogenesis of Systemic Sclerosis
also appears to differ among ethnic groups. African-American persons are more likely to have anti-topoisomerase I
antibodies and more severe visceral manifestations, including a higher frequency of pulmonary fibrosis. In contrast,
anticentromere antibodies are more common in white persons, who are also more likely to have limited disease with
less severe systemic manifestations (27).
In addition to these genetic characteristics, which may
predispose persons to systemic sclerosis, other genetic factors may influence the expression of the disease. Recent
studies have examined mutations or polymorphisms (see
Glossary) in relevant genes that may result in their increased expression. For example, in patients with systemic
sclerosis, the upstream region of COL1A2 (see Glossary),
the region of the gene preceding the initiation of gene
transcription, harbors numerous dinucleotide repeats that
may increase gene activity (see Glossary) (28). Similarly, 2
single nucleotide polymorphisms at codon 10 of the transforming growth factor (TGF)-␤1 gene were found in statistically significant higher frequency in patients with systemic sclerosis (see Glossary) (29). This suggests a genetic
predisposition to higher production of TGF-␤1 (29). Furthermore, patients who had the TGF-␤1 polymorphism
had a higher frequency of pulmonary fibrosis and graft
fibrosis following lung transplantation (30). As discussed
later in more detail, TGF-␤1 is a potent profibrotic cytokine (see Glossary) secreted from activated macrophages
and T lymphocytes that may play a central role in the
pathogenesis of tissue fibrosis in systemic sclerosis.
Another genetic polymorphism that may influence expression of systemic sclerosis has been described in the gene
encoding fibrillin-1, a large extracellular matrix protein
that is a structural component of connective tissue microfibrils. The polymorphism is located in the upstream region (vide supra) of the gene, and its presence is strongly
associated with the occurrence of systemic sclerosis in Native American persons from the Choctaw tribe and in Japanese persons (31). These collective studies on the influence of genetic polymorphisms on the development or
expression of systemic sclerosis, however, must be performed in larger cohorts to corroborate their relevance.
Microchimerism
Microchimerism is a novel and provocative hypothesis
of the cause of systemic sclerosis (32–34). The hypothesis
suggests that, during pregnancy, allogenic (see Glossary)
fetal or maternal cells cross the placenta in bidirectional
traffic and persist in the circulation and tissues of the
mother or child, respectively, as a result of HLA II (DRB1)
compatibility between the mother and the fetus. These
engrafted foreign cells may become activated by a second
event and may mount a graft-versus-host reaction, which
manifests as systemic sclerosis. The remarkable similarities
in clinical, histopathologic, and serologic features between
graft-versus-host disease and systemic sclerosis, including
esophageal, lung, and skin involvement; lymphocytic infil42 6 January 2004 Annals of Internal Medicine Volume 140 • Number 1
tration and fibrosis of affected organs; and production of
autoantibodies, strongly support this hypothesis. Researchers suggested this theory when fetal cells were found in the
circulation of normal women several decades after the birth
of their children and fetal DNA and fetal cells were subsequently identified in affected skin samples from women
with systemic sclerosis who had previously been pregnant
with a male fetus (32). Microchimeric cells of maternal
origin have also been identified in the circulation of offspring (35). These findings might explain the occurrence of
systemic sclerosis in nulliparous women and men.
Although some studies found that the frequency of
male chromosome sequences in the skin of women with
systemic sclerosis who had male offspring was similar to
that of normal controls, quantification of microchimeric
fetal cells showed a significant difference in the amount of
male DNA in affected skin between the 2 groups (36).
This indicates that it is the quantity and not only the mere
presence of fetal cells that might contribute to the pathogenesis of systemic sclerosis. A more recent study confirmed the quantitative difference in the number of microchimeric cells between patients with systemic sclerosis and
healthy individuals and also showed that immunologic
stimulation expected to trigger antigen-specific T cells
caused a potent amplification of the microchimeric cells in
patients with systemic sclerosis but not in controls (37).
Despite these observations, at present, the role of microchimerism in the pathogenesis of systemic sclerosis remains
undetermined.
Humoral Immune System Alterations
The presence of specific autoantibodies is one of the
most common manifestations of systemic sclerosis. More
than 90% of patients with systemic sclerosis harbor antinuclear antibodies in their serum. Numerous autoantibodies, some of which are extremely specific for systemic sclerosis, have been described in patients with the disease;
other autoantibodies are associated with different clinical
manifestations (38).
