Our studies of the Mendelian interferonopathy Aicardi-Goutières syndrome (AGS), and the related disorder familial chilblain lupus, have highlighted the role of cell-intrinsic nucleic acid detection in the causation of autoimmunity, and emphasised the importance of type I interferon (IFN) in the pathogenesis of systemic lupus erythematosus (SLE). This experience has prompted us to consider the identification and analysis of single-gene disorders predisposing to the development of SLE as a tractable approach to understanding the pathogenesis of lupus; such “experiments of nature” representing the equivalent of genetically engineered animal models of disease – in the human context1.
In line with this research strategy, we became interested in the immuno-osseous dysplasia spondyloenchondrodysplasia (SPENCD). Although regarded primarily as a skeletal dysplasia, SPENCD patients have been reported to show immune dysfunction, with a particular susceptibility to the development of SLE. We confirmed a very high frequency of autoimmune phenotypes, including lupus, in SPENCD patients, and subsequently identified biallelic mutations in the ACP5 gene, encoding tartrate resistant acid phosphatase (TRAP), as causative of the disease2. Considering both the importance of the cytokine IFN-alpha (IFN-α) in the pathogenesis of SLE, and the clinical overlap of SPENCD with AGS, we then went on to demonstrate increased type I IFN activity, and increased expression of type I IFN-stimulated genes, a so-called IFN signature, in cells from affected individuals. In an accompanying paper, Lausch et al implicated osteopontin, a known substrate of TRAP with a recognized role in both IFN-αproduction in plasmacytoid dendritic cells and type I IFN production in lupus, as relevant to the pathology of SPENCD3.
Together with deficiency of early components of the classical complement pathway and mutations in TREX1, TRAP deficiency now represents a third monogenic disorder associated with the development of SLE also demonstrating an up-regulation of type I interferon activity. Thus, our findings identify a previously unrecognised link between TRAP and type I interferon, and further emphasise the importance of the type I interferon response to autoimmunity4.
Crow YJ. Lupus: how much “complexity” is really (just) genetic heterogeneity? Arthritis Rheum 2011;63:3661-4.
Briggs TA, et al. Tartrate-resistant acid phosphatase deficiency causes a bone dysplasia with autoimmunity and a type I interferon expression signature. Nat Genet 2011;43: 127-31.
Lausch E et al. Genetic deficiency of tartrate-resistant acid phosphatase associated with skeletal dysplasia, cerebral calcifications and autoimmunity. Nat Genet 2011;43:132-7.
Crow YJ. Type I interferonopathies: a novel set of inborn errors of immunity. Ann N Y Acad Sci. 2011;1238:91-8.
Disclosure of Interest None Declared
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