Introduction
SLE is an idiopathic heterogeneous chronic systemic autoimmune disease.1 Among many implicated cytokine systems, evidence suggests that the tumour necrosis factor (TNF) superfamily ligand Fas ligand (FasL), which signals through Fas, may play a role in SLE pathogenesis.2 Signalling by FasL through Fas leads to apoptosis,3 and impaired activation-induced cell death induced by mutations in mouse genes encoding for Fas (lpr) and FasL (gld) leads to spontaneous mouse models reminiscent of human SLE.4–6 The soluble forms of Fas (sFas) and FasL (sFasL) both act mainly as decoys for the Fas-mediated apoptosis pathway,7–11 potentially leading to increased survival of Fas-bearing target cells. However, sFasL mediates proinflammatory effects through Fas,12–14 while a proapoptotic function of oligomeric, but not monomeric, sFas has been described,15 indicating potentially divergent functions of sFasL and sFas that are especially relevant when sFas is abundant, such as in autoimmune disease.15 16
Compared with healthy controls (HC), serum sFas concentrations are reported in most studies to be elevated in patients with SLE.10 17–25 However, reported findings are inconsistent in regard to the relationship between serum sFas and disease activity, in that a positive relationship is shown in some studies,17 18 22 25 26 but not in others.16 19 24 Only a very few studies have investigated serum sFas as a biomarker for specific organ activity, particularly associated with renal, neurological and mucocutaneous SLE.16 18 20 27 28 Fewer studies have focused on sFasL in SLE, although it has been reported to be elevated compared with HC in most studies.21 23 26 29 A positive relationship between sFasL and SLE disease activity has been reported in one study,26 but not in another.30
In light of these discrepancies, measuring the ratio between sFas and sFasL may be of interest, since both proteins belong to the same immunological pathway and are able to modulate the Fas/FasL system.21 The use of this ratio may better reflect the Fas/FasL system biological activity as a whole, where sFas and sFasL may have divergent biological functions.21 31 While the ratio has been investigated in other conditions,32–35 only one prior study in a small cohort of 15 patients assessed this ratio in relation to SLE disease activity.21
B cell-activating factor from the TNF family (BAFF) is a key pathogenic cytokine in SLE.36 The Fas/FasL disrupted MRL-lpr/lpr lupus-prone mouse model is characterised by high serum BAFF concentrations,37 38 and our group previously described an interaction between the BAFF system and Fas/FasL system-mediated marginal zone B cell apoptosis in mice.39 Since BAFF potentially plays a role in the regulation of the Fas/FasL apoptotic pathway,39 measuring the key components of both BAFF and Fas/FasL systems is an interest in human SLE. To date, only one study has measured both BAFF and components of the Fas/FasL system in their soluble forms, within a larger pool of 52 soluble factors.40
Here, we aimed to investigate the clinical associations of serum sFas and sFasL as well as the ratio of these molecules in an SLE cohort larger and better characterised than any previously described, and investigate whether associations with SLE are independent of serum BAFF concentrations. We also assessed the associations of baseline measurements of these factors with clinical progression over time.