The interferon signature in autoimmune diseases.
TL;DR: The observed IFN signature in several autoimmune diseases is a biomarker of active disease and is investigated as a tool when selecting treatment for individual patients.
Abstract: Purpose of reviewAn increased expression of type I interferon (IFN) regulated genes (an IFN signature) has been reported in blood and tissue cells from patients with SLE and other autoimmune diseases. We review the possible mechanisms behind the IFN signature as well as clinical and therapeutic cons
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TL;DR: Primordial neutrophil functions are discussed, and more recent evidence that interactions between neutrophils and adaptive immune cells establish a feed-forward mechanism that amplifies pathologic inflammation is presented.
Abstract: Neutrophils and neutrophil-like cells are the major pathogen-fighting immune cells in organisms ranging from slime molds to mammals. Central to their function is their ability to be recruited to sites of infection, to recognize and phagocytose microbes, and then to kill pathogens through a combination of cytotoxic mechanisms. These include the production of reactive oxygen species, the release of antimicrobial peptides, and the recently discovered expulsion of their nuclear contents to form neutrophil extracellular traps. Here we discuss these primordial neutrophil functions, which also play key roles in tissue injury, by providing details of neutrophil cytotoxic functions and congenital disorders of neutrophils. In addition, we present more recent evidence that interactions between neutrophils and adaptive immune cells establish a feed-forward mechanism that amplifies pathologic inflammation. These newly appreciated contributions of neutrophils are described in the setting of several inflammatory and autoimmune diseases.
914 citations
Cites background from "The interferon signature in autoimm..."
...A major feature of mononuclear and tissue cells from SLE patients is a gene expression profile that makes them appear as if they were stimulated by type I interferons; this profile is referred to as the interferon signature (215)....
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TL;DR: Recent progress in the field of pDC biology is summarized, focusing on the molecular mechanisms that regulate the development and functions of p DCs, the pathways involved in their sensing of pathogens and endogenous nucleic acids, their functions at mucosal sites, and their roles in infection, autoimmunity and cancer.
Abstract: Plasmacytoid dendritic cells (pDCs) are a unique DC subset that specializes in the production of type I interferons (IFNs). pDCs promote antiviral immune responses and have been implicated in the pathogenesis of autoimmune diseases that are characterized by a type I IFN signature. However, pDCs can also induce tolerogenic immune responses. In this Review, we summarize recent progress in the field of pDC biology, focusing on the molecular mechanisms that regulate the development and functions of pDCs, the pathways involved in their sensing of pathogens and endogenous nucleic acids, their functions at mucosal sites, and their roles in infection, autoimmunity and cancer.
808 citations
TL;DR: The ability to therapeutically target intracellular signalling pathways has already created a new paradigm for the treatment of rheumatologic disease.
Abstract: Cytokines are major drivers of autoimmunity, and biologic agents targeting cytokines have revolutionized the treatment of immune-mediated diseases. Despite the effectiveness of these drugs, they do not induce complete remission in all patients, prompting the development of alternative strategies - including targeting of intracellular signal transduction pathways downstream of cytokines. Many cytokines that bind type I and type II cytokine receptors are critical regulators of immune-mediated diseases and employ the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathway to exert their effect. Pharmacological inhibition of JAKs blocks the actions of type I/II cytokines, and within the past 3 years therapeutic JAK inhibitors, or Jakinibs, have become available to rheumatologists. Jakinibs have proven effective for the treatment of rheumatoid arthritis and other inflammatory diseases. Adverse effects of these agents are largely related to their mode of action and include infections and hyperlipidemia. Jakinibs are currently being investigated for a number of new indications, and second-generation selective Jakinibs are being developed and tested. Targeting STATs could be a future avenue for the treatment of rheumatologic diseases, although substantial challenges remain. Nonetheless, the ability to therapeutically target intracellular signalling pathways has already created a new paradigm for the treatment of rheumatologic disease.
448 citations
TL;DR: The combinatorial role played by cytokines in mediating the overlapping innate and adaptive immune responses associated with disease onset and persistence, and also those cytokine pathways that, in turn, drive the stromal response that is critical for tissue localization and associated articular damage are considered.
Abstract: Cytokine-mediated pathways are central to the pathogenesis of rheumatoid arthritis (RA). The purpose of this short Opinion article is to briefly overview the roles of cytokine families in the various phases and tissue compartments of this disease. In particular, we consider the combinatorial role played by cytokines in mediating the overlapping innate and adaptive immune responses associated with disease onset and persistence, and also those cytokine pathways that, in turn, drive the stromal response that is critical for tissue localization and associated articular damage. The success of cytokine inhibition in the clinic is also considerable, not only in offering remarkable therapeutic advances, but also in defining the hierarchical position of distinct cytokines in RA pathogenesis, especially IL-6 and TNF. This hierarchy, in turn, promises to lead to the description of meaningful clinical endotypes and the consequent possibility of therapeutic stratification in future.
380 citations
TL;DR: In this paper, the authors describe the consequences of defective LC3-associated phagocytosis in vivo and show that mice lacking any of several components of the LAP pathway show increased serum levels of inflammatory cytokines and autoantibodies, glomerular immune complex deposition, and evidence of kidney damage.
Abstract: Defects in clearance of dying cells have been proposed to underlie the pathogenesis of systemic lupus erythematosus (SLE). Mice lacking molecules associated with dying cell clearance develop SLE-like disease, and phagocytes from patients with SLE often display defective clearance and increased inflammatory cytokine production when exposed to dying cells in vitro. Previously, we and others described a form of noncanonical autophagy known as LC3-associated phagocytosis (LAP), in which phagosomes containing engulfed particles, including dying cells, recruit elements of the autophagy pathway to facilitate maturation of phagosomes and digestion of their contents. Genome-wide association studies have identified polymorphisms in the Atg5 (ref. 8) and possibly Atg7 (ref. 9) genes, involved in both canonical autophagy and LAP, as markers of a predisposition for SLE. Here we describe the consequences of defective LAP in vivo. Mice lacking any of several components of the LAP pathway show increased serum levels of inflammatory cytokines and autoantibodies, glomerular immune complex deposition, and evidence of kidney damage. When dying cells are injected into LAP-deficient mice, they are engulfed but not efficiently degraded and trigger acute elevation of pro-inflammatory cytokines but not anti-inflammatory interleukin (IL)-10. Repeated injection of dying cells into LAP-deficient, but not LAP-sufficient, mice accelerated the development of SLE-like disease, including increased serum levels of autoantibodies. By contrast, mice deficient in genes required for canonical autophagy but not LAP do not display defective dying cell clearance, inflammatory cytokine production, or SLE-like disease, and, like wild-type mice, produce IL-10 in response to dying cells. Therefore, defects in LAP, rather than canonical autophagy, can cause SLE-like phenomena, and may contribute to the pathogenesis of SLE.
350 citations
References
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TL;DR: Global gene expression profiling of peripheral blood mononuclear cells is used to identify distinct patterns of gene expression that distinguish most SLE patients from healthy controls, and identify a subgroup of patients who may benefit from therapies targeting the IFN pathway.
Abstract: Systemic lupus erythematosus (SLE) is a complex, inflammatory autoimmune disease that affects multiple organ systems. We used global gene expression profiling of peripheral blood mononuclear cells to identify distinct patterns of gene expression that distinguish most SLE patients from healthy controls. Strikingly, about half of the patients studied showed dysregulated expression of genes in the IFN pathway. Furthermore, this IFN gene expression “signature” served as a marker for more severe disease involving the kidneys, hematopoetic cells, and/or the central nervous system. These results provide insights into the genetic pathways underlying SLE, and identify a subgroup of patients who may benefit from therapies targeting the IFN pathway.
2,075 citations
"The interferon signature in autoimm..." refers background in this paper
...The signature was found to correlate with disease activity and severity, the latter measured as nephritis and involvement of the CNS [3], and it could be modulated by glucocorticosteroid treatment [2]....
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...A role of type I IFN in diseases affecting central nervous system (CNS), such as neuropsychiatric SLE and Aicardi–Goutieres syndrome have also been suggested (rev. in [22])....
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...In the initial studies, it was noted that almost all children with SLE display an IFN signature [2], whereas only half of the adult SLE patients exhibited a clear IFN signature [3]....
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TL;DR: Microarray analysis of blood cells reveals that immature granulocytes may be involved in SLE pathogenesis, and the IFN signature confirms the central role of this cytokine in Sle, using oligonucleotide microarrays.
Abstract: Systemic lupus erythematosus (SLE) is a prototype systemic autoimmune disease characterized by flares of high morbidity. Using oligonucleotide microarrays, we now show that active SLE can be distinguished by a remarkably homogeneous gene expression pattern with overexpression of granulopoiesis-related and interferon (IFN)-induced genes. Using the most stringent statistical analysis (Bonferroni correction), 15 genes were found highly up-regulated in SLE patients, 14 of which are targets of IFN and one, defensin DEFA-3, a major product of immature granulocytes. A more liberal correction (Benjamini and Hochberg correction) yielded 18 additional genes, 12 of which are IFN-regulated and 4 granulocyte-specific. Indeed immature neutrophils were identified in a large fraction of SLE patients white blood cells. High dose glucocorticoids, a standard treatment of disease flares, shuts down the interferon signature, further supporting the role of this cytokine in SLE. The expression of 10 genes correlated with disease activity according to the SLEDAI. The most striking correlation (P < 0.001, r = 0.55) was found with the formyl peptide receptor-like 1 protein that mediates chemotactic activities of defensins. Therefore, while the IFN signature confirms the central role of this cytokine in SLE, microarray analysis of blood cells reveals that immature granulocytes may be involved in SLE pathogenesis.
1,873 citations
"The interferon signature in autoimm..." refers background in this paper
...The signature was found to correlate with disease activity and severity, the latter measured as nephritis and involvement of the CNS [3], and it could be modulated by glucocorticosteroid treatment [2]....
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...In the initial studies, it was noted that almost all children with SLE display an IFN signature [2], whereas only half of the adult SLE patients exhibited a clear IFN signature [3]....
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TL;DR: The data uncover a fundamental role of an endogenous antimicrobial peptide in breaking innate tolerance to self-DNA and suggest that this pathway may drive autoimmunity in psoriasis.
Abstract: Plasmacytoid dendritic cells (pDCs) sense viral and microbial DNA through endosomal Toll-like receptors to produce type 1 interferons. pDCs do not normally respond to self-DNA, but this restriction seems to break down in human autoimmune disease by an as yet poorly understood mechanism. Here we identify the antimicrobial peptide LL37 (also known as CAMP) as the key factor that mediates pDC activation in psoriasis, a common autoimmune disease of the skin. LL37 converts inert self-DNA into a potent trigger of interferon production by binding the DNA to form aggregated and condensed structures that are delivered to and retained within early endocytic compartments in pDCs to trigger Toll-like receptor 9. Thus, our data uncover a fundamental role of an endogenous antimicrobial peptide in breaking innate tolerance to self-DNA and suggest that this pathway may drive autoimmunity in psoriasis.
1,628 citations
"The interferon signature in autoimm..." refers background in this paper
...[13] found that the antimicrobial peptide LL37 binds and protects DNA or RNA from degradation, and allowed access of such complexes to early endosomes and triggering of TLR9 and TLR7....
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TL;DR: Not only have genome-wide association studies demonstrated that this pathway is highly relevant to human autoimmunity, but targeting JAKs is now a reality in immune-mediated disease.
870 citations
TL;DR: The results support a disease mechanism in SLE that involves key components of the type I IFN system, and identify SNPs that displayed strong signals in joint analysis of linkage and association with SLE.
Abstract: Systemic lupus erythematosus (SLE) is a complex systemic autoimmune disease caused by both genetic and environmental factors. Genome scans in families with SLE point to multiple potential chromosomal regions that harbor SLE susceptibility genes, and association studies in different populations have suggested several susceptibility alleles for SLE. Increased production of type I interferon (IFN) and expression of IFN-inducible genes is commonly observed in SLE and may be pivotal in the molecular pathogenesis of the disease. We analyzed 44 single-nucleotide polymorphisms (SNPs) in 13 genes from the type I IFN pathway in 679 Swedish, Finnish, and Icelandic patients with SLE, in 798 unaffected family members, and in 438 unrelated control individuals for joint linkage and association with SLE. In two of the genes—the tyrosine kinase 2 (TYK2) and IFN regulatory factor 5 (IRF5) genes—we identified SNPs that displayed strong signals in joint analysis of linkage and association (unadjusted P
590 citations
"The interferon signature in autoimm..." refers background in this paper
...The first identified SLE risk gene in the type I IFN pathway was IRF5 [15], which has an increased expression in SLE patients [16] and is activated in these individuals [17 & ]....
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...& Wang C, Sandling JK, Hagberg N, et al. Genome-wide profiling of target genes for the systemic lupus erythematosus-associated transcription factors IRF5 and STAT4....
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...[Epub ahead of print] This is the first study of Chromatin Immunoprecipitation-sequencing of genes targeted by IRF5 and STAT4....
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...The SLE risk haplotype in IRF5 is associated with serum IFN-a activity [18] and recent studies [19 & ] have shown that IRF5 target thorized reproduction of this article is prohibited. ins www.co-rheumatology.com 249 C Immunopathogenesis and treatment of autoimmune diseases genes are enriched for type I IFN regulated genes and that the expression pattern of these are characteristics for SLE patients....
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...This is the first study that demonstrates an increased nuclear translocation of IRF5 in cells from SLE patients....
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