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. One patient was evaluated in NIH Clinical Center this year. The patient was not found to have Jak3-SCID, but interestingly was found to have a new form of primary immunodeficiency. 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. In further efforts to clarify the immunopathogenesis of Job's syndrome, we created a mouse model of this disorder by knocking in patient-derived mutants into the mouse Stat3 locus. The mouse model recapitulated the important features of the human disease, but also allowed us to establish that these mutations of STAT3 result in intrinsic defects in B cell function.
| 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 |
| 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 |
| Afzali, Behdad; Grönholm, Juha; Vandrovcova, Jana et al. (2017) BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency. Nat Immunol 18:813-823 |
| 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 |
| O'Shea, John J; Schwartz, Daniella M; Villarino, Alejandro V et al. (2015) The JAK-STAT pathway: impact on human disease and therapeutic intervention. Annu Rev Med 66:311-28 |
| Villarino, Alejandro V; Kanno, Yuka; Ferdinand, John R et al. (2015) Mechanisms of Jak/STAT signaling in immunity and disease. J Immunol 194:21-7 |
| Hirahara, Kiyoshi; Onodera, Atsushi; Villarino, Alejandro V et al. (2015) Asymmetric Action of STAT Transcription Factors Drives Transcriptional Outputs and Cytokine Specificity. Immunity 42:877-89 |
| Steward-Tharp, Scott M; Laurence, Arian; Kanno, Yuka et al. (2014) A mouse model of HIES reveals pro- and anti-inflammatory functions of STAT3. Blood 123:2978-87 |
| 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 |
| Kontzias, Apostolos; Kotlyar, Alexander; Laurence, Arian et al. (2012) Jakinibs: a new class of kinase inhibitors in cancer and autoimmune disease. Curr Opin Pharmacol 12:464-70 |
Showing the most recent 10 out of 22 publications
