Ioannis Tassiulas, MD, PhD
- ASSOCIATE PROFESSOR | Medicine, Rheumatology
Aristotle University Medical School, Thessaloniki, Greece 1991.
Research Fellowship in Immunology at the National Institute of Arthritis Musculoskeletal and Skin Diseases/NIH, Bethesda MD (1995-1997).
Internal Medicine residency at Albert Einstein MedicalCenter, Philadelphia PA (1997-2000).
Fellowship in Rheumatology at the Hospital for Special Surgery/Cornell, New York,NY (2000-2003).
Assistant professor of Medicine at the Hospital for Special Surgery (2003-2007).
Senior Investigator at the Institute of Molecular Biology/University of Crete Medical School, Greece (2007-2011)
Associate Professor of Medicine, New York Medical College, Valhalla, NY (2011-2015)
Associate Professor of Medicine, Icahn School of Medicine at Mount Sinai (2015-)
American Board of Internal Medicine
- Ankylosing Spondylitis
- Behcet's Disease
- Frozen Shoulder
- Paget's Disease
- Polymyalgia Rheumatica And Giant Cell Arteritis
- Reiter's Syndrome
- Rheumatic Fever
- Rheumatoid Arthritis
- Sjogren's Syndrome
- Systemic Lupus Erythematosus
- Temporal Arteritis
- Wegener's Granulomatosis
Residency, Internal Medicine, Albert Einstein Medical Center
Fellowship, Rheumatology, Hospital for Special Surgery
EULAR Basic Sciences Abstract Award
The Charles Christian Research Fellowship
ACR Rheumatology Fellow Award
Rheumatology Fellowship Award
Abbott Scholar Award in Rheumatology Research
American College of Rheumatology (ACR) Research and Education Foundation Award
American Society of Nephrology Blue Ribbon Award
Autoimmunity, Cytokines, Interferon, Lupus Nephritis, Receptors, Signal Transduction
Cytokines and the Jak-STAT signaling pathway.
Cytokines are secreted proteins that mediate communication between cells and are critical for the development and regulation of the immune response. Cytokines act by binding with high affinity and specificity to cell surface receptors, triggering signal transduction pathways that ultimately lead to gene activation cascades that regulate cellular activation, differentiation, proliferation and survival. Deregulation of cytokine production or cytokine networks have been implicated in the pathogenesis of a number of human autoimmune/ inflammatory diseases including SLE.
Cytokines relay their intracellular signals by utilizing the Jak-Stat signal transduction pathway. The binding of the cytokines to their receptors that lack intrinsic kinase activity, activates Janus kinases (Jaks), protein tyrosine kinases that are associated with the receptor. Typically each cytokine activates a distinct pair of of two of the four known Jaks. Jak kinases are required for tyrosine phosphorylation and activation of latent cytoplasmic transcription factors termed signal transducers and activators of transcription (STATs). After cytokine stimulation, STATs are rapidly tyrosine phosphorylated, and subsequently dimerize and translocate to the nucleus, where they can activate gene transcription. Tyrosine phosphorylation of STATs is essential for activation, dimerization and DNA binding.
We have shown that IFN signaling is regulated by crosstalk with the ITAM-Syk pathway, a signal transduction pathway that is used specifically by immune cells and is key in cell activation. Crosstalk between IFN and Syk-mediated pathways is not static but depends on the activation state of macrophages and is induced by priming with IFN (Fig. 2). Thus, macrophage responses to IFN are determined by integration of signals from two main pathways that regulate immune responses (1).
Thus, the nature of cytokine responses can be altered or reprogrammed by the nature of a particular stimulus or the microenvironment that the cells are exposed.
Immune cell receptors
A growing number of receptors including the Toll-like receptors (TLRs) and receptors that transmit signals via the ITAM containing adaptor molecules FcR and DAP12 play important roles in the activation status of the cells of the immune system. Activation of these receptors by their ligands seems to be very important for effective development and resolution of an immune response. Signaling pathways activated downstream of these receptors include the NF-kB, MAPKs, PI3K and Ca++-induced pathways that play a central role in the activation, differentiation and survival of the cells. There is experimental evidence of regulation and crosstalk between cytokine and immune receptor signaling in cells of the immune system. A paradigm is the inhibition of interleukin-10 (IL-10) signaling in macrophages after ligation of the FcgRs by immune complexes (2). In this case macrophages become refractory to the anti-inflammatory actions of IL-10, a mechanism that may play important role in the perpetuation of inflammation in diseases characterized by the presence of immune complexes such as inflammatory arthritis and systemic lupus erythematosus.
Tumor progression locus 2 (Tpl2) encodes a serine/threonine protein kinase that is activated by provirus integration in Moloney murine leukemia virus-induced T cell lymphomas and mouse mammary tumor virus-induced mammary adenocarcinomas. Tpl2 transduces Toll-like and death receptor signals in a variety of cell types and plays an important role in innate immunity and inflammation. Tpl2 knockout (Tpl2-/-) mice develop normally and have no obvious phenotypic defects. However, Tpl2-/- mice are resistant to LPS-induced endotoxin-shock, as well as to TNF-induced inflammatory bowel disease. Tpl2 plays an obligatory role in the transduction of extracellular signal-regulated kinase (ERK) activation signals induced by LPS and CD40L inmacrophages and B cells and by TNF in macrophages. The failure of ERK activation by LPS in Tpl2-/- macrophages gives rise to defects in the expression of cytokines, chemokines and other molecules involved in the regulation of innate and adaptive immunity.
We have shown that Tpl2 kinase is activated downstream of the FcgRs and regulate phagocytosis and cytokine and chemokine production. Moreover in an animal model of immune thrombocytopenia pharmacological targeting of Tpl2 prevented the development of thrombocytopenia. These data identify Tpl2 kinase as a potential therapeutic target for autoimmune diseases.
Tassiulas I, Davis JC, Fessler BJ, Hama N, Fleisher TA, Austin HA, Boumpas DT. Fludarabine in non-malignant disorders. In: Nucleoside Analogs in Cancer Therapy. In: Cheson BD, Keating MJ, Plunket W, editors. Neucleoside Analogs in Cancer Therapy. New York, NY, Marcel Decker Inc;.
Boumpas DT, Tassiulas I. Psoriatic Arthritis. In: Klippel JH, Weyand CM, Wortmann R, editors. Primer on the Rheumatic Diseases (11th Edition). Atlanta, Arthritis Foundation;.
Tassiulas I, Wilder R, Boumpas DT, Koopman W. Arthritis and Allied Conditions (15th Edition). In: Corticosteroids. Philadelphia, Lippincot Williams and Wilkins;.
Tassiulas I, Lockshin MD. Systemic Lupus erythematosus. In: Expert Guide to Rheumatology (1st Edition). Philadelphia, ACP;.
Tassiulas I, Paget SA. Rheumatoid Arthritis. In: Paget SA, editor. Manual of Rheumatology and outpatient orthopedic disorders. (3rd Ed). Philadelphia, Lippincot Williams and Wilkins;.
Tassiulas I, Boumpas DT. Clinical features and treatment of SLE. In: Harris E, editor. Kelley’s Textbook of Rheumatology. (8th Ed). Philadelphia, Saunders;.
Tassiulas I, Boumpas DT. Management of lupus nephritis. Part1: Pathogenesis, clinical, histologic evaluation. J Muscl Med 2003; 20(7): 336-340.
Tratenberg M, Mehta S, Kleinmann G, Gazivoda V, Tassiulas I. Severe rhabdomyolysis associated with Catha edulis (khat) use. Case Reports Clin Pathol;.
Nakou M, Knowlton N, Frank MB, Bertsias G, Osban J, Sandel CE, Papadaki H, Raptopoulou A, Sidiropoulos P, Kritikos I, Tassiulas I, Centola M, Boumpas DT. Gene expression in systemic lupus erythematosus: bone marrow analysis differentiates active from inactive disease and reveals apoptosis and granulopoiesis signatures. Arthritis and rheumatism 2008 Nov; 58(11).
Wang L, Tassiulas I, Park-Min KH, Reid AC, Gil-Henn H, Schlessinger J, Baron R, Zhang JJ, Ivashkiv LB. 'Tuning' of type I interferon-induced Jak-STAT1 signaling by calcium-dependent kinases in macrophages. Nature immunology 2008 Feb; 9(2).
Tassiulas I, Park-Min KH, Hu Y, Kellerman L, Mevorach D, Ivashkiv LB. Apoptotic cells inhibit LPS-induced cytokine and chemokine production and IFN responses in macrophages. Human immunology 2007 Mar; 68(3).
Tassiulas I, Hu X, Ho H, Kashyap Y, Paik P, Hu Y, Lowell CA, Ivashkiv LB. Amplification of IFN-alpha-induced STAT1 activation and inflammatory function by Syk and ITAM-containing adaptors. Nature immunology 2004 Nov; 5(11).
Sharif MN, Tassiulas I, Hu Y, Mecklenbräuker I, Tarakhovsky A, Ivashkiv LB. IFN-alpha priming results in a gain of proinflammatory function by IL-10: implications for systemic lupus erythematosus pathogenesis. Journal of immunology (Baltimore, Md. : 1950) 2004 May; 172(10).
Bertsias GK, Ioannidis JP, Aringer M, Bollen E, Bombardieri S, Bruce IN, Cervera R, Dalakas M, Doria A, Hanly JG, Huizinga TW, Isenberg D, Kallenberg C, Piette JC, Schneider M, Scolding N, Smolen J, Stara A, Tassiulas I, Tektonidou M, Tincani A, van Buchem MA, van Vollenhoven R, Ward M, Gordon C, Boumpas DT. EULAR recommendations for the management of systemic lupus erythematosus with neuropsychiatric manifestations: report of a task force of the EULAR standing committee for clinical affairs. Annals of the rheumatic diseases 2010 Dec; 69(12).
Takada K, Danning CL, Kuroiwa T, Schlimgen R, Tassiulas IO, Davis JC, Yarboro CH, Fleisher TA, Boumpas DT, Illei GG. Lymphocyte depletion with fludarabine in patients with psoriatic arthritis: clinical and immunological effects. Annals of the rheumatic diseases 2003 Nov; 62(11).
Kyrmizi I, Ioannou M, Hatziapostolou M, Tsichlis PN, Boumpas DT, Tassiulas I. Tpl2 kinase regulates FcγR signaling and immune thrombocytopenia in mice. Journal of leukocyte biology 2013 Oct; 94(4).
Nakou M, Bertsias G, Stagakis I, Centola M, Tassiulas I, Hatziapostolou M, Kritikos I, Goulielmos G, Boumpas DT, Iliopoulos D. Gene network analysis of bone marrow mononuclear cells reveals activation of multiple kinase pathways in human systemic lupus erythematosus. PloS one 2010; 5(10).
Davis JC, Tassiulas