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Tyk2 review

Ana Karen Rodríguez-Elías, Karina Maldonado-Murillo, Luis Fernando López-Mendoza, Julián Ramírez-Bello
Rheumatoid arthritis is a chronic inflammatory autoimmune disease that affects approximately 0.5-1% of the general population and leads to chronic synovial inflammation, destruction of cartilage and bone, and disability. The heritability of rheumatoid arthritis has been estimated to be about 60%, while the contribution of HLA to heritability has been estimated to be 11-37%. Other genes, such as PTPN22, STAT4, CTLA4, TRAF1, PADI4, IRF5, FCRL3, TNFIP3, TNF-α, miRNAs, CD28, CD40, TYK2, etc., have been associated with susceptibility, severity, activity, and treatment response of rheumatoid arthritis...
March 2016: Gaceta Médica de México
Anne Op de Beeck, Decio L Eizirik
Type 1 diabetes mellitus (T1DM) is caused by progressive autoimmune-mediated loss of pancreatic β-cell mass via apoptosis. The onset of T1DM depends on environmental factors that interact with predisposing genes to induce an autoimmune assault against β cells. Epidemiological, clinical and pathology studies in humans support viral infection--particularly by enteroviruses (for example, coxsackievirus)--as an environmental trigger for the development of T1DM. Many candidate genes for T1DM, such as MDA5, PTPN2 and TYK2, regulate antiviral responses in both β cells and the immune system...
May 2016: Nature Reviews. Endocrinology
Andrea Sukhov, Iannis E Adamopoulos, Emanual Maverakis
Cutaneous psoriasis (e.g., psoriasis vulgaris (PsV)) and psoriatic arthritis (PsA) are complex heterogeneous diseases thought to have similar pathophysiology. The soluble and cellular mediators of these closely related diseases are being elucidated through genetic approaches such as genome-wide association studies (GWAS), as well as animal and molecular models. Novel therapeutics targeting these mediators (IL-12, IL-23, IL-17, IL-17 receptor, TNF) are effective in treating both the skin and joint manifestations of psoriasis, reaffirming the shared pathophysiology of PsV and PsA...
August 2016: Clinical Reviews in Allergy & Immunology
Nicole R Leitner, Agnieszka Witalisz-Siepracka, Birgit Strobl, Mathias Müller
Tyrosine kinase 2 (TYK2) is a member of the Janus kinase (JAK) family, which transduces cytokine and growth factor signalling. Analysis of TYK2 loss-of-function revealed its important role in immunity to infection, (auto-) immunity and (auto-) inflammation. TYK2-deficient patients unravelled high similarity between mice and men with respect to cellular signalling functions and basic immunology. Genome-wide association studies link TYK2 to several autoimmune and inflammatory diseases as well as carcinogenesis...
November 26, 2015: Cytokine
Jamie L Harden, James G Krueger, Anne M Bowcock
Psoriasis vulgaris is a common, chronic inflammatory skin disease with a complex etiology involving genetic risk factors and environmental triggers. Here we describe the many known genetic predispositions of psoriasis with respect to immune genes and their encoded pathways in psoriasis susceptibility. These genes span an array of functions that involve antigen presentation (HLA-Cw6, ERAP1, ERAP2, MICA), the IL-23 axis (IL12Bp40, IL23Ap19, IL23R, JAK2, TYK2), T-cell development and T-cells polarization (RUNX1, RUNX3, STAT3, TAGAP, IL4, IL13), innate immunity (CARD14, c-REL, TRAF3IP2, DDX58, IFIH1), and negative regulators of immune responses (TNIP1, TNFAIP3, NFKBIA, ZC3H12C, IL36RN, SOCS1)...
November 2015: Journal of Autoimmunity
Trine H Mogensen
In recent years a number of primary immunodeficiencies (PIDs) characterized by elevated Immunoglobulin E (IgE) levels have been uncovered and termed as Hyper-IgE syndrome (HIES). In addition to the elevated levels of IgE, patients with these PIDs display a spectrum of infections by staphylococci and fungi, and in some cases viruses, particularly affecting skin and lungs. Most of these PIDs also have a non-infectious phenotype, comprising musculoskeletal, vascular, and neurological abnormalities. The genetic basis for the majority of conditions with elevated IgE has now been established and includes mutations in STAT3, DOCK8, TYK2, and most recently PGM3 molecules...