Anti–Scl-70 antibodies have been shown to react with
DNA topoisomerase I and are almost exclusively present in
serum specimens from patients with the diffuse form of
systemic sclerosis, although only about 30% to 40% of
these patients harbor these autoantibodies. Anticentromere
antibodies are present in 80% to 90% of patients with the
limited form of systemic sclerosis but are found in fewer
than 10% of patients with diffuse systemic sclerosis. These
2 autoantibodies rarely coexist in the same patient.
Other autoantibodies are less common in patients with
systemic sclerosis. They include anti-RNA polymerases I
and III antibodies in patients with rapidly progressive disease and severe internal organ involvement; antifibrillarin
antibodies, which are commonly found in diffuse systemic
sclerosis; and anti–PM-Scl antibodies, which are usually
found in patients with systemic sclerosis who develop an
inflammatory myopathy. Although autoantibodies are
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Pathogenesis of Systemic Sclerosis
common in systemic sclerosis, they are not directly involved in the clinical manifestations of the disease. However, owing to their high frequency and their specificity for
certain clinical disease subsets, their presence is very helpful
in establishing the diagnosis and predicting a probable pattern of organ involvement, severity, and disease progression
(38).
Tissue Inflammation: An Early Event in the Cascade?
Some of the earliest evidence suggesting that chronic
and persistent inflammation may play a role in the pathogenesis of systemic sclerosis was provided by the demonstration of lymphocytic infiltrates in affected skin from patients with disease of recent onset (15, 16). Subsequently,
researchers found that the extent of lymphocytic infiltration correlated with the severity and the progression of skin
sclerosis (39). The mononuclear cells within the skin infiltrates are predominantly CD4⫹ T cells and express the
activation marker class II MHC antigen DR (40, 41). Subsequent expansion of these cells within the tissue appears to
be oligoclonal, as shown in studies of T-cell receptor transcripts (see Glossary) in the skin of patients with systemic
sclerosis (42). These results suggest an antigen-driven response, although at present there is no information on the
putative antigen or antigens that may be involved. The
expanded populations of inflammatory cells in affected tissues release cytokines and growth factors that initiate or
perpetuate the fibrotic process as well as the endothelial
and vascular alterations. Indeed, clones of T cells established from infiltrating lymphocytes isolated from affected
skin of patients with systemic sclerosis produce cytokines
that can stimulate fibroblast collagen production (43).
The mechanisms responsible for the migration of distinct populations of T cells from peripheral blood to skin
and other affected tissues in patients with systemic sclerosis
are not completely understood. However, it is likely that
their retention and accumulation in such tissues result
from specific interactions between certain T-cell subsets
and fibroblast membrane proteins or extracellular matrix,
which are mediated by integrins and cell adhesion molecules such as the adhesive protein intercellular adhesion
molecule-1 (see Glossary) (44).
The inflammatory changes in affected tissues are also
reflected in quantitative and functional alterations in peripheral blood cells (45). For example, the proportions and
absolute numbers of total CD4⫹ CD45RA⫹ (suppressorinducer) T cells and CD8⫹/CDIIb⫹ suppressor T cells are
decreased. Thus, the balance between immunoregulatory
T-cell populations appears to be substantially impaired. Peripheral blood T cells in systemic sclerosis manifest evidence of previous activation, indicated by the spontaneous
expression of high affinity interleukin-2 receptor (IL-2R)
on their membranes (see Glossary). Several observations
further support the evidence for in vivo T-cell activation in
systemic sclerosis. First, serum specimens from patients
with systemic sclerosis contain approximately 3-fold higher
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levels of soluble IL-2R than specimens from normal controls. In addition, mononuclear cells obtained from bronchoalveolar lavage fluid in patients with systemic sclerosis
display ongoing activation. Finally, elevated levels of serum
interleukin-2 and increased production of this cytokine by
T cells in vitro have also been demonstrated in patients
with systemic sclerosis. Abnormalities in numerous other
cytokines have also been described (45). However, whether
the alterations in the proportions of regulatory T-cell subsets and the various cytokines are secondary to disease activity or reflect a more fundamental pathogenic event is
unknown.
