Systemic Sclerosis

An Update

Uwe-Frithjof Haustein, MD, PhD


Lab Med. 2011;42(9):562-572. 

In This Article


In the majority of SSc sera, Auto-ab to intracellular antigens are detectable (Table 3). However, an individual patient's serum contains only a limited number of Auto-ab, often in a disease-specific manner. The particular autoantibody present is often indicative of clinical expression, disease course, and overall severity. In SSc with highly variable clinical features, such information is a valuable aid to the diagnosis and prognosis of an individual patient.

Antinuclear antibodies are detected in approximately 85% of SSc patients. With repeated investigations during the course of the disease, they have been found in approximately 98%.[55] The following 3 Auto-ab are of diagnostic importance:

  1. 1) Anti-topoisomerase antibodies correlate with dSSc. The association of ATA with DR3 and DRW52a means a significantly higher risk of pulmonary interstitial fibrosis. While ATA I positive idiopathic SSc cases were associated with DR2 and DR5,[56] an association between ATA I positive silica-associated SSc (SI-SSc) and the HLA-A-DR3 alleles has been shown.[57]

  2. 2) The ACA group has the best prognosis of the 3 with the longest cumulative survival times and the lowest frequency of dSSc, pulmonary involvement, and renal disease.[58]

  3. 3) Patients with anti-RNAP III antibodies exhibit the greatest risk of dSSc, the highest mean maximum skin thickness score, the shortest cumulative survival times, and the greatest likelihood of renal involvement compared with patients in either of the other 2 groups.

Autoantibodies are important for the early diagnosis of the specific type of SSc and then the initiation of the appropriate therapy. Consequently, it is now possible to classify more than 85% of SSc patients by these main 3 Auto-ab. Antigen-driven and molecular mimicry hypotheses have been proposed for ANA induction in SSc. Some Auto-ab are homologous to certain mammalian p30gag retroviral proteins.[59,60]

The pathogenetic role of these Auto-ab is mostly unknown. Although some of these SSc-specific Auto-ab are capable of inhibiting the cellular function of the autoantigens they recognize in vitro, they are unlikely to have access to the intracellular locations of these antigens in vivo. On the other hand, some of the Auto-ab may recognize extracellular antigens or those exposed on the cell surface. These Auto-ab could be involved in the disease pathogenesis.

  1. Thus, the EC-antibodies (AECA) are able to activate EC; to increase the synthesis and release of coagulation factors such as factor VIII, vascular adhesion molecules, endothelin-1, and thrombomodulin; as well as induce EC apoptosis;[61] the last of these possibly triggering the fibrosing process in SSc.[42] Altogether AECA may affect microvessels more distinctly than macrovessels. Their prevalence in SSc is between 28% and 86%. For example, AECA have been associated with vascular involvement, digital ischemic ulcers, gangrene, alveolocapillary impairment, and pulmonary arterial hypertention,[39,62,63] and they correlate with apoptotic progenitors. In addition, they can mediate EC cytotoxicity by direct complement activation (antibody dependent cell-mediated cytotoxicity).

  2. Anti-matrix metalloproteinase (MMP) antibodies are directed against MMP1 and 3 that block ECM degradation and may promote fibrosis due to imbalance between synthesis and degradation of collagen.[64]

  3. Anti-FB antibodies are directed against fibrillin-1 and activate FBs via the TGFβ pathway, resulting in increased collagen synthesis.

  4. Autoantibodies against the PDGF rec activate the platelet derived growth factor rec (PDGFR) and stimulate collagen synthesis as well as reactive oxygen species (ROS).[65] The PDGFR-Auto-ab are profibrotic, appearing to be relevant not only for matrix formation but also for vascular pathology. They stimulate tyrosine phosphorylation and up-regulate the intracellular Ha-Ras-extracellular-signal-regulated kinases 1 and 2 (ERK1/2) pathway.[66]


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