Alice Wiedeman

Tartrate-resistant acid phosphatase deficiency causes a bone dysplasia with autoimmunity and a type I interferon expression signature

We studied ten individuals from eight families showing features consistent with the immuno-osseous dysplasia spondyloenchondrodysplasia. Of particular note was the diverse spectrum of autoimmune phenotypes observed in these individuals (cases), including systemic lupus erythematosus, Sjögrens syndrome, hemolytic anemia, thrombocytopenia, hypothyroidism, inflammatory myositis, Raynauds disease and vitiligo. Haplotype data indicated the disease gene to be on chromosome 19p13, and linkage analysis yielded a combined multipoint log10 odds (LOD) score of 3.6. Sequencing of ACP5, encoding tartrate-resistant acid phosphatase, identified biallelic mutations in each of the cases studied, and in vivo testing confirmed a loss of expressed protein. All eight cases assayed showed elevated serum interferon alpha activity, and gene expression profiling in whole blood defined a type I interferon signature. Our findings reveal a previously unrecognized link between tartrate-resistant acid phosphatase activity and interferon metabolism and highlight the importance of type I interferon in the genesis of autoimmunity.

Type I IFN system in the development and manifestations of SLE.

Purpose of reviewType I interferon (IFN-I) is strongly implicated in the pathogenesis of systemic lupus erythematosus (SLE). Here, we focus on new developments in pathways of IFN-I stimulation, the role of IFN-I in syndromes associated with lupus-like diseases, the utility of IFN-I signatures as biomarkers, and the progress of therapeutic agents targeting IFN-I pathways in SLE. Recent findingsImmune complexesimmune complex are a dominant driver of IFN-I production by activating toll-like receptors (TLRs) in plasmacytoid dendritic cells (pDC) in SLE. The level of IFN-I production is attenuated by C1q in immune complexes and enhanced by natural killer (NK) cells as well as by activated platelets that express CD40L. In addition to immune complexs, cell-intrinsic activation pathways utilize recently described non-TLR RNA and DNA sensors. Some modules or clusters of IFN-I stimulated genes or proteins correlate with disease activity, whereas IFN-I biomarkers of disease flare or specific clinical manifestations need further study. IFN-I blocking studies have reached phase II clinical trials. SummarySignificant progress has been made in defining both TLR as well as non-TLR mediated stimulation of IFN-I. This has helped elucidate the mechanisms of several mutations and common genetic variations in predisposing to SLE. Challenges remain in the establishing the utility of biomarkers and the role of IFN-I blockade in the clinical management of patients with this disease.

Overexpression of TLR7 promotes cell-intrinsic expansion and autoantibody production by transitional T1 B cells

Transgenic expression of TLR7 results in the expansion and hyperactivation of T1 B cells in response to endogenous RNA complexes, leading to increased autoantibody production.

Plasmacytoid Dendritic Cells and C1q Differentially Regulate Inflammatory Gene Induction by Lupus Immune Complexes

Immune complexes (ICs) play a pivotal role in causing inflammation in systemic lupus erythematosus (SLE). Yet, it remains unclear what the dominant blood cell type(s) and inflammation-related gene programs stimulated by lupus ICs are. To address these questions, we exposed normal human PBMCs or CD14+ isolated monocytes to SLE ICs in the presence or absence of C1q and performed microarray analysis and other tests for cell activation. By microarray analysis, we identified genes and pathways regulated by SLE ICs that are both type I IFN dependent and independent. We also found that C1q-containing ICs markedly reduced expression of the majority of IFN-response genes and also influenced the expression of multiple other genes induced by SLE ICs. Surprisingly, IC activation of isolated CD14+ monocytes did not upregulate CD40 and CD86 and only modestly stimulated inflammatory gene expression. However, when monocyte subsets were purified and analyzed separately, the low-abundance CD14dim (“patrolling”) subpopulation was more responsive to ICs. These observations demonstrate the importance of plasmacytoid dendritic cells, CD14dim monocytes, and C1q as key regulators of inflammatory properties of ICs and identify many pathways through which they act.