Role of Transforming Growth Factor-␤, Connective
Tissue Growth Factor, and Smad Proteins
At present, it is unknown whether the exaggerated
connective tissue production by systemic sclerosis fibroblasts is a response to an unknown injury, thus representing an abnormal regulation of a physiologic process, or
whether the primary event is an alteration in the regulation
of expression of the relevant matrix protein genes. It has
been postulated that alterations in the regulation of extracellular matrix gene expression may be induced by cytokines and growth factors released from the tissue-infiltrating inflammatory cells. Numerous alterations in the
expression of cytokines and growth factors with potent effects on fibroblast collagen synthesis, endothelial cell functions, and T-cell responses have been demonstrated in patients with systemic sclerosis (45). Many studies have
examined the effects of various products of inflammatory
cells, including TGF-␤, connective tissue growth factor,
platelet-derived growth factor, interleukin-1, interleukin-2,
interleukin-4, interferons, and tumor necrosis factor, on
many different aspects of fibroblast biology (see Glossary)
(46). These proteins exert stimulatory or inhibitory effects
on fibroblast proliferation and collagen production and
sometimes exert bifunctional effects, depending on their
concentrations and on the context of the other cytokines
and growth factors present simultaneously in the pericellular environment.
One of the growth factors that appears to play a crucial
role in the fibrosis that accompanies systemic sclerosis is
TGF-␤. The 3 functionally and structurally similar human
isoforms of TGF-␤ play important roles in embryonic development, in immune responses, and in the regulation of
tissue repair following injury (47). One of the most important effects of TGF-␤ is the stimulation of extracellular
matrix synthesis by stimulating the production of various
collagens and other matrix proteins, including fibronectin
(see Glossary) (48). Small amounts of TGF-␤ appear to
sensitize fibroblasts and maintain them in a persistently
activated state involving an autocrine signaling mechanism
that causes further production of TGF-␤. Systemic sclerosis fibroblasts also seem to express increased levels of
TGF-␤ receptors on their surface. This might account for
the increased TGF-␤–induced signaling and the resulting
6 January 2004 Annals of Internal Medicine Volume 140 • Number 1 43
Review
Pathogenesis of Systemic Sclerosis
Figure 2. Schematic diagram of the transforming growth factor-␤ (TGF-␤) and Smad pathways involved in stimulation of collagen
gene expression.
R ⫽ receptor.
increased collagen production by these fibroblasts (49). In
addition to its stimulatory effects on extracellular matrix
synthesis, TGF-␤ also decreases the production of collagen-degrading metalloproteinases and stimulates the production of protease (see Glossary) inhibitors, such as tissue
inhibitor of metalloproteinases-1, which prevent breakdown of the extracellular matrix (46).
Recent studies have provided a clearer picture of the
intricate pathways that mediate the stimulation of collagen
gene expression by TGF-␤ (50, 51). These include the
binding of TGF-␤ to specific cell surface receptors and the
transduction (see Glossary) of the binding signal into the
nucleus to influence the activity and expression of TGF␤–responsive genes, such as those encoding extracellular
matrix proteins. Briefly, TGF-␤ is secreted from activated
lymphocytes or monocytes in an inactive form and requires
complex events to become activated. Once active TGF-␤
comes into contact with a given target cell, it binds to a
specific TGF-␤II receptor on the target cell surface, which
in turn recruits and phosphorylates a TGF-␤I receptor to
form an active receptor complex. Subsequent signaling to
the nucleus then occurs through the Smad family of proteins (see Glossary) (50, 51). Smad 2 or Smad 3 binds to
the TGF-␤ receptor complex and then becomes phosphorylated and able to form a complex with Smad 4, a cytoplasmic protein involved in the translocation of the Smad
complex into the nucleus. Smad 7 is an inhibitory Smad
that can bind to the TGF-␤ receptor complex and prevent
44 6 January 2004 Annals of Internal Medicine Volume 140 • Number 1
Smad 2 or Smad 3 phosphorylation. It appears that both
interferon-␥ and tumor necrosis factor-␣, 2 potent collagen synthesis inhibitory cytokines, stimulate increased expression of Smad 7. This results in decreased signaling of
TGF-␤–induced collagen gene expression. Following nuclear translocation, the stimulatory Smad complexes bind
to specific promoter sites in target genes and activate their
expression. The pathways involved in the activation of collagen genes following TGF-␤ binding to target cell surface
receptors are shown in Figure 2. The potential involvement of Smad proteins in the pathogenesis of systemic
sclerosis has been reviewed elsewhere (52). Furthermore, a
recent study described substantially reduced levels of Smad
7 in systemic sclerosis (53). The reduction of Smad 7 inhibitory effects may be responsible for an exaggerated and
unregulated TGF-␤ signaling cascade resulting in excessive
extracellular matrix tissue accumulation.
