Bone Abstracts

Background: Biallelic pathogenic variants in ACP5, encoding tartrate-resistant acid phosphatase (TRAP), result in the immuno-osseous disorder spondyloenchondrodysplasia (SPENCD), characterized by metaphyseal dysplasia and a variety of autoimmune phenotypes, particularly systemic lupus erythematosus (SLE). Importantly, patients with SPENCD demonstrate an upregulation of type 1 interferon (IFN) stimulated genes (ISGs) similar to that observed in SLE. Since very little is known about the function of TRAP in immune cells, our objectives were: i) to determine the consequences of TRAP deficiency in human immune cells, ii) to identify substrates of TRAP, and iii) to establish whether ACP5 mutations occur in ‘idiopathic’ SLE.

Results: i) We knocked down TRAP expression in plasmacytoid dendritic cells (pDCs), the sentinel IFN producing immune cell, and observed increased expression of ISGs. ii) TRAP interacted or co-localised with the osteo-immune molecule Osteopontin (OPN) as determined by Yeast 2 Hybrid, confocal microscopy and by IP-western in human immune cells. Furthermore, mass spectometry demonstrated that TRAP dephosphorylated OPN at two serine residues in vitro. iii) Sequencing of ACP5 in 856 SLE patients suggested an excess of heterozygous, possibly pathogenic missense, ACP5 variants, when compared to controls. Transient transfection of several mutants and SLE patient serum assays revealed a reduction in TRAP enzyme activity.

Conclusions: We have shown that TRAP deficiency in pDCs leads to increased IFN production, partially explaining why ACP5 mutations cause lupus in the context of SPENCD. Furthermore, TRAP and OPN co-localise and OPN is a substrate for TRAP in immune cells, which is of particular interest as OPN has a role in IFN production in pDCs. Detection of ACP5 missense variants in lupus patients suggests that impaired function of TRAP may play a role increasing susceptibility to adult-onset idiopathic lupus. We hope that our ongoing studies of the interaction between TRAP, IFN and OPN will facilitate the use ‘smart medicines’ in SPENCD, and perhaps other IFN driven autoimmune disorders.