Increased Ribonuclease Expression Reduces Inflammation and Prolongs Survival in TLR7 Transgenic Mice

TLR7 activation is implicated in the pathogenesis of systemic lupus erythematosus. Mice that overexpress TLR7 develop a lupus-like disease with autoantibodies and glomerulonephritis and early death. To determine whether degradation of the TLR7 ligand RNA would alter the course of disease, we created RNase A transgenic (Tg) mice. We then crossed the RNase Tg to TLR7 Tg mice to create TLR7 × RNase double Tg (DTg) mice. DTg mice had a significantly increased survival associated with reduced activation of T and B lymphocytes and reduced kidney deposition of IgG and C3. We observed massive hepatic inflammation and cell death in TLR7 Tg mice. In contrast, hepatic inflammation and necrosis were strikingly reduced in DTg mice. These findings indicate that high concentrations of serum RNase protect against immune activation and inflammation associated with TLR7 stimulation and that RNase may be a useful therapeutic strategy in the prevention or treatment of inflammation in systemic lupus erythematosus and, possibly, liver diseases.

TNF-α and TGF-β Counter-Regulate PD-L1 Expression on Monocytes in Systemic Lupus Erythematosus

Monocytes in patients with systemic lupus erythematosus (SLE) are hyperstimulatory for T lymphocytes. We previously found that the normal program for expression of a negative costimulatory molecule programmed death ligand-1 (PD-L1) is defective in SLE patients with active disease. Here, we investigated the mechanism for PD-L1 dysregulation on lupus monocytes. We found that PD-L1 expression on cultured SLE monocytes correlated with TNF-α expression. Exogenous TNF-α restored PD-L1 expression on lupus monocytes. Conversely, TGF-β inversely correlated with PD-L1 in SLE and suppressed expression of PD-L1 on healthy monocytes. Therefore, PD-L1 expression in monocytes is regulated by opposing actions of TNF-α and TGF-β. As PD-L1 functions to fine tune lymphocyte activation, dysregulation of cytokines resulting in reduced expression could lead to loss of peripheral T cell tolerance.

Tartrate-Resistant Acid Phosphatase Deficiency in the Predisposition to Systemic Lupus Erythematosus

Mutations in the ACP5 gene, which encodes tartrate‐resistant acid phosphatase (TRAP), cause the immuno‐osseous disorder spondyloenchondrodysplasia, which includes as disease features systemic lupus erythematosus (SLE) and a type I interferon (IFN) signature. Our aims were to identify TRAP substrates, determine the consequences of TRAP deficiency in immune cells, and assess whether ACP5 mutations are enriched in sporadic cases of SLE.

Genetic and functional investigation of a Mendelian form of systemic lupus erythematosus

Abstract We have shown that bi-allelic mutations in ACP5 result in a deficiency of the encoded protein, tartrate-resistant acid phosphatase (TRAP), which causes the immuno-osseous disease spondyloenchondrodysplasia. In addition to having a bone and neurological phenotype, patients with spondyloenchondrodysplasia exhibit a wide spectrum of autoimmune manifestations, including autoantibody production, systemic lupus erythematosus, increased interferon α (IFNα), and an interferon signature. In bone, TRAP produced by osteoclasts regulates cell migration by dephosphorylation of osteopontin. However, TRAP is also produced by immune cells, particularly macrophages and dendritic cells (DCs). In murine plasmacytoid dendritic cells (pDC), phosphorylated osteopontin is integral to IFN-α production. Whereas osteopontin has been shown to be a TRAP substrate in murine bone cells, nothing is known about whether TRAP regulates osteopontin in immune cells. We hypothesise that TRAP dephosphorylates osteopontin in human pDCs and negatively regulates IFN-α production. We studied the interaction between TRAP and osteopontin. By confocal microscopy, we showed that TRAP co-localised with osteopontin in the Golgi in primary human macrophages, DCs, and pDCs. In a TRAP and osteopontin overexpression system in human embryonic kidney 293 cells, we co-immunoprecipitated TRAP and osteopontin, suggesting that they interact with each other. We also showed in an in-vitro assay that recombinant human TRAP could dephosphorylate osteopontin, demonstrating that osteoponin is a substrate for TRAP. These findings suggest that osteopontin is a target for TRAP in immune cells. To test whether TRAP deficiency leads to hyperphosphorylation of osteopontin and increased IFNα, we are generating TRAP knockdowns in a pDC cell line. Understanding of the mechanism by which TRAP regulates IFNα, potentially via osteopontin, may eventually allow for directed therapeutic approaches in spondyloenchondrodysplasia and other autoimmune diseases associated with an interferon signature, particularly systemic lupus erythematosus. Funding Wellcome Trust.