Connective tissue growth factor also appears to play a
crucial role in fibrosis (54). It participates in angiogenesis,
axial development of the musculoskeletal system, structural
organization of connective tissues, and embryo implantation. Transforming growth factor-␤ causes potent stimulation of connective tissue growth factor synthesis in fibroblasts, vascular smooth-muscle cells, and endothelial cells.
Connective tissue growth factor also seems to be involved
in an autocrine loop stimulating its own production and,
thus, maintaining a continuous or prolonged cycle of excessive fibrosis. Although studies on the role of connective
www.annals.org
Pathogenesis of Systemic Sclerosis
tissue growth factor in the pathogenesis of fibrotic diseases
are just emerging, it is likely that this growth factor may
become recognized as an important mediator in the tissue
accumulation of extracellular matrix in systemic sclerosis.
Tissue and Vascular Fibrosis: The Final Step in the
Pathogenic Pathway
The most prominent clinical manifestations of systemic sclerosis are caused by the exaggerated accumulation
of collagen and other connective tissue components in the
affected organs. The excessive collagen deposition in systemic sclerosis is due to overproduction of this protein by
fibroblasts. Regardless of the etiologic event, the resulting
alterations in the biosynthetic phenotype of collagen-producing cells are crucial in the pathogenesis of systemic sclerosis. Indeed, it is the persistent activation of the genes
encoding various collagens in systemic sclerosis fibroblasts
that distinguishes controlled repair, such as that occurring
during normal wound healing, from the uncontrolled fibrosis that is the hallmark of systemic sclerosis.
Despite recent advances in the understanding of the
regulation of collagen gene expression under normal conditions or under the effects of various cytokines and growth
factors, the intimate mechanisms responsible for the pathologic increase in the expression of collagen genes in systemic sclerosis remain obscure. The exaggerated production of extracellular matrix macromolecules by systemic
sclerosis fibroblasts largely results from increased transcription rates of their corresponding genes (55, 56). The most
important molecule in the fibrotic processes of systemic
sclerosis is type I collagen, the prototype of the interstitial
collagens, which is largely responsible for the functional
failure of the affected organs. Normal fibroblasts are capable of regulating collagen production according to the requirements of the situation during development, differentiation, and repair. As for most eukaryotic genes, the
regulation of transcription rates of collagen genes involves
precise interactions between specific nucleotide sequences
present in the promoters and, often, in their first introns
(see Glossary) and various transcription factors (see Glossary) capable of recognizing and binding specifically to
these sequences. The entire complement of regulatory elements in collagen genes is not yet known, and the number
of identified transcription factors that interact with these
elements continues to increase. Numerous transcription
factors capable of regulating the expression of collagen
genes have been identified (57).
One of the most extensively studied transcription factors is Sp1. Sp1 recognizes a specific sequence in the promoters of various Sp1-responsive genes. Sp1 appears to
play a pivotal function in the increased expression of
COL1A1 (see Glossary) in systemic sclerosis. Increased
Sp1 binding activity has been demonstrated in systemic
sclerosis fibroblast nuclear extracts in comparison with nuclear extracts from normal cells (58), and increased Sp1
phosphorylation associated with increased expression of
www.annals.org
Review
type I collagen genes has also been found in these cells
(59). Another study showed that activated hepatic stellate
cells, which are the primary cells responsible for increased
type I collagen production during liver fibrosis, also display
increased Sp1 binding activity (60). Binding of Sp1 to its
recognition sites has also been implicated in the regulation
of expression of type I collagen genes under the influence
of TGF-␤. Furthermore, numerous studies have shown
that specific inhibition of Sp1 binding to its cognate elements within collagen genes caused potent and selective
inhibition of collagen production in normal fibroblasts and
fibroblasts cultured from patients with systemic sclerosis
(61, 62).
Another transcription factor that appears to play an
important role in collagen gene regulation is the CCAATbinding factor (CBF). Both CBF and Sp1 transcription
factors are involved in a protein–protein interaction in the
collagen gene promoter, and both appear to be crucial regulatory factors in the expression of collagen genes. The role
of CBF in the regulation of collagen gene expression in
systemic sclerosis has also been examined, and it has been
shown that CBF binding activity is increased in systemic
sclerosis fibroblasts (63). In contrast with the stimulatory
effects of Sp1 and CBF, the transcription factor c-Krox
mediates tissue-specific inhibition of collagen gene expression (64), although its role in pathologic fibrosis has not
been investigated.