2016: International Reviews of Immunology
Darren D O'Rielly, Proton Rahman
Spondyloarthritis (SpA) represents a group of inflammatory rheumatic diseases that cluster within families and possess overlapping clinical features. The pathogenesis of SpA encompasses a complex array of genetic, immunological and environmental factors. In this article, we will briefly review the genetics of PsA, and then focus on the genes that may be potentially linked either directly or indirectly to the immunopathology of the Th-17 pathway. The most consistent and dominant genetic effect of PsV and PsA is located on chromosome 6p21...
October 2014: Best Practice & Research. Clinical Rheumatology
Christel J Menet
The family of JAK comprises four members and has received significant attention in recent years from the pharmaceutical industry as a therapeutic target. The role of JAK is central to cytokine signaling pathways. It is believed that selective modulation of one specific JAK can lead to the inhibition of a restricted set of cytokines, which should avoid undesired side effects and get closer to the profile of biologic therapies. Consequently, selective JAK inhibition has become a major focus area of drug discovery research...
July 2014: Pharmaceutical Patent Analyst
Jeffrey J Babon, Isabelle S Lucet, James M Murphy, Nicos A Nicola, Leila N Varghese
The JAK (Janus kinase) family members serve essential roles as the intracellular signalling effectors of cytokine receptors. This family, comprising JAK1, JAK2, JAK3 and TYK2 (tyrosine kinase 2), was first described more than 20 years ago, but the complexities underlying their activation, regulation and pleiotropic signalling functions are still being explored. Here, we review the current knowledge of their physiological functions and the causative role of activating and inactivating JAK mutations in human diseases, including haemopoietic malignancies, immunodeficiency and inflammatory diseases...
August 15, 2014: Biochemical Journal
Yan Liang, Yan Zhu, Yi Xia, Hui Peng, Xiao-Ke Yang, Yan-Yan Liu, Wang-Dong Xu, Hai-Feng Pan, Dong-Qing Ye
INTRODUCTION: Tyrosine kinase 2 (Tyk2) is a Janus kinase family member that is crucial for signaling transduction in response to a wide variety of cytokines, including type I IFNs, IL-6, IL-10, IL-12 and IL-23. An appropriate expression of Tyk2-mediated signaling might be essential for maintaining normal immune responses. AREAS COVERED: This review summarizes that Tyk2 is essential for the differentiation and function of a wide variety of immune cells, including natural killer cells, B cells, as well as T helper cells...
May 2014: Expert Opinion on Therapeutic Targets
Muhammad Furqan, Nikhil Mukhi, Byung Lee, Delong Liu
JAK-STAT (Janus associated kinase-signal transducer and activator of transcription) pathway plays a critical role in transduction of extracellular signals from cytokines and growth factors involved in hematopoiesis, immune regulation, fertility, lactation, growth and embryogenesis. JAK family contains four cytoplasmic tyrosine kinases, JAK1-3 and Tyk2. Seven STAT proteins have been identified in human cells, STAT1-6, including STAT5a and STAT5b. Negative regulators of JAK-STAT pathways include tyrosine phosphatases (SHP1 and 2, CD45), protein inhibitors of activated STATs (PIAS), suppressors of cytokine signaling (SOCS) proteins, and cytokine-inducible SH2-containing protein (CIS)...
2013: Biomarker Research
Christel J Menet, Luc Van Rompaey, Raphaël Geney
In this review, we describe the current knowledge of the biology of the JAKs. The JAK family comprises the four nonreceptor tyrosine kinases JAK1, JAK2, JAK3, and Tyk2, all key players in the signal transduction from cytokine receptors to transcription factor activation. We also review the progresses made towards the optimization of JAK inhibitors and the importance of their selectivity profile. Indeed, the full array of many medicinal chemistry enabling tools (HTS, X-ray crystallography, scaffold morphing, etc...
2013: Progress in Medicinal Chemistry
Brian W Dymock, Cheng Shang See
INTRODUCTION: Janus kinases (JAKs) comprise a family of four enzymes, JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2), centrally implicated in cell signaling processes important in cancer and immune-inflammatory diseases. Progression in the field has taken a recent step forward with the approval of ruxolitinib (Jakafi), a selective inhibitor of JAK1/2 and very recently tofacitinib (Xeljanz), a pan-JAK inhibitor. There are many new JAK family enzyme inhibitors in the clinic now with a range of selectivity profiles...
