The transcriptional programs that guide lymphocyte differentiation depend on the precise expression and timing of transcription factors (TFs). The TF BACH2 is essential for T and B lymphocytes and is ...associated with an archetypal super-enhancer (SE). Single-nucleotide variants in the BACH2 locus are associated with several autoimmune diseases, but BACH2 mutations that cause Mendelian monogenic primary immunodeficiency have not previously been identified. Here we describe a syndrome of BACH2-related immunodeficiency and autoimmunity (BRIDA) that results from BACH2 haploinsufficiency. Affected subjects had lymphocyte-maturation defects that caused immunoglobulin deficiency and intestinal inflammation. The mutations disrupted protein stability by interfering with homodimerization or by causing aggregation. We observed analogous lymphocyte defects in Bach2-heterozygous mice. More generally, we observed that genes that cause monogenic haploinsufficient diseases were substantially enriched for TFs and SE architecture. These findings reveal a previously unrecognized feature of SE architecture in Mendelian diseases of immunity: heterozygous mutations in SE-regulated genes identified by whole-exome/genome sequencing may have greater significance than previously recognized.
Genetic variants in
IL6ST
encoding the shared cytokine receptor for the IL-6 cytokine family GP130 have been associated with a diverse number of clinical phenotypes and disorders. We provide a ...molecular classification for 59 reported rare
IL6ST
pathogenic or likely pathogenic variants and additional polymorphisms. Based on loss- or gain-of-function, cytokine selectivity, mono- and biallelic associations, and variable cellular mosaicism, we grade six classes of
IL6ST
variants and explore the potential for additional variants. We classify variants according to the American College of Medical Genetics and Genomics criteria. Loss-of-function variants with (i) biallelic complete loss of GP130 function that presents with extended Stüve-Wiedemann Syndrome; (ii) autosomal recessive hyper-IgE syndrome (HIES) caused by biallelic; and (iii) autosomal dominant HIES caused by monoallelic
IL6ST
variants both causing selective IL-6 and IL-11 cytokine loss-of-function defects; (iv) a biallelic cytokine-specific variant that exclusively impairs IL-11 signaling, associated with craniosynostosis and tooth abnormalities; (v) somatic monoallelic mosaic constitutively active gain-of-function variants in hepatocytes that present with inflammatory hepatocellular adenoma; and (vi) mosaic constitutively active gain-of-function variants in hematopoietic and non-hematopoietic cells that are associated with an immune dysregulation syndrome. In addition to Mendelian
IL6ST
coding variants, there are common non-coding cis-acting variants that modify gene expression, which are associated with an increased risk of complex immune-mediated disorders and trans-acting variants that affect GP130 protein function. Our taxonomy highlights
IL6ST
as a gene with particularly strong functional and phenotypic diversity due to the combinatorial biology of the IL-6 cytokine family and predicts additional genotype-phenotype associations.
Janus kinases in immune cell signaling Ghoreschi, Kamran; Laurence, Arian; O'Shea, John J
Immunological reviews,
March 2009, Letnik:
228, Številka:
1
Journal Article
Recenzirano
Odprti dostop
The Janus family kinases (Jaks), Jak1, Jak2, Jak3, and Tyk2, form one subgroup of the non-receptor protein tyrosine kinases. They are involved in cell growth, survival, development, and ...differentiation of a variety of cells but are critically important for immune cells and hematopoietic cells. Data from experimental mice and clinical observations have unraveled multiple signaling events mediated by Jaks in innate and adaptive immunity. Deficiency of Jak3 or Tyk2 results in defined clinical disorders, which are also evident in mouse models. A striking phenotype associated with inactivating Jak3 mutations is severe combined immunodeficiency syndrome, whereas mutation of Tyk2 results in another primary immunodeficiency termed autosomal recessive hyperimmunoglobulin E syndrome. By contrast, complete deletion of Jak1 or Jak2 in the mouse are not compatible with life and, unsurprisingly, do not have counterparts in human disease. However, activating mutations of each of the Jaks are found in association with malignant transformation, the most common being gain-of-function mutations of Jak2 in polycythemia vera and other myeloproliferative disorders. Our existing knowledge on Jak signaling pathways and fundamental work on their biochemical structure and intracellular interactions allow us to develop new strategies for controlling autoimmune diseases or malignancies by developing selective Jak inhibitors, which are now coming into clinical use. Despite the fact that Jaks were discovered only a little more than a decade ago, at the time of writing there are 20 clinical trials underway testing the safety and efficacy of Jak inhibitors.
