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Frontiers in Immunology 2023Interleukin 6 (IL-6) is a pleiotropic cytokine executing a diverse number of functions, ranging from its effects on acute phase reactant pathways, B and T lymphocytes,... (Review)
Review
Interleukin 6 (IL-6) is a pleiotropic cytokine executing a diverse number of functions, ranging from its effects on acute phase reactant pathways, B and T lymphocytes, blood brain barrier permeability, synovial inflammation, hematopoiesis, and embryonic development. This cytokine empowers the transition between innate and adaptive immune responses and helps recruit macrophages and lymphocytes to the sites of injury or infection. Given that IL-6 is involved both in the immune homeostasis and pathogenesis of several autoimmune diseases, research into therapeutic modulation of IL-6 axis resulted in the approval of a number of effective treatments for several autoimmune disorders like neuromyelitis optica spectrum disorder (NMOSD), rheumatoid arthritis, juvenile idiopathic arthritis, polyarticular juvenile idiopathic arthritis, giant cell arteritis (GCA), and cytokine release syndrome, associated with SARS-CoV2 pneumonia. This review discusses downstream inflammatory pathways of IL-6 expression and therapeutic applications of IL-6 blockade, currently investigated for the treatment of several other autoimmune conditions such as autoimmune encephalitis, autoimmune epilepsy, as well as myelin oligodendrocyte glycoprotein associated demyelination (MOGAD). This review further highlights the need for clinical trials to evaluate IL-6 blockade in disorders such neuropsychiatric lupus erythematosus (SLE), sarcoidosis and Behcet's.
Topics: Humans; Interleukin-6; RNA, Viral; COVID-19; SARS-CoV-2; Arthritis, Juvenile; Cytokines
PubMed: 37841263
DOI: 10.3389/fimmu.2023.1255533 -
Nature Reviews. Immunology Dec 2023Protein kinases play a major role in cellular activation processes, including signal transduction by diverse immunoreceptors. Given their roles in cell growth and death... (Review)
Review
Protein kinases play a major role in cellular activation processes, including signal transduction by diverse immunoreceptors. Given their roles in cell growth and death and in the production of inflammatory mediators, targeting kinases has proven to be an effective treatment strategy, initially as anticancer therapies, but shortly thereafter in immune-mediated diseases. Herein, we provide an overview of the status of small molecule inhibitors specifically generated to target protein kinases relevant to immune cell function, with an emphasis on those approved for the treatment of immune-mediated diseases. The development of inhibitors of Janus kinases that target cytokine receptor signalling has been a particularly active area, with Janus kinase inhibitors being approved for the treatment of multiple autoimmune and allergic diseases as well as COVID-19. In addition, TEC family kinase inhibitors (including Bruton's tyrosine kinase inhibitors) targeting antigen receptor signalling have been approved for haematological malignancies and graft versus host disease. This experience provides multiple important lessons regarding the importance (or not) of selectivity and the limits to which genetic information informs efficacy and safety. Many new agents are being generated, along with new approaches for targeting kinases.
