Introduction
Scleroderma or Systemic Sclerosis (SSc) is a multisystem disorder
of unknown cause, which is characterized
by fibrosis of skin, blood
vessels, and visceral organs, including the gastrointestinal tract,
lungs, heart, and kidneys. There are two main types of subsets: diffuse
cutaneous Scleroderma and limited cutaneous Scleroderma. There may be
an overlap between the two subsets.
Etiopathogenesis
The etiopathogenesis of systemic sclerosis (SSc) is unclear. The
association with class II antigens of the major histocompatibility
complex (MHC), includes HLA-DR1, DR2, DR3, DR5, and DR52
Autoantibody Profile
Patients with scleroderma may have
antibodies against topoisomerase
I, RNA polymerases, centromere proteins B & C, B23, Th/To-RNP,
PM/Scl, U1-RNP or U3 RNPs (including fibrillarin). Amongst these
antibodies, anti-topoisomerase I antibodies are seen most frequently.
The presence of this antibody is
associated with interstitial pulmonary
fibrosis, cardiac involvement, and cancer. Severe skin involvement and
renal crisis is associated with anti-RNA polymerase III antibodies, and
anti-fibrillarin antibodies associate with primary pulmonary arterial
hypertension and involvement of cardiac and skeletal muscle.Antifibrillarin,
is a nucleolar autoantibody, and serves as a marker for severe SSc
(especially in blacks and males). This antibody is associated with a
unique HLA haplotype, as well as with combinations of certain HLA-DQB1
alleles. Patients with CREST syndrome (calcinosis, Raynaud phenomenon,
esophageal dysfunction, sclerodactyly, telangiectasia), or limited SSc,
have antibodies against centromere proteins or Th/To RNPs. The Th/To
antigen, although rare, associates with hypothyroidism and small bowel
involvement.
Novel autoantigens
These include anti-Th/To antibodies, B23, and U3-RNP. Anti-Th/To
antibodies are seen in a subset of patients with limited skin disease
but significant lung disease. B23, has a strong association with
pulmonary hypertension and lung disease. U3-RNP (of which fibrillarin
is a component) is associated with pulmonary hypertension (in diffuse
or limited SSc). Serologic testing is of great diagnostic and
prognostic value in scleroderma because SSc clinical phenotypes are
associated with autoantibody profiles, which may appear before the
onset of new symptoms.
Direct Pathogenicity
The direct pathogenic role of antibodies in Scleroderma has been
described, which may account for some of the heterogeneity observed in
the presentation and outcome of SSc disease. These include:
anti-endothelial cell antibodies (not specific for SSc, observed in 25
to 85%), autoantibodies against matrix-metalloproteinase-1 (75% of
patients with diffuse SSc)(Harris ML, Rosen A), and IgG antibodies
reacting with myenteric neurons.
Immunopathologic aspects of Scleroderma
Immunological abnormalities are present very early in the
development of SSc. Fibrosis in scleroderma is caused by profibrotic
cytokines like transforming growth factor-beta (TGF-B), interleukin-4
(IL-4), platelet-derived growth factor (PDGF), and connective tissue
growth factor. TGF-B, and PDGF causes vasculopathy. Anti-endothelial
cell autoantibodies are the cause of paucity of vessels in skin
lesions. In the pathogenesis of SSc, activation of the immune
system plays a major role. CD4+, CD8+ T cells, and a subset of gamma
delta T cells may all play a role. There is an increase in both the
expression of a variety of adhesion molecules on fibroblasts and
endothelial cells in SSc patients, as well as an increase in the
circulating levels (White B, 1995). The antigen activates T Cells,
(preferentially composed of CD8+ T lymphocytes), which infiltrate skin
lesions early in SSc, and produce the profibrotic cytokine IL-4. The
effects of IL-4 are added to that of transforming growth factor B
(TGF-B) and connective tissue growth factor (CTGF), which stimulates
collagen synthesis by fibroblastss (Mouthon L, Garcia De La
Pena-Lefebvre P, Chanseaud Y, et al., 2002). B cells may also
contribute to fibrosis. Collagen synthesis is normally
inhibited by gamma interferon (INF-gamma), produced by T lymphocytes.
However, in SSc patients, the inhibitory effect of INF-gamma on
collagen synthesis is diminished. Conclusion
The etiopathogenesis of systemic sclerosis (SSc) is unclear.
Various antibodies like topoisomerase I, RNA polymerases, centromere
proteins B & C, B23, Th/To-RNP, PM/Scl, U1-RNP or U3 RNPs have been
described in patients with scleroderma. The activation of the immune
system plays a major role in the pathogenesis of SSc. The autoantibody
response in scleroderma provides important diagnostic and prognostic
information. Studying autoantigen expression and structure in the
target tissue associated with the specific antibody response is likely
to provide important insights into disease mechanism.