Endothelial Cells
Vascular dysfunction is one of the earliest alterations
of systemic sclerosis, and it has been suggested that it may
represent the initiating event in its pathogenesis (65). Severe alterations in small blood vessels of skin and internal
organs, including fibrosis and perivascular cellular infiltration with activated T cells, are almost always present in
systemic sclerosis. Cytokines such as TGF-␤ are secreted
by these activated lymphocytes and in turn injure the endothelial cells, inducing their expression of MHC class I
and II antigens and adhesion ligand intercellular adhesion
molecule-1. Transforming growth factor-␤ causes an upregulation of connective tissue growth factor, which also
results in increased production of extracellular matrix components as well as an upregulation of platelet-derived
growth factor. Elevated expression of platelet-derived
growth factor causes increased endothelial cell proliferation
and a downregulation of vascular endothelial growth factor, the endogenous growth factor that promotes neovascularization. Chemoattraction of fibroblasts into the vessel
wall also occurs as a result of the effects of the cytokines
released locally, leading to increased collagen synthesis and
deposition in the vessel wall. Transforming growth factor-␤ may also induce transdifferentiation of vessel wall
fibroblasts into myofibroblasts, which are phenotypically
distinct cells with contractile properties and increased extracellular matrix biosynthetic ability.
The endothelial injury initiated by the release of cyto6 January 2004 Annals of Internal Medicine Volume 140 • Number 1 45
Review
Pathogenesis of Systemic Sclerosis
Figure 3. Diagram of the pathogenesis of systemic sclerosis according to the hypothesis of microchimerism.
CTGF ⫽ connective tissue growth factor; IL ⫽ interleukin; NO ⫽ nitric oxide; PDGF ⫽ platelet-derived growth factor; TGF-␤ ⫽ transforming growth
factor-␤; TNF-␣ ⫽ tumor necrosis factor-␣.
kines causes the subendothelium to become exposed to
circulating platelets, which eventually adhere to it and initiate fibrin deposition and intravascular thrombus formation. It has also been suggested that endothelial cell damage
in systemic sclerosis may be due to a direct effect of cytotoxic factors for endothelium, since serum specimens from
patients with systemic sclerosis contain cytotoxic activity
directed against endothelial cells (66). Other proposed
mechanisms of endothelial cell injury in systemic sclerosis
are those mediated by proteolytic activities present in serum (67) or by serum IgG antibodies that result in antibody-dependent cell-mediated cytotoxicity (68). These antibodies occasionally coexist with Clq-binding immune
complexes and anticardiolipin antibodies, both of which
are associated with thrombosis.
Vasodilation, which is controlled by both endothelial
and nonendothelial (neural) mechanisms, also appears to
be impaired in patients with systemic sclerosis. Endothelial
cells normally secrete vasoactive substances that control
46 6 January 2004 Annals of Internal Medicine Volume 140 • Number 1
vascular tone, such as the potent vasodilators prostacyclin,
nitric oxide, and calcitonin gene–related peptide (see Glossary) (69). On the other hand, they also produce endothelin-1, a 21-amino acid polypeptide that has potent vasoconstrictor activities and stimulates extracellular matrix
production and deposition in the vessel wall (70). Patients
with systemic sclerosis appear to have a relative deficiency
of vasodilators and a remarkable increase in levels of endothelin-1. This imbalance in turn causes further vascular
hypoxia, which leads to increased collagen gene expression
as well as endothelial injury, thus maintaining the vicious
cycle of endothelial injury and fibrosis.
DISCUSSION
Although the exact mechanisms involved in the pathogenesis of systemic sclerosis are not known, there is sufficient evidence to allow cogent hypotheses about the possible pathway the disease takes from its causation to organ
www.annals.org
Pathogenesis of Systemic Sclerosis
Review
Figure 4. Diagram of the pathogenesis of systemic sclerosis according to the hypothesis of an environmental agent causing initial
tissue inflammation.
