Etiology and Pathogenesis of Scleroderma in children
Francesco Zulian, MD
The cause of
Juvenile Systemic Sclerosis (JSSc) is unknown despite
significant advances in the understanding of the pathogenetic
The disease onset
and persistence is essentially due to three main alterations:
immune system, endothelium and fibroblasts. These three elements
are mutually involved in a complex process characterized
prominently by fibrosis of the skin or internal organs.
that usually is deputed to defend us from infections, plays a
major role in the initiation of scleroderma. This is clearly
supported by the presence, in early lesions, of mononuclear
cells that release various substances such as cytokines,
chemokines and growth factors. These mediators act as messengers
between different varieties of cells, maintaining inflammation
and in turn have effects on both endothelial cells and
that normally represent the inner layer of the vessel, become
activated and proliferate leading to fibrosis and narrowing of
the vascular lumen. This results in circulation defects and
eventually ischemic damage.
Fibroblasts are cells that usually produce a certain amount of
collagen, a substance that acts as support for various
structures such as vessel, muscles and even bones. Under the
influence of cytokines and chemokines, fibroblasts increase the
synthesis of extracellular matrix components and promote
fibrosis. Specific cytokines, such as TNF, promote fibrosis
others, such as IFN-γ, are potent suppressors of collagen
synthesis and this can be useful for the development of
innovative treatments with biological agents.
Microchimerism as a
possible cause of scleroderma was postulated from studies of
scleroderma in adults. Microchimerism is defined by the
presence within an individual of a very low level of cells
derived from different individuals. Common situations in which
microchimerism occurs are women who had previous pregnancies,
individuals who have had blood transfusions or children with
cells either from their mothers or a twin.
It is known that maternal cells can persist
in an offspring even in adult life. Fetus-derived hemopoietic
cells can persist in maternal circulation for many years
postpartum. Although microchimerism can be identified in normal
subjects, it has been proposed as a possible factor in the
production of autoimmune diseases. In scleroderma, chimeric
cells are increased in number and are more similar to the
maternal cells compared to normals. Quantitative analysis of
microchimerism in mothers with scleroderma documented high
persistent concentrations of male DNA in cells of the vascular
department years after giving birth to a son. Although this
theory of a chronic graft-versus-host reaction is attractive,
studies offer no data to explain the occurrence of scleroderma
in women who have never had children or in men.
The etiology of the
juvenile localized scleroderma (JLS) is unknown. As in JSSc, the
focus of much investigation is on abnormalities of regulation of
fibroblasts, production of collagen and immunologic
abnormalities. Autoimmunity, environmental factors, infection,
and trauma have all been associated with localized disease.
It seems certain
that autoimmunity is important in etiology, given the presence
of abnormal serum antibodies such as antinuclear antibodies
occurring in 42% of the patients, rheumatoid factor in 16% or
anti cardiolipin in 13%.
In a recent multicenter study from our group
in Padua, we observed that 13.3% of 750 patients with JLS
reported specific events which occurred very close to the
disease onset and were thus considered significant triggers by
both parents and reporting physicians.
Mechanical events accounted for 67% of these
factors, followed by infections (25%), drugs (5%) and
psychological distress (3%). Local mechanical factors, including
accidental trauma, insect bite and vaccination were reported in
approximately 10% of the patients. Although interesting, the
mechanism by which a physical trauma may contribute to the
development of scleroderma is unclear. Again, the role of some
cytokines such as endothelin-1, normally involved in the process
of wound healing, has been suggested by some authors but other
studies are needed to fully elucidate the pathogenetic process.
A number of drugs and environmental toxins
have resulted in scleroderma-like reactions, including bleomycin,
bromocriptine, pentazocine, carbidopa and vitamin K.
Some investigators have
examined the possibility of an association between scleroderma
and Borrelia Burgdorferi, a micro organism responsible for the
Lyme disease. Since 1985, serum antibodies against B.
Burgdorferi have been found in patients with JLS living in
endemic area. More recently this association has been denied and
seems to be a coincidence more than a causative event. For this
reason serologic testing for Lyme disease is not likely to be
helpful per se, in the evaluation of patients with JLS, unless
they have been in an endemic area.
Finally, a positive
family history for rheumatic or autoimmune diseases was reported
in around 12% of children with JLS, indicating that a familial
predisposition can partially be responsible as co-factor in the
development of the disease.
Please keep in mind, this webpage is for your information only.
Please check with your child's physician for any treatments.
For more information on Juvenile Scleroderma, contact:
Juvenile Scleroderma Network, Inc.
1204 W. 13th Street, San Pedro, CA 90731
Tel: (310)519-9511 (Pacific Time)
Speak to another JSD parent for emotional and logistical support
provided by home-based JSD volunteers. For medical advice, please
contact your child's physician.
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