Molecular Immunology Section
Dr. Egwuagu received his Ph.D from Yale University and M.P.H from Yale School of Medicine in 1987. He completed a 3- year Research Fellowship at NIH (1990). Served as a Commissioned Officer of the United States Public Health Service from 1990 and left the PHS in 2000 after promotion to the rank of Captain (06). He became a Senior Investigator in the Laboratory of Immunology in 1999 and has been the Chief, Section on Molecular Immunology since 2000.
Overall thrust of research in the Molecular Immunology Section is governed, to a large extent, by the presupposition that most infectious and chronic diseases result from inadequate immune responses or due to exuberant and over-reactive immune system. Consequently our work has focused on understanding molecular and cellular mechanisms that regulate immune homeostasis, with particular emphasis on: (i) epigenetic mechanisms that regulate lymphocyte development and cell-fate decisions; (ii) roles played by proinflammatory and anti-inflammatory cytokines in the development of central nervous system (CNS) inflammatory diseases, such as Uveitis, Multiple Sclerosis and Age-related Macular Degeneration (AMD). These investigations are carried out using primary cells or well established eukaryotic cell lines and validated in transgenic mouse and rat models of human autoimmune diseases. The overall goal is to develop non-steroidal, cytokine-based therapy for treatment of autoimmune and neurodegenerative diseases.
Major Areas of Investigation and Findings:
1. Cytokine signaling and regulation of immune homeostasis
Current research activities in this area are focused on three major themes:
(i) Mechanisms of T cell differentiation and lineage commitment. Specific interest is to understand how cytokines, transcription factors and chromatin remodeling mechanisms cooperate to determine T cell fate choices and ensure the generation of protective immunity.
(ii) Understanding the roles played by inflammation and inflammatory mediators in retinal neovascularization, insulin resistance and in mechanisms that protect the neuroretina from environmental and metabolic stress. We seek to understand negative feedback mechanisms that regulate activities of proinflammatory cytokines in the eye and how crosstalk between the plethora of cytokines that converge on inflammatory and resident ocular cells is coordinated. Particular attention is given to a family of intracellular regulators called SOCS (suppressors of cytokine signaling). These proteins regulate the intensity and duration of cytokine signals and activities.
(iii) Therapeutic control of CNS inflammatory diseases. Focus is on targeting STAT (signal transducers and activators of transcription) pathways that regulate the activation, recruitment and expansion of autoreactive T cells in the eye and brain. STAT and SOCS proteins have neuroprotective functions in the CNS and are potential targets for immune-modulation therapy.
- Suppressors of Cytokine Signaling (SOCS) Proteins Induce Insulin-Resistance in the Retina and Promote Survival of Retinal Cells. (Diabetes. 57:1651-8. 2008.) PubMed
- STAT3 is required for entry of Th17 cells into the retina and brain and a potential therapeutic target for modulating CNS inflammatory diseases. (J Immunol. 180:6070-6. 2008.) PubMed
- SOCS1 regulates the migration of T cells into peripheral tissues. (J Immunol. 181:1190-8. 2008.) PubMed
- TH17 cells contribute to uveitis and scleritis and are potential therapeutic targets for preventing or mitigating uveitis or scleritis. (Nature Medicine. 13(6): 711-718. 2007.) PubMed
- SOCS genes are differentially regulated in breast cancer cells. (Oncogene. 26:1941-1948, 2007.) PubMed
- SOCS proteins are T-helper (Th) cell lineage markers and potential therapeutic targets for immune modulation therapy. (J Immunol. 168:3181, 2002). PubMed
- SOCS3 has a gate-keeper function in T cells and role in maintaining naive Th cells in a quiescent state prior to activation (J Biol. Chem. 278:29752, 2003). PubMed
- SOCS proteins play important roles in regulating cross-talk between Th1 and Th2 cytokines during Th cell differentiation (J. Immunol. 173-737-746, 2004). PubMed
- SOCS mRNA levels are prognostic marker for monitoring response to antiuveitic drugs. (J. Autoimmunity 24:39-46, 2005. PubMed J. Neuroimmunology 168:118-127, 2005) PubMed
2. Role of Interferon-gamma in inflammatory and degenerative diseases of the eye
Interferon-g (IFNg) has been implicated in the immunopathogenic mechanisms of several organ-specific autoimmune diseases. Because this proinflammatory cytokine plays a central role in immunopathogenic mechanisms of ocular diseases of infectious or putative autoimmune etiology, we have used IFNg as a paradigm for understanding effects of cytokines in the eye and ocular diseases. Our investigations have focused on positive regulatory transcription factors activated by IFNg signaling pathways, with the goal of understanding pathophysiological consequences of prolonged secretion of IFNg in the eye, as occurs during chronic intraocular infections. Particular interest is on potential role of proinflammatory cytokines in retinal degenerative diseases.