CTGF ⫽ connective tissue growth factor; HCMV ⫽ human cytomegalovirus; NO ⫽ nitric oxide; PDGF ⫽ platelet-derived growth factor; TGF␤ ⫽ transforming growth factor-␤.
fibrosis and resulting clinical manifestations. At present,
there is no single unifying concept but rather several possible pathways, as shown in Figures 3, 4, and 5. The novel
hypothesis of a graft-versus-host reaction secondary to engrafted microchimeric cells is illustrated in Figure 3. In this
pathway, it is necessary to postulate an environmental
agent (for example, physical, chemical, or infectious) acting
as a required second event that will trigger this reaction. In
contrast, in Figure 4, it is hypothesized that the environmental agent or agents is the inciting factor that acts on a
genetically predisposed host and results in the subsequent
recruitment and homing of macrophages and T cells to the
affected tissues. The inflammatory cells would undergo sewww.annals.org
lective proliferation and expansion, perhaps because of an
antigen-driven response, and then release cytokines and
growth factors that initiate the process of tissue and vascular fibrosis. Finally, in Figure 5, it is postulated that the
environmental factor or factors, most likely of an infectious
origin acting in a genetically susceptible host, cause a profound phenotypic change in various target cells of different
lineages (immune cells, fibroblasts, and endothelial and
vascular smooth-muscle cells). This phenotypic change
could be caused by integration of genetic material (for example, of retroviral origin) within the genetic sequence of
the target cells that through unknown mechanisms would
induce the expression of specific regulatory genes, altering
6 January 2004 Annals of Internal Medicine Volume 140 • Number 1 47
Review
Pathogenesis of Systemic Sclerosis
Figure 5. Diagram of the pathogenesis of systemic sclerosis according to the hypothesis of phenotypic change in target cells.
CTGF ⫽ connective tissue growth factor; HCMV ⫽ human cytomegalovirus; IFN ⫽ interferon-␥; IL ⫽ interleukin; NO ⫽ nitric oxide;
PDGF ⫽ platelet-derived growth factor; TGF-␤ ⫽ transforming growth factor-␤; TNF-␣ ⫽ tumor necrosis factor-␣.
the function and behavior of the target cells. These
alterations are manifested by increased collagen and extracellular matrix production in fibroblasts, generation of autoantibodies and cellular immune abnormalities in lymphocytes, and severe fibroproliferative and prothrombotic
alterations in endothelial cells. The target cell effects of
cytokines and growth factors, particularly TGF-␤ and connective tissue growth factor, and of the various components of their regulatory cascades are downstream components common to all 3 pathways.
All 3 hypotheses, and other plausible ones that can be
construed on the basis of currently known molecular abnormalities in systemic sclerosis, may prove to be correct,
since the disease exhibits a remarkably heterogeneous spec48 6 January 2004 Annals of Internal Medicine Volume 140 • Number 1
trum of clinical manifestations and its pathogenesis may be
different in different individuals. Although the ultimate
goal of research studies about the pathogenesis of a disease
is to find a unifying mechanism, in the case of systemic
sclerosis, a single common pathogenetic mechanism may
not be the correct answer.
In the past 30 years, the study of systemic sclerosis has
evolved from the concept that the disease was purely due to
collagen overproduction by affected fibroblasts to the current stage, in which it is possible to postulate various distinct and extremely complex processes during the initial
phases. Regardless of whether the answer to the puzzle of
systemic sclerosis pathogenesis is a single, unified mechanism or a constellation of different ones, the knowledge
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Pathogenesis of Systemic Sclerosis
acquired in this search will undoubtedly uncover novel targets, including those involving regulatory transcription factors for collagen gene expression, such as Sp1; intracellular
mediators, such as Smad proteins; and TGF-␤⫺signaling
cascades. These targets may lead to the development of
long-awaited and potentially effective therapeutic options
for this incurable disease.
From Thomas Jefferson University, Philadelphia, Pennsylvania.
Acknowledgments: The authors thank Kate Salmon for expert assis-
tance in the preparation of the manuscript and M. Sonsoles PieraVelazquez, PhD, for assistance in the preparation of some of the illustrations.
Grant Support: By National Institutes of Health Grant AR19616. Dr.
Derk was supported by National Institutes of Health Training Grant
AR07583.
Potential Financial Conflicts of Interest: None disclosed.
Requests for Single Reprints: Sergio A. Jimenez, MD, Division of
Rheumatology, Thomas Jefferson University, 233 South 10th Street,
Room 509 BLSB, Philadelphia, PA 19107-5541.
Current author addresses are available at www.annals.org.
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www.annals.org
Current Author Addresses: Dr. Jimenez: Division of Rheumatology,
Thomas Jefferson University, 233 South 10th Street, Room 509 BLSB,
Philadelphia, PA 19107-5541.
Dr. Derk: Division of Rheumatology, Thomas Jefferson University,
1025 Walnut Street, Room 613 Curtis, Philadelphia, PA 19107-5541.
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