Functional autoantibodies in systemic sclerosis: influence of autologous stem cell transplantation and correlation with clinical outcome

Abstract

Objectives To evaluate the effect of autologous stem cell transplantation (aSCT) on functional antibodies (abs) to the angiotensin II type-1-receptor (AT1R) and topoisomerase-I(topo-I) in systemic sclerosis (SSc)-patients and to analyse their prognostic relevance Methods Forty-three SSc-patients in whom aSCT was performed were analysed. Thirty-one patients had a favourable outcome after aSCT (group 1), 12 patients showed no response or relapse (group 2). Patients’ sera were tested for anti-AT1R and anti-topo-I-antibodies by ELISA and in a luminometric assay (LA) using AT1R-expressing Huh7-cells for inhibitory or stimulatory anti-AT1R antibodies before and after aSCT (4–217 months, median 28 months). Anti-topo-I-antibodies were also analysed for their capacity to inhibit enzyme function. Results 70% of the SSc-patients had anti-topo-I- and 51% anti-AT1R-antibodies in the ELISA before aSCT. In all instances, anti-topo-I-antibodies inhibited topo-I-enzyme function. In the LA, 40% had stimulatory and 12% inhibitory anti-AT1R-antibodies. Anti-topo-I- and anti-AT1R-reactivity (ELISA) significantly decreased after aSCT. Before aSCT, anti-topo-I-reactivity was significantly higher in group 2- than in group 1-patients(p< 0.001), while there was no difference between both groups for anti-AT1R-antibodies detected by ELISA. Stimulatory anti-AT1R antibodies detected by LA were confined to group 1-patients. Conclusions Reactivity of functionally active anti-AT1R-antibodies was not influenced by aSCT, while anti-topo-I-antibodies decreased after aSCT. The fact that anti-topo-I antibodies inhibited enzyme function in all instances supports the hypothesis of a pathogenetic role of the topo-I antigen/antibody-system in SSc. High anti-topo-I reactivity before aSCT was associated with an unfavourable, presence of stimulatory anti-AT1R antibodies with a favourable course after aSCT.

When natural antibodies become pathogenic: autoantibodies targeted against G protein-coupled receptors in the pathogenesis of systemic sclerosis

“…However, the effect of this scenario on functional Abs against GPCRs is not yet well investigated. A recent study has shown that the reactivity and the levels of functional AT1R Abs are not touched by this therapy ( 101 ). Moreover, despite the advantages of the AHSCT, potential challenges such as providing an optimal therapeutic regimen, limitations in the availability of biomarkers that help in selecting patients who may benefit from transplantation, and late-onset adverse events remain to be determined ( 102 ).…”

The Renin-Angiotensin System: The Challenge behind Autoimmune Dermatological Diseases

“…The cause of SSc is unknown, involving genetic, environmental and immunological factors, as well as mechanisms related to cell senescence and inflamm-aging [80]. Up to 95% of patients diagnosed with SSc exhibit the presence of anti-nuclear Abs.…”

“…In vitro experiments have revealed that anti-AT1R Abs can elicit specific responses in ECs. They induce the phosphorylation of ERK 1/2 and stimulate the expression of messenger RNA for TGF-β, VCAM-1 and IL-8 [80]. The interaction between receptors, such as the heterodimerization of AT1R and ETAR, can lead to receptor hypersensitization (adapted after [9]).…”

“…Moreover, it is noteworthy that PMNs themselves express AT1R, and it was suggested that these specific Abs may activate AT1R on PMNs within blood vessels. The activation of PMN AT1R may direct these cells to areas of inflammation, where they can exacerbate tissue damage and contribute to the progression of the disease [9,51,80,83].…”

“…In vitro experiments have revealed that anti-AT1R Abs can elicit specific responses in ECs. They induce the phosphorylation of ERK 1/2 and stimulate the expression of messenger RNA for TGF-β, VCAM-1 and IL-8 [80].…”