- Interferon-gamma induces regression of epithelial cell carcinoma. (Oncogene. 25: 3670-3679, 2006.) PubMed
- Role of SOCS proteins in neuroprotection. (Adv Exp Med Biol. 572:275-281, 2006.) PubMed
- Prolonged secretion of IFN-g is a susceptibility factor for development of uveitis and induces retinal degenerative changes. (Clinical Immunology 91:196-205, 1999 PubMed; J Immunol. 162: 510-517, 1999 PubMed)
- Interferon Regulatory Transcription Factors (IRFs) are constitutively expressed and spatially regulated in the mouse lens. Dysregulated expression of IRFs alters developmental fates of lens cells. (Developmental Biology 210: 44-55, 1999 PubMed; J. Biol. Chem. 274:9686-9691, 1999 PubMed; Invest. Ophthalmol. Vis. Sci. 40:976-982, 1999 PubMed; Developmental Biology 166:557-568, 1994 PubMed; Invest Ophthalmol Vis Sci. 45:872-8 PubMed).
3. Identification of biological markers of susceptibility to uveitis
An important and unresolved issue in autoimmunity relates to the definition of risk factors for development of an organ-specific autoimmune disease. Why are some individuals resistant while others are susceptible to an organ-specific autoimmune disease? We have addressed these issues by studying molecular basis of susceptibility to experimental autoimmune uveitis (EAU), an animal model of human uveitis.
The degree of susceptibility to autoimmune disease depends on the relative amounts of the antigens present in the thymus, suggesting that resistance to an organ-specific autoimmune disease may be regulated at least in part by the capacity of the host to establish central tolerance to the relevant autoantigen.
|Charles E. Egwuagu, MPH, Ph.D.
|Cheng-Rong Yu, MD, Ph.D.||Staff Scientist||YuC@NEI.NIH.GOV|
|Hyun-Mee Ho, Ph.D.||Post-Doctoral Fellowfirstname.lastname@example.org|
|Ahjoku Amadi-Obi, MD, FRCS||Post-Doctoral Fellowemail@example.com|
|Yunsang Lee, Ph.D.||Post-Doctoral Fellowfirstname.lastname@example.org|
|Rashid M. Mahdi||Biologist||MahdiR@NEI.NIH.GOV|
Egwuagu C.E., R-C. Yu, M. Zhang, R. M. Mahdi, S. J. Kim and I. Gery. 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. 168:3181, 2002). PubMed
Yu CR, Mahdi RM, Ebong S, Vistica BP, Gery I, Egwuagu CE. Suppressor of cytokine signaling 3 regulates proliferation and activation of T-helper cells. (J Biol. Chem. 278:29752, 2003).PubMed
Yu CR, Mahdi RM, Ebong S, Vistica BP, Chen J, Guo Y, Gery I and Egwuagu CE. Proliferation and STAT6 Signaling Pathways are Negatively Regulated in T-helper Cells by STAT1 and Suppressors of Cytokine Signaling (SOCS). (J. Immunol. 173-737-746, 2004).PubMed
Jackson SH, Yu CR, Mahdi RM, Ebong S, Egwuagu CE. Dendritic cell maturation requires STAT1 and is under feedback regulation by suppressors of cytokine signaling. (J Immunol. 172:2307-15, 2004).PubMed
Cytokine Signaling in the Eye
Egwuagu C.E.,Sztein J., Chan C.C., Reid W., Mahdi R., Nussenblatt R.B. and Chepelinsky A.B. Gamma Interferon Expression Disrupts Lens and Retinal Differentiation in Transgenic Mice. (Developmental Biology 166:557-568, 1994).PubMed