April 2013: Expert Opinion on Therapeutic Patents
Peter Norman
INTRODUCTION: The JAK family comprises of the four non-receptor tyrosine kinases JAK1, JAK2, JAK3 and Tyk2, which play key, but differing, roles in cytokine receptor signal transduction. A non-selective JAK inhibitor, ruxolitinib, has recently been approved to treat myelofibrosis whereas tofacitinib is poised for approval to treat rheumatoid arthritis. Selective inhibition of JAK3, JAK1 or Tyk2 provides the opportunity to achieve clinical efficacy in the treatment of inflammatory diseases while reducing the risk of dose-limiting effects attributable to JAK2 inhibition...
October 2012: Expert Opinion on Therapeutic Patents
Jean-Laurent Casanova, Steven M Holland, Luigi D Notarangelo
Inborn errors of the genes encoding two of the four human JAKs (JAK3 and TYK2) and three of the six human STATs (STAT1, STAT3, and STAT5B) have been described. We review the disorders arising from mutations in these five genes, highlighting the way in which the molecular and cellular pathogenesis of these conditions has been clarified by the discovery of inborn errors of cytokines, hormones, and their receptors, including those interacting with JAKs and STATs. The phenotypic similarities between mice and humans lacking individual JAK-STAT components suggest that the functions of JAKs and STATs are largely conserved in mammals...
April 20, 2012: Immunity
George R Stark, James E Darnell
We look back on the discoveries that the tyrosine kinases TYK2 and JAK1 and the transcription factors STAT1, STAT2, and IRF9 are required for the cellular response to type I interferons. This initial description of the JAK-STAT pathway led quickly to additional discoveries that type II interferons and many other cytokines signal through similar mechanisms. This well-understood pathway now serves as a paradigm showing how information from protein-protein contacts at the cell surface can be conveyed directly to genes in the nucleus...
April 20, 2012: Immunity
Vinod Chandran
Genetic epidemiological studies have demonstrated a significant genetic basis to both psoriasis and psoriatic arthritis (PsA). Although candidate gene association studies had identified genes for disease susceptibility, recent genome-wide association studies have demonstrated robust associations both within and outside the major histocompatibility region on chromosome 6p. The susceptibility genes identified include HLA-C, IL13, IL4, TNFAIP3, IL23A, IL23R, IL28RA, REL, IFIH1, ERAP, TRAF3IP2, NFKBIA, TYK2, ZNF313, NOS2, FBXL19 and NFKBIA in subjects of European ethnicity and HLA-C, IL12B, LCE3D, ERAP1, TNIP1, PTTG1, CSMD1, GJB2, SERPINB8 and ZNF816A in subjects of Chinese ethnicity...
April 2013: Clinical Reviews in Allergy & Immunology
Qian Zhang, Helen C Su
PURPOSE OF REVIEW: The hyper-IgE syndromes (HIES) are primary immunodeficiencies characterized by eczema, sinopulmonary infections, and elevated serum IgE. This review discusses the clinical similarities and differences between the autosomal dominant HIES (AD-HIES) and autosomal recessive HIES (AR-HIES) forms, as well as their causative genetic and pathophysiological mechanisms. RECENT FINDINGS: Over the past 4 years, three genetic defects have been identified in HIES...
December 2011: Current Opinion in Pediatrics
Ross L Levine
Although the Janus family of kinases (JAK1, JAK2, JAK3, and TYK2) has been extensively characterized and investigated, the role of Janus kinase activation in the pathogenesis and therapy of human malignancies was not fully appreciated until recently when multiple studies identified a recurrent somatic mutation in the JAK2 tyrosine kinase (JAK2V617F) in the majority of patients with BCR-ABL-negative myeloproliferative neoplasms (MPN), polycythemia vera, essential thrombocytosis, and primary myelofibrosis. Other mutations that activate the JAK-STAT signaling pathway have since been identified in JAK2V617F-negative MPN patients and in a subset of patients with acute myeloid leukemia and acute lymphoid leukemia...
2012: Current Topics in Microbiology and Immunology
C W Lees, J C Barrett, M Parkes, J Satsangi
Complex disease genetics has been revolutionised in recent years by the advent of genome-wide association (GWA) studies. The chronic inflammatory bowel diseases (IBDs), Crohn's disease and ulcerative colitis have seen notable successes culminating in the discovery of 99 published susceptibility loci/genes (71 Crohn's disease; 47 ulcerative colitis) to date. Approximately one-third of loci described confer susceptibility to both Crohn's disease and ulcerative colitis. Amongst these are multiple genes involved in IL23/Th17 signalling (IL23R, IL12B, JAK2, TYK2 and STAT3), IL10, IL1R2, REL, CARD9, NKX2...
December 2011: Gut
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