Topics: Humans; Protein Kinases; Protein Kinase Inhibitors; Signal Transduction; Immune System Diseases
PubMed: 37188939
DOI: 10.1038/s41577-023-00877-7 -
Aging Cell Jul 2023Emerging evidence has shown that leukocyte telomere length (LTL) is associated with various health-related outcomes, while the causality of these associations remains... (Meta-Analysis)
Meta-Analysis Review
Emerging evidence has shown that leukocyte telomere length (LTL) is associated with various health-related outcomes, while the causality of these associations remains unclear. We performed a systematic review and meta-analysis of current evidence from Mendelian randomization (MR) studies on the association between LTL and health-related outcomes. We searched PubMed, Embase, and Web of Science up to April 2022 to identify eligible MR studies. We graded the evidence level of each MR association based on the results of the main analysis and four sensitive MR methods, MR-Egger, weighted median, MR-PRESSO, and multivariate MR. Meta-analyses of published MR studies were also performed. A total of 62 studies with 310 outcomes and 396 MR associations were included. Robust evidence level was observed for the association between longer LTL and increased risk of 24 neoplasms (the strongest magnitude for osteosarcoma, GBM, glioma, thyroid cancer, and non-GBM glioma), six genitourinary and digestive system outcomes of excessive or abnormal growth, hypertension, metabolic syndrome, multiple sclerosis, and clonal hematopoiesis of indeterminate potential. Robust inverse association was observed for coronary heart disease, chronic kidney disease, rheumatoid arthritis, juvenile idiopathic arthritis, idiopathic pulmonary fibrosis, and facial aging. Meta-analyses of MR studies suggested that genetically determined LTL was associated with 12 neoplasms and 9 nonneoplasm outcomes. Evidence from published MR studies supports that LTL plays a causal role in various neoplastic and nonneoplastic diseases. Further research is required to elucidate the underlying mechanisms and to bring insight into the potential prediction, prevention, and therapeutic applications of telomere length.
Topics: Humans; Mendelian Randomization Analysis; Arthritis, Rheumatoid; Glioma; Hypertension; Telomere; Genome-Wide Association Study; Polymorphism, Single Nucleotide
PubMed: 37232505
DOI: 10.1111/acel.13874 -
Turkish Archives of Pediatrics Jul 2023Uveitis in childhood poses a distinct challenge, mainly because of the insidious onset and chronic course of intraocular inflammation in most cases, which may result in...
Uveitis in childhood poses a distinct challenge, mainly because of the insidious onset and chronic course of intraocular inflammation in most cases, which may result in permanent visual loss due to delayed diagnosis and treatment. Although anterior uveitis, frequently associated with juvenile idiopathic arthritis, is the most common form of ocular involvement, idiopathic intermediate uveitis (pars planitis) is also a common uveitic entity in childhood. Posterior or panuveitis of a variety of noninfectious or infectious etiologies may be seen as well. Pediatric uveitis needs to be closely monitored since serious ocular complications such as intraocular pressure elevation, cataract, and macular edema may rapidly develop due to inadequately controlled inflammation and/or the use of corticosteroids. Methotrexate is generally the first- line corticosteroid-sparing agent, and adalimumab is the first-line biologic in refractory cases of noninfectious uveitis. A multidisciplinary approach is essential to monitor systemic disease associations, treatment response, and adverse events in children with uveitis.
PubMed: 37357450
DOI: 10.5152/TurkArchPediatr.2023.23086 -
Balkan Medical Journal Sep 2023Behçet syndrome (BS) is a systemic vasculitis of unknown etiology that affects the skin, mucosa, joints, eyes, central nervous system, gastrointestinal system,... (Review)
Review
Behçet syndrome (BS) is a systemic vasculitis of unknown etiology that affects the skin, mucosa, joints, eyes, central nervous system, gastrointestinal system, arteries, and veins. It is generally believed to have a complex genetic background where both innate and adaptive immune systems are activated through environmental factors, such as infections, and auto-antigens. Heat shock proteins (HSPs) are highly conserved and immunogenic endogenous proteins that are thought to play both an enhancing and regulating role in several autoimmune and inflammatory diseases, such as rheumatoid arthritis, juvenile idiopathic arthritis, and Type I diabetes. There is evidence supporting the role of various microorganisms in BS, which may be using a common pathway to trigger or activate BS through molecular mimicry. The significant homology between microbial and human HSPs suggests that HSPs could serve as a common trigger. This review summarizes the work on the role of HSPs in the pathogenesis of BS. However, it remains unknown whether the HSPs detected in BS lesions play a causative role, their presence is a result of the ongoing inflammation, or they have a protective role against inflammation, as suggested in some other diseases.
Topics: Humans; Heat-Shock Proteins; Behcet Syndrome; Inflammation; Arthritis, Juvenile; Diabetes Mellitus, Type 1
PubMed: 37525514
DOI: 10.4274/balkanmedj.galenos.2023.2023-6-76