Cytokines represent a large number of secreted proteins that regulate cell growth and differentiation. These factors are especially important in regulating immune and inflammatory responses, regulating lymphoid development and differentiation. Cytokines also regulate immune homeostasis, tolerance, and memory. Not surprisingly, cytokines are critical in the pathogenesis of autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease and psoriasis. Understanding the molecular basis of cytokine action provides important insights into the pathogenesis of immune-mediated disease and offers new therapeutic targets. We discovered Jak3, a kinase essential for signaling by cytokines that bind the common gamma chain, gc (IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21). We found that mutation of Jak3 results in a primary immunodeficiency disorder termed severe combined immunodeficiency (SCID). We have a clinical protocol that allows us to evaluate patients with suspected Jak3 deficiency. No new patients were enrolled this year. Recent work by NIH scientists has revealed that another primary immunodeficiency syndrome, Job's or Hyperimmunoglobulin E syndrome is due to STAT3 mutations. Based on our studies in the mouse, we investigated if mutations of STAT3 in humans are associated with impaired Th17 differentiation. We found this to be the case in patients with Job's syndrome. Mutations of STAT3 underlie hyper-IgE syndrome (HIES), but deciphering STAT3s role in pathogenesis has been hampered by the lethality associated with germline deletion of Stat3. Furthermore, the mechanisms responsible for IgE hyperproduction are unknown. We show that transgenic mice expressing a HIES-Stat3 allele recapitulate aspects of HIES, including elevated serum IgE. Surprisingly, mutant B cells display increased Ig germline transcription and switch recombination upon ex-vivo activation, demonstrating the hyper-IgE defect is B cell intrinsic. Using ChIP- and mRNA-Seq we show that Stat3 directly regulates B cell expression of Id2, an inhibitor of - switching. Ectopic Id2 expression restores normal Ig transcription and recombination, arguing that failure to induce Id2 is an important mechanism underlying the hyper-IgE aspect of this disease

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Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2010
Total Cost
$294,866
Indirect Cost
Name
National Institute of Arthritis and Musculoskeletal and Skin Diseases
Department
Type
DUNS #
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Gadina, Massimo; Johnson, Catrina; Schwartz, Daniella et al. (2018) Translational and clinical advances in JAK-STAT biology: The present and future of jakinibs. J Leukoc Biol 104:499-514
Schwartz, Daniella M; Kanno, Yuka; Villarino, Alejandro et al. (2017) JAK inhibition as a therapeutic strategy for immune and inflammatory diseases. Nat Rev Drug Discov 17:78
Villarino, Alejandro V; Kanno, Yuka; O'Shea, John J (2017) Mechanisms and consequences of Jak-STAT signaling in the immune system. Nat Immunol 18:374-384
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O'Shea, John J; Holland, Steven M; Staudt, Louis M (2013) JAKs and STATs in immunity, immunodeficiency, and cancer. N Engl J Med 368:161-70
Laurence, Arian; Amarnath, Shoba; Mariotti, Jacopo et al. (2012) STAT3 transcription factor promotes instability of nTreg cells and limits generation of iTreg cells during acute murine graft-versus-host disease. Immunity 37:209-22

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