Systemic Sclerosis

An Update

Uwe-Frithjof Haustein, MD, PhD

Lab Med. 2011;42(9):562-572.

Matrix Protein Metabolism

In SSc, abundant deposits of collagen type I are found in the perivascular region of the dermis and at the border between deep dermis and subcutis, as demonstrated by immunohistochemistry and in situ hybridization. In addition, collagen types III, V, VI, VII, as well as fibronectin and tenascin are also overexpressed in the skin.^[76] Recently, an increased formation of bone-type cross-links due to activation of lysyl hydroxylase 2 has been reported in SSc skin as well as bone-type degradation products in the serum (collagen telopeptides may be used as a surrogate marker of disease activity). Hypoxia may contribute in the process of transdifferentiation of FBs to an altered bone-like phenotype.^[77,78]

Increased collagen synthesis and decreased collagenase expression may result in excessive accumulation of collagen, indicating that the balance between these synthesizing and degrading processes (MMPs) is crucial and may be modulated

by TIMP-1 expression.^[79] On the other hand, increase in the proteolytic activity (cathepsin K) could indicate major remodeling as a counter-regulatory mechanism.^[80]

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Cite this: Systemic Sclerosis - Medscape - Sep 01, 2011.

Table 1. Systemic Sclerosis Subsets According to LeRoy and Colleagues⁶
Limited Cutaneous SSc
Raynaud's phenomenon for years at presentation Skin sclerosis limited to hands, feet, face, and forearms, or absent Significant late incidence of PHT, trigeminal neuralgia, calcinosis, and telangiectases Dilated nailfold capillary loops, usually without capillary dropouts detected by widefield nailfold capillaroscopy
Diffiuse SSc
Onset of Raynaud's phenomenon within 1 year of onset of skin changes Truncal and acral skin involvement Presence of tendon friction rubs Early and significant incidence of interstitial lung disease, oliguric renal failure, diffuse gastrointestinal disease, and myocardial involvement Presence of anti-DNA topoisomerase I (anti-Scl-70) antibodies Absence of anti-centromere antibodies Nailfold capillary dilatation and destruction detected by widefield nailfold capillaroscopy

Table 2. Cytokines, Chemokines, Growth Factors Involved in Systemic Sclerosis
Mediators	Findings in SSc
Proinflammatory
IL-2, IL-2R	Elevated in serum
IL-6	Elevated in serum
MCP-1	Elevated in lesions, correlation with disease activity
TNF-α	Increased in serum and tissue, up-regulation of TNF-α converting enzyme (TACE) in monocytes, inhibition of collagen synthesis in FB
IFN-α	Increased in tissue, monocyte activation
Pro-fibrotic
TGF-β	Increased in tissue, reduced in serum, increased TRβ1 receptor expression, increased activation of latent TGF-β by integrins
IL-4, IL-13	Increased collagen synthesis, myofibroblast differentiation
PDGF	Receptor stimulation by Auto-ab via tyrosine phosphorylation and stimulation of the ERK pathway
BAFF	Increased in serum

Table 3. Autoantibodies in Systemic Sclerosis
Autoantibody	Target, Function	Pathogenicity
ATA	Topoisomerase, FB surface 100kD molecule, mediates relaxation of supercoiled DNA	Unknown
ACA	Centromeres A,B,C,D kinetochore, interacts with cell division	Unknown
A-RNA-P-A	RNA-polymerase I, II, III protein biosynthesis by ribosomes	Unknown
A-U3RNP(fibrillarin)-A	Fibrillarin, 34kD basic protein, processing of peri-ribosomal RNA	Unknown
AECA	NAG-2, topoisomerase I centromeric protein B	Apoptosis, ECM expression, EC cytotoxicity by direct complement activation
A-FiB-A	Fibrillin-1, NAG-2	ECM expression via TGF-ß pathway, FB activation/ECM expression
A-MMP-A	MMP-1 and -3	Inhibition of ECM degradation
A-PDGF-A	PDGF-R	Collagen expression, production of ROS, tyrosine phosphorylation, and stimulation of the ERK pathway

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Systemic Sclerosis

An Update

Matrix Protein Metabolism

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