Systemic Sclerosis

An Update

Uwe-Frithjof Haustein, MD, PhD

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

Pathophysiology

The course and even the initial events in the pathogenesis of SSc are still poorly understood. The microvasculature (EC, platelets, capillaries) is 1 of the first affected systems, sometimes preceding the outbreak of the disease even by years (Raynaud's phenomenon). There is evidence that the disease may be immunologically triggered, again as an early event.^[28] T lymphocytes in collaboration with monocytes, EC, platelets, and mast cells act as mediators and targets in the pathophysiological network. These cells express and release adhesion molecules, ILs, and growth factors that act on FBs. In addition, hypoxia causes oxidative stress in various organs. The excessive tissue fibrosis is due to an expansion of fibrogenic clones of tissue FBs and their transformation into myofibroblasts that behave relatively autonomously and over-express genes encoding ECM components.^[29] Tyrosine kinases have been shown to regulate the release and activity of various cytokines and growth factors such as transforming growth factor β (TGFβ) and platelet-derived growth factor (PDGF). This leads to excessive deposition of collagen and other connective tissue matrix proteins in the skin and internal organs as well as in the walls of blood vessels.

As known from many other autoimmune diseases, the pathogenesis of SSc is partly based on genetic background and modulated by environmental factors.^[30] The following sections will discuss the 3 main pathogenetic pathways. These include microvasculature abnormalities, abnormal immune response, and dysregulation of FB activity (Figure 1).

(Enlarge Image)

Figure 1.

Pathogenesis of SSc. The crosstalk of genetics with environmental influences involves a network between vascular alterations (EC), autoimmune aberrations (T cells, B cells, Auto-ab), and activation of FBS by adhesion molecules, cytokines, chemokines, and growth factors with the consequences of an excessive deposition of collagen and other ECM substances in the connective tissue (fibrosis).

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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

Pathophysiology

Tables

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Tables

References

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Authors and Disclosures

Figure 1.

Figure 1.

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