The Role of PTEN in Innate and Adaptive Immunity Taylor, Henry; Laurence, Arian D J; Uhlig, Holm H
Cold Spring Harbor perspectives in medicine,
12/2019, Letnik:
9, Številka:
12
Journal Article
Recenzirano
Odprti dostop
The lipid and protein phosphatase and tensin homolog (PTEN) controls the differentiation and activation of multiple immune cells. PTEN acts downstream from T- and B-cell receptors, costimulatory ...molecules, cytokine receptors, integrins, and also growth factor receptors. Loss of PTEN activity in human and mice is associated with cellular and humoral immune dysfunction, lymphoid hyperplasia, and autoimmunity. Although most patients with PTEN hamartoma tumor syndrome (PHTS) have no immunological symptoms, a subclinical immune dysfunction is present in many, and clinical immunodeficiency in few. Comparison of the immune phenotype caused by PTEN haploinsufficiency in PHTS, phosphoinositide 3-kinase (PI3K) gain-of-function in activated PI3K syndrome, and mice with conditional biallelic
deletion suggests a threshold model in which coordinated activity of several phosphatases control the PI3K signaling in a cell-type-specific manner. Emerging evidence highlights the role of PTEN in polygenic autoimmune disorders, infection, and the immunological response to cancer. Targeting the PI3K axis is an emerging therapeutic avenue.
The Janus kinase (JAK)-signal transducer of activators of transcription (STAT) pathway is now recognized as an evolutionarily conserved signaling pathway employed by diverse cytokines, interferons, ...growth factors, and related molecules. This pathway provides an elegant and remarkably straightforward mechanism whereby extracellular factors control gene expression. It thus serves as a fundamental paradigm for how cells sense environmental cues and interpret these signals to regulate cell growth and differentiation. Genetic mutations and polymorphisms are functionally relevant to a variety of human diseases, especially cancer and immune-related conditions. The clinical relevance of the pathway has been confirmed by the emergence of a new class of therapeutics that targets JAKs.
In this era, it is axiomatic that cytokines have critical roles in cellular development and differentiation, immune homeostasis, and host defense. Equally, dysregulation of cytokines is known to ...contribute to diverse inflammatory and immune‐mediated disorders. In fact, the past 20 years have witnessed the rapid translation of basic discoveries in cytokine biology to multiple successful biological agents (mAbs and recombinant fusion proteins) that target cytokines. These targeted therapies have not only fundamentally changed the face of multiple immune‐mediated diseases but have also unequivocally established the role of specific cytokines in human disease; cytokine biologists have many times over provided remarkable basic advances with direct clinical benefit. Numerous cytokines rely on the JAK‐STAT pathway for signaling, and new, safe, and effective small molecule inhibitors have been developed for a range of disorders. In this review, we will briefly summarize basic discoveries in cytokine signaling and briefly comment on some major unresolved issues. We will review clinical data pertaining to the first generation of JAK inhibitors and their clinical indications, discuss additional opportunities for targeting this pathway, and lay out some of the challenges that lie ahead.
Review on first generation of JAK inhibitors, including opportunities for targeting this pathway and some of the challenges that lie ahead.
Highlights ► Cytokines are critical contributors to autoimmune disease, cancer, and other diseases. ► Janus kinases (Jaks) selectively associate with type I and II cytokine receptors. ► Jaks have ...essential, nonredundant roles in mediating signals via these receptors. ► Ruxolitinib is approved for treatment of myelofibrosis, a disorder associated with Jak2 mutations. ► Tofacitinib has shown efficacy in trials in rheumatoid arthritis and other autoimmune diseases.
CD4+ T helper (Th) differentiation is regulated by diverse inputs, including the vitamin A metabolite retinoic acid (RA). RA acts through its receptor RARα to repress transcription of inflammatory ...cytokines, but is also essential for Th-mediated immunity, indicating complex effects of RA on Th specification and the outcome of the immune response. We examined the impact of RA on the genome-wide transcriptional response during Th differentiation to multiple subsets. RA effects were subset-selective and were most significant in Th9 cells. RA globally antagonized Th9-promoting transcription factors and inhibited Th9 differentiation. RA directly targeted the extended Il9 locus and broadly modified the Th9 epigenome through RARα. RA-RARα activity limited murine Th9-associated pulmonary inflammation, and human allergic inflammation was associated with reduced expression of RA target genes. Thus, repression of the Th9 program is a major function of RA-RARα signaling in Th differentiation, arguing for a role for RA in interleukin 9 (IL-9) related diseases.
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•Global effects of retinoic acid (RA) were evaluated by RNA sequencing in major Th subsets•RA impacts the transcriptome of Th9 cells more so than that of other effector subsets•RA-RARα represses the Il9 locus and Th9 program independently of Foxp3•RA-RARα activity controls pathology in Th9-associated allergic lung disease
Schwartz et al. examine the impact of retinoic acid (RA) on the genome-wide transcriptional response during differentiation of CD4+ T cells to different Th subsets, revealing a role for RA in repressing the Th9 differentiation program. Their findings argue for the importance of this dietary metabolite in immune homeostasis and in Th9-associated inflammatory disease.
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