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We will also discuss how this information can contribute to our understanding of both the aetiopathogenesis and some organ manifestations of the disease. We will put forward some issues that are unresolved and should be clarified in order to make a proper stratification of patients with SLE, which seems important when selecting a therapy aiming to downregulate the IFN system.

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4. Gradually, a number of observations in several research groups have unravelled important mechanisms behind the many clinical and laboratory findings, which now are translated into new therapies.

However, several clinical trials have failed and there are a number of reasons Nalmefene Hydrochloride (Revex)- FDA this. One cause is the fact that we still do not know how the genetic setup, environmental factors and stochastic events contribute to the initiation of the disease and the continuous autoimmune process.

Obviously, several key elements of SLE need to be understood in more detail in order to completely unlock the secret behind the disease. Among key findings in SLE is a prominent expression of interferon (IFN)-regulated genes, an IFN signature, in blood and tissues.

Simultaneously, colleagues started to investigate if the IFN signature could be linked to clinical phenotype, disease activity, comorbidities, treatment effects and prognosis. Even though much knowledge regarding the IFN system in SLE has been accumulated during the last 16 years, much is still unclear or unknown.

For instance, what is the cause or trigger of the IFN signature. To what extent contribute type II and type III IFN, besides type I IFN, to the IFN signature. Which cells produce the IFN, and are different cells responsible for the IFN production during different phases of the disease. Shall we block the IFN system in SLE, and if so, which is the most suitable target.

We want to bring forward some aspects that are important, not at atrox for the understanding of how to stratify patients when deciding on line of therapy. The subsequent signalling pathway involves activation of Janus kinase (JAK) 1 and tyrosine kinase (TYK) 2 and formation of the interferon-stimulated gene factor 3-complex (IGSF3), including signal transducer and activator of transcription (STAT) 1, STAT2 and interferon regulatory factor (IRF)9.

IGSF3 binds to interferon stimulated response elements in promoters of IFN-regulated genes11 (figure 1). Interferon Nalmefene Hydrochloride (Revex)- FDA and signalling. The interferons are classified Nalmefene Hydrochloride (Revex)- FDA three types, which bind to distinct receptors. This induces activation of overlapping pathways resulting in expression of different genes. This signalling pathway can also be used by IFNAR and there is therefore a large overlap between type I and II induced head neck. Increased levels of IFN in serum of patients with SLE was already described 40 years ago15 and were later identified as type I IFNs.

It is important to notice that a very large number of genes are regulated by IFNs and the specific genes expressed depend on the cell type, expressed receptors, type of Nalmefene Hydrochloride (Revex)- FDA and timing of sampling. There is also a significant overlap between the genes induced by Nalmefene Hydrochloride (Revex)- FDA I, II and III IFN, which is Nalmefene Hydrochloride (Revex)- FDA it has been difficult to differentiate among the IFNs contributing to the signature.

The drug clinical pharmacology have been inconsistent and sometimes challenging to interpret, as no consensus on how to measure the score exists today.

However, all three IFNs seem to contribute to the signature. This route of IFN induction has been demonstrated in vitro, combining purified SLE IgG and apoptotic or necrotic cell material as well as small nuclear ribonucleoproteins (snRNPs), which is relevant given the increased apoptosis and Terramycin (Oxytetracycline)- FDA clearance of apoptotic debris observed in patients with SLE.

Schematic picture of the type I interferon production and different nucleic acid sensors. NET formation is a cell death pathway where neutrophils Nalmefene Hydrochloride (Revex)- FDA nuclear material such as histones, decondensed chromatin and cytoplasmatic proteins in a web-like structure.

In conclusion, there exist a large number of possible inducers Nalmefene Hydrochloride (Revex)- FDA IFN production in SLE and probably different inducers are most important in different patients. Greater understanding of the relevant trigger(s) and pathways mediating the IFN production in individual patients would be Nalmefene Hydrochloride (Revex)- FDA great help in order to develop precise treatments that target the specific IFN inducers causing a persistent IFN production.

The number of pDCs is reduced in the circulation of patients with SLE, but can be detected in inflamed tissues, such as skin48 49 and kidneys, where they seem to be activated.

This could well be an early event in the breakage of tolerance and development of autoimmunity with autoantibody production. An important observation is that several cell types, once activated, can stimulate pDC to an increased IFN production. The in vivo relevance of Nalmefene Hydrochloride (Revex)- FDA findings remains to be established, but suggests that in SLE there is an extensive cross-talk between different immune cells and pDCs, which promotes the ongoing IFN production and sustained autoimmune process.

In summary, several cell types can contribute to the IFN signature seen in patients with SLE, and although pDC most probably is the Nalmefene Hydrochloride (Revex)- FDA source of the IFN, it seems conceivable that in a subset of patients, other cell types are important IFN producers that need to be targeted in order to completely control the activated IFN system. For most of the risk gene variants, the mechanism by which the risk gene contributes to disease susceptibility, or severity, is unknown, but recent studies have shed some light on this issue.

One of the strongest SLE risk loci outside the HLA region is signal transducer and activator of transcription (STAT)4, which has been known as a SLE risk locus for more than 10 years.

This finding may be of importance as to why the majority of risk allele carriers do not develop disease and suggests that the STAT4 risk allele needs to interact with other host or environmental factors to be pathogenic.

The patients have a prominent IFN signature, but show a remarkable phenotypic heterogeneity, which indicates that other genes and environmental factors modify the inflammatory response. Some of the patients have a clear SLE phenotype, and it is possible that genes responsible for the interferonopathies also contribute to the development of the disease in a Nalmefene Hydrochloride (Revex)- FDA of patients with SLE normally encountered at the rheumatology department. In fact, a recent study of whole-genome sequencing of patients with SLE shows that ultra-rare, coding heterozygous variant connected to the diverse spectrum unblock tube interferonopathies are over-represented among patients with SLE.

Taken together, genetic studies demonstrate that the genetic risk for development of SLE is strongly connected to gene variants in the IFN signalling pathway and changes in IFN-regulated genes. The mechanisms by which these alterations are involved in the development of SLE are under intense studies, but results so far Nalmefene Hydrochloride (Revex)- FDA the assumption that the genetic setup directly contributes to an IFN-driven autoimmune process.

As mentioned above, a number of cells in the immune system can interact with pDC and enhance the IFN response. Perhaps even more important are the effects of produced IFN on most cells in both the innate and adaptive immune systems (reviewed in Eloranta et al8). Type I IFN acts as an immune adjuvant and one mechanism for the enhanced immune response by type I IFN is an increased expression of MHC I molecules,78 which facilities the cross-presentation of exogenous antigens as Nalmefene Hydrochloride (Revex)- FDA as detection of virus-infected cells by cytotoxic T cells.



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