Charles E. Egwuagu, Ph.D.
Molecular Immunology Section
Building 10, Room 10N248G
10 Center Drive
Bethesda, MD 20892
Major Areas of Investigation and Findings
(i)Cellular/molecular mechanisms that mediate or suppress ocular inflammatory diseases (uveitis)
Ocular inflammatory diseases are a major cause of severe visual handicap in the USA and include sight-threatening idiopathic inflammatory ocular diseases such as Scleritis and Uveitis. T lymphocytes are currently thought to be the etiologic agents. Our studies have implicated Th17 cells as a pathogenic T cell subset that mediates Uveitis or Scleritis while IL-10- and IL-35-producing regulatory B cells (Bregs) suppress Uveitis and mitigate ocular pathology. A great deal of our effort is aimed at understanding factors that promote Th17-mediated uveitis and mechanisms by which Breg cells mitigate ocular pathology.
(ii)Development of Biologics and Regulatory B cell (Breg) therapy for autoimmune diseases
Interleukin 12 (IL-12) cytokines play critical roles in initiating adaptive immune responses. They also regulate the intensity, duration and quality of innate and adaptive immune responses. However, unbridled activation of immune cells by IL-12 cytokines is implicated in the development of autoimmune diseases. Each of its 4 members is comprised of an alpha and beta chain, with some members (IL-12, IL-23) promoting inflammation and autoimmune pathology while others (IL-27, IL-35) suppress inflammation and limit tissue injury. IL-12 family cytokines regulate the differentiation and effector functions of lymphoid and myeloid cell types through the activation of JAK/STAT pathways and duration of the STAT signal is under stringent negative feedback regulation by suppressor of cytokine signaling 1 (SOCS1) and SOCS3. Our drug discovery program to identify effective immune-suppressive Biologics focus on:
Utilizing membrane-penetrating JAK inhibitors and SOCS1 or SOCS3 mimetic peptides to target JAK/STAT pathways that activate pro-inflammatory effector functions of pathogenic lymphocytes.
Genetic engineering of each ?? and ?? IL-12 subunit protein and novel combinations of these subunits for use as Biologics and potential therapeutic cytokines to regulate inflammation.
Our bioengineered recombinant IL-35 suppresses autoimmune diseases. Our IL-35 studies led to our discovery of IL-10-producing Breg cells and a novel Breg cells that produce IL-35 (i35-Breg). Both Breg types suppress CNS autoimmune diseases by antagonizing pathogenic Th17 responses.
Amadi-Obi A, Yu CR, Liu X, Mahdi RM, Clarke GL, Nussenblatt RB, Gery I, Lee YS, Egwuagu CE. TH17 cells contribute to uveitis and scleritis and are expanded by IL-2 and inhibited by IL-27/STAT1. Nat Med. 2007;13(6):711-8.
Egwuagu CE, Yu CR. Interleukin 35-Producing B Cells (i35-Breg): A New Mediator of Regulatory B-Cell Functions in CNS Autoimmune Diseases. Crit Rev Immunol. 2015;35(1):49-57.
He C, Yu CR, Sun L, Mahdi RM, Larkin J 3rd, Egwuagu CE. Topical administration of a suppressor of cytokine signaling-1 (SOCS1) mimetic peptide inhibits ocular inflammation and mitigates ocular pathology during mouse uveitis. J Autoimmun. 2015;62:31-8.
Dambuza IM, He C, Choi JK, Yu CR, Wang R, Mattapallil MJ, Wingfield PT, Caspi RR, Egwuagu CE. IL-12p35 induces expansion of IL-10 and IL-35-expressing regulatory B cells and ameliorates autoimmune disease. Nat Commun. 2017;8(1):719.
Wang RX, Yu CR, Dambuza IM, Mahdi RM, Dolinska MB, Sergeev YV, Wingfield PT, Kim SH, Egwuagu CE. Interleukin-35 induces regulatory B cells that suppress autoimmune disease. Nat Med. 2014;20(6):633-41.
Related Scientific Focus Areas
Molecular Biology and Biochemistry
This page was last updated on August 17th, 2018