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The Section’s work has focused on understanding molecular and cellular mechanisms that regulate immune homeostasis, with particular emphasis on epigenetic mechanisms that regulate lymphocyte development and cell-fate decisions and roles played by pro-inflammatory and anti-inflammatory cytokines in the development of central nervous system (CNS) inflammatory diseases. This Section is part of the Laboratory of Immunology.
The Molecular Immunology Section seeks to understand molecular and cellular mechanisms that regulate host immunity with particular focus on lymphocytes that mediate CNS autoimmune diseases, such as Uveitis and Multiple Sclerosis. Major interest is on: Auto-reactive lymphocytes that mediate remitting and recurrent CNS autoimmune diseases; Development of Biologics and cytokine-based therapies for autoimmune and neurodegenerative diseases; Role of JAK/STAT signal transduction pathway and suppressors of cytokine signaling (SOCS) proteins in the regulation of lymphocyte development and cell-fate decisions. Major Areas of Investigation and Findings: (i) Auto-reactive lymphocytes that mediate CNS autoimmune diseases Intraocular inflammatory diseases (Uveitis) are a major cause of severe visual handicap and include sight-threatening idiopathic inflammatory ocular disease such as Behcet disease, birdshot retinochoroidopathy, Vogt-Koyanagi-Harada, sympathetic ophthalmia and ocular sarcoidosis. Uveitis may be of infectious or autoimmune etiology. Similar to other organ-specific autoimmune diseases such multiple sclerosis, Uveitis is characterized by repeated cycles of remission and recurrent inflammation. We established that Th17 cells might be the etiologic agents of uveitis by studies showing that blood of patients with uveitis contain more Th17 cells than that of healthy individuals and the expansion of Th17 is inhibited in part by immunosuppressive cytokines. A great deal of our effort is now devoted to studies aimed at understanding factors that promote Th17-mediated uveitis and mechanisms by which anti-inflammatory cytokines including IL-27 and IL-35 inhibit uveitis and mitigate ocular pathology. (ii) Development of Biologics for treating autoimmune diseases IL-12 family cytokines have emerged as important players in the development of CNS autoimmune diseases. Each member is comprised of an alpha and beta chain and 4 heterodimeric IL-12 cytokines have been described, with some members (IL-12, IL-23) promoting autoimmune pathology while others (IL-27, IL-35) suppress inflammation and limit tissue injury. A major goal of our drug discovery program is to genetically engineer each and IL-12 subunit protein and novel combinations of these subunits for use as potential therapeutic cytokines. To this end we have genetically engineered: (i) Recombinant mouse IL-35; (ii) Novel IL-12 member (IL-39); (iii) Novel rIL27p28/IL12p40 fusokine; (iv) rIL12p35, rIL12p40; rIL27p28; and rEbi3 single chain proteins. We have shown that; (i) rIL-35, rIL-27 or rIL27p28/IL12p40 inhibits Uveitis; (ii) rIL12p35 and Ebi3 suppresses lymphocyte proliferation and IL-39 producing B cells maybe the etiologic agent of systemic Lupus Erythematosus (SLE). These proof-of-concept studies suggest that cytokines comprising of unique IL-12 α and β subunits pairing may constitute a new class of therapeutic cytokines or therapeutic targets. (iii) Mechanisms that regulate lymphocyte development and cell-fate decisions The innate and adoptive immune systems have distinct functions in host immunity. The innate immune system provides instructional signals for lymphocyte differentiation while lymphocytes regulate the intensity and duration of the inflammatory response by coordinating activities of most immune cells. Innate and adaptive immune cell function is mediated by cytokines, signaling proteins that allow cells to communicate with other cell types and movement of immune cells towards sites of inflammation, infection and trauma. Most cytokines activate the JAK/STAT signal transduction pathway, an evolutionarily conserved mechanism that regulates lymphocyte development, differentiation and lineage commitment. On the other hand, the initiation, duration and intensity of JAK/STAT signaling is under stringent feedback regulation by suppressors of cytokine signaling (SOCS) proteins and diverse array of pathologic conditions including immunodeficiency and autoimmune diseases arise from aberrant regulation of the JAK/STAT proteins. We have and continue to characterize JAK/STAT signaling pathways of resident ocular cells and inflammatory cells that mediate ocular diseases using cell lines or primary cells and validate our findings in transgenic and knockout mouse and rat models.
Auto-reactive lymphocytes that mediate CNS autoimmune diseases Amadi-Obi A, Yu CR, Liu X, Mahdi RM, Clarke GL, Nussenblatt RB, Gery I, Lee YS and Egwuagu CE. (2007). TH17 cells are expanded by IL-2 in Uveitis or Scleritis and inhibited by IL-27/STAT1-dependent mechanisms. Nature Medicine. 13(6):711-718. He C, Yu CR, Sun L, Mahdi RM, Larkin J 3rd, Egwuagu CE. (2015) Topical administration of a suppressor of cytokine signaling-1 (SOCS1) mimetic peptide inhibits ocular inflammation and mitigates ocular pathology during mouse uveitis. J Autoimmun. 62:31-8. Escobar T, Yu CR, Muljo S, Egwuagu CE. (2013). STAT3 Activates miR-155 in Th17 cells and Acts in Concert to Promote Experimental Autoimmune Uveitis. Invest Oph Vis Sci. 54:4017-25 Amadi-Obi A, Yu CR, Dambuza I, Kim SH, Marrero B, Egwuagu CE 2012. Interleukin 27 Induces the Expression of Complement Factor H (CFH) in the Retina. PLoS One. 7(9):e45801. Yu CR, Lee YS, Mahdi RM, Surendran N, Egwuagu CE (2012). Therapeutic Targeting of STAT3 (Signal Transducers and Activators of Transcription 3) Pathway Inhibits Experimental Autoimmune Uveitis. PLoS One. 7(1):e29742. Oh HM, Yu CR, YongJun Lee Y, Chan CC, Maminishkis A and Charles E. Egwuagu CE. (2011) Autoreactive Memory CD4+ T Lymphocytes that mediate Chronic Uveitis Reside in the Bone Marrow through STAT3-dependent Mechanisms. J Immunol. 187:3338-46 Liu X, Mameza MG, Lee YS, Eseonu CI, Yu CR, Kang-Derwent JJ and Egwuagu CE. (2008). Suppressors of Cytokine Signaling (SOCS) Proteins Induce Insulin-Resistance in the Retina and Promote Survival of Retinal Cells. Diabetes. 57:1651-8. Liu X, Lee YS, Yu CR, and Egwuagu CE (2008) Loss of STAT3 in CD4+ T cells prevents development of experimental autoimmune diseases. J Immunol. 180:6070-6. Egwuagu C.E., Charukamnoetkanok, P and Gery I. (1997). Thymic Expression of Autoantigens Correlates with Resistance to Autoimmune Disease. J. Immunol. (Cutting Edge Paper) 159: 3109-3112. Development of Biologics for treating autoimmune diseases Wang RX, Yu CR, Dambuza IM, Mahdi RM, Dolinska MB, Sergeev YV, Wingfield PT, Kim SH, Egwuagu CE. (2014). Interleukin-35 induces regulatory B cells that suppress autoimmune disease Nat Med. 20(6):633-41. Wang X, Wei Y, Xiao H, Liu X, Zhang Y, Han G, Chen G, Hou C, Ma N, Shen B, Li Y, Egwuagu CE, Wang R. (2016). A novel IL-23p19/Ebi3 (IL-39) cytokine mediates inflammation in Lupus-like mice. Eur J Immunol. [Epub ahead of print] Egwuagu CE, Yu CR. (2015). Interleukin 35-Producing B Cells (i35-Breg): A New Mediator of Regulatory B-Cell Functions in CNS Autoimmune Diseases. Crit Rev Immunol. 35(1):49-57. Wang X, Wei Y, Xiao H, Liu X, Zhang Y, Han G, Chen G, Hou C, Zhang L, Ma N, Shen B, Li Y, Egwuagu CE, Wang R. (2016). Pre-existing CD19-independent GL7- Breg cells are expanded during inflammation and in mice with lupus-like disease. Mol Immunol. 71: 54-63 Egwuagu CE, Yu CR, Sun L, Wang R. 2015. Interleukin 35: Critical regulator of immunity and lymphocyte-mediated diseases. Cytokine Growth Factor Rev. 2015 26:587-93. Sun L, He C, Nair L, Yeung J, Egwuagu CE. (2015). Interleukin 12 (IL-12) family cytokines: Role in immune pathogenesis and treatment of CNS autoimmune disease. Cytokine. 75:249-55. Wang RX, Yu CR, Mahdi RM, Egwuagu CE. 2012. Novel IL27p28/IL12p40 Cytokine Suppressed Experimental Autoimmune Uveitis by Inhibiting Autoreactive Th1/Th17 Cells and Promoting Expansion of Regulatory T Cells. J Biol Chem. 287:36012-21. Mechanisms that regulate lymphocyte development and cell-fate decisions Kim SH, Burton J, Yu CR, Sun L, He C, Wang H, Morse HC 3rd, Egwuagu CE (2015) Dual Function of the IRF8 Transcription Factor in Autoimmune Uveitis: Loss of IRF8 in T Cells Exacerbates Uveitis, Whereas Irf8 Deletion in the Retina Confers Protection. J Immunol. 195:1480-8. Yu CR, Kim SH, Mahdi RM, Egwuagu CE (2013) SOCS3 deletion in T lymphocytes suppresses development of chronic ocular inflammation via upregulation of CTLA-4 and expansion of regulatory T cells. J Immunol. 191(10):5036-43 Oh HM, Yu CR, Golestaneh N, Amadi-Obi A, Lee YS, Eseonu A, Mahdi RM, Egwuagu CE. (2011). STAT3 promotes T cell survival and inhibits IL-2 production through up-regulation of Class O Forkhead transcription factors. J Biol Chem. 286:30888-97. Oh HM, Yu CR, Dambuza I, Marrero B, Egwuagu CE. 2012. STAT3 protein interacts with Class O Forkhead transcription factors in the cytoplasm and regulates nuclear/cytoplasmic localization of FoxO1 and FoxO3a proteins in CD4(+) T cells. J Biol Chem. 287(36):30436-43. Yu CR, Mahdi RM, Liu X, Zhang A, Naka T, Kishimoto T, Egwuagu CE. (2008) SOCS1 Regulates CCR7 Expression and Migration of CD4+ T Cells into Peripheral Tissues. J Immunol. 181:1190-8. Egwuagu CE, Li W, Yu CR, Che Mei Lin M, Chan CC, Nakamura T, Chepelinsky AB. (2006). Interferon-gamma induces regression of epithelial cell carcinoma: critical roles of IRF-1 and ICSBP transcription factors. Oncogene. 25: 3670-9. Yu CR, Mahdi RM, Ebong S, Vistica BP, Gery I, Egwuagu CE (2003) Suppressor of cytokine sign aling 3 regulates proliferation and activation of T-helper cells. J Biol Chem 278:29752-9. Egwuagu C.E., R-C. Yu, M. Zhang, R. M. Mahdi, S. J. Kim and I. Gery 2002. Suppressors of Cytokine Signaling (SOCS) Proteins are Constitutively and Differentially Expressed in Th1 and Th2 Cells: Implications for Th Cell Lineage Commitment and Maintenance. J Immunol. 168(7):3181-7.
|Charles E. Egwuagu, MPH, Ph.D.
|Cheng-Rong Yu, MD, Ph.D.||Staff Scientist||YuC@NEI.NIH.GOV|
|Daniel Gebreselassie, Ph.D||Biologist/Lab Manageremail@example.com|
|Venkat Mohanram, Ph.D||Research Fellowfirstname.lastname@example.org|
|Jin Kyeong Choi, Ph.D||Post-Doctoral Fellowemail@example.com|
|Chang He, MD, Ph.D||Post-Doctoral Fellowfirstname.lastname@example.org|
|Lin Sun, Ph.D||Post-Doctoral Fellowemail@example.com|
|Anita Uche, BS.||Post baccalaureate Fellowfirstname.lastname@example.org|