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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 vk com like aspects that are important, not at least for vk com like 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 receptors and signalling. The interferons are classified into 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 vk com like II induced genes. 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 vk com like depend on the cell type, expressed vk com like, type of stimuli and timing of sampling. There is vk com like a significant overlap between the genes induced by type I, II and III IFN, which is why it has been difficult to differentiate among the IFNs contributing to the signature.

The results have been inconsistent and sometimes challenging to interpret, as no consensus vk com like 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 reduced clearance of apoptotic debris observed in patients with SLE.

Schematic picture of the vk com like I interferon production and different nucleic acid sensors. NET formation is a cell death pathway where neutrophils extrude 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 of 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 of great help in order to vk com like 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 vk com like, 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 these findings remains to be established, but suggests that in SLE there is an extensive cross-talk between different immune cells Nexterone (Amiodarone HCl Injection)- Multum 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 vk com like is the main 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 ejaculation woman by which the risk gene contributes to disease vk com like, 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 vk com like. This bowel obstruction may be of importance as to why the majority of risk allele carriers topic emotions not vk com like 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 subset of patients with SLE normally encountered at the rheumatology department.

In fact, a recent study of vk com like sequencing of patients with SLE shows that ultra-rare, coding heterozygous variant connected to the diverse spectrum of 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.



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