Egwuagu C.E.,Sztein J., Chan C.C., Reid W., Mahdi R., Nussenblatt R.B. and Chepelinsky A.B. Ectopic Expression of Gamma Interferon in The Eyes Of Transgenic Mice Induces Ocular Pathology and MHC Class II Gene Expression. (Invest. Opthalmol. Vis. Sci. 35:332-341, 1994).PubMed
Li, W., Nagineni, C.N., Ohtaka-Marayuma, C., Efiok, B., Chepelinsky, A.B. and Egwuagu, C.E. Interferon Regulatory Transcription Factors (IRFs) are Constitutively Expressed and Spatially Regulated in the Mouse Lens. (Developmental Biology 210: 44-55, 1999).PubMed
Li, W., Nagineni, C.N., Ohtaka-Marayuma, C., Efiok, B., Chepelinsky, A.B. and Egwuagu, C.E. Interferon Consensus Sequence Binding Protein (ICSBP) is Constitutively Expressed and Differentially Regulated in the Ocular Lens. (J. Biol. Chem. 274:9686-9691, 1999).PubMed
Egwuagu, C.E., Sztein, J., Mahdi, R.M., Li, W., Chan, C.C., Smith, J.A. and Chepelinsky, A.B. Constitutive Expression of IFN-g in the Eye Exacerbates Anterior Uveitis and Induces Retinal Degenerative Changes in Transgenic Rats. (Clinical Immunology 91:196-205, 1999). PubMed
Li, W., Nagineni, C.N., Hooks, J.J., Chepelinsky, A.B. and Egwuagu, C.E. Intereferon-? Signaling in Human Retinal Pigment Epithelial Cells is Mediated by STAT1, ICSBP and IRF-1 Transcription Factors. (Invest. Ophthalmol. Vis. Sci. 40:976-982, 1999). PubMed
Egwuagu, C.E., Sztein, J., Mahdi, R.M., Li, W., Chan, C.C., Smith, J.A., Charukamnoetkanok, P. and Chepelinsky, A.B. Interferon-? (IFN?) Increases the Severity and Accelerates the Onset of Experimental Autoimmune Uveitis in Transgenic Rats. (J. Immunol. 162: 510-517, 1999). PubMed
Ebong S, Yu CR, Carper DA, Chepelinsky AB, Egwuagu CE. Activation of STAT signaling pathways and induction of suppressors of cytokine signaling (SOCS) proteins in mammalian lens by growth factors. (Invest Ophthalmol Vis Sci. 45:872-8, 2004). PubMed
Egwuagu, C.E., Charukamnoetkanok, P. and Gery, I. Thymic Expression of Autoantigens Correlates with Resistance to Autoimmune Disease. (J. Immunol. (Cutting Edge Paper) 159: 3109-3112, 1997). PubMed
Gery I and Egwuagu CE. Central tolerance mechanisms in control of susceptibility to autoimmune uveitic disease. (Intern. Rev. Immunol., 21: 89-100, 2002).PubMed
Egwuagu CE and Smith JA. Uveitis. (Emerging Therapeutic Targets, 4(6): 715-733, 2000).
Takase H, Yu CR, Mahdi RM, Douek DC, Dirusso GB, Midgley FM, Dogra R, Allende G, Rosenkranz E, Pugliese A, Egwuagu CE, Gery I. Thymic expression of peripheral tissue antigens in humans: a remarkable variability among individuals. (Int Immunol. 17:1131-40, 2005). PubMed
Egwuagu CE, Yu CR, Li Z, Nussenblatt RB. SOCS5 mRNA Levels in Peripheral Blood Mononuclear Cells (PMBC): A Potential Bio-Marker for Monitoring Response of Uveitis Patients to Daclizumab Therapy. (J. Autoimmunity 24:39-46, 2005). PubMed
Takase H, Yu CR, Liu X, Fujimoto C, Gery I, Egwuagu CE. Induction of Suppressors of Cytokine Signaling (SOCS) in the Retina during Experimental Autoimmune Uveitis (EAU): Potential Neuroprotective Role of SOCS Proteins (J. Neuroimmunology 168:118-127, 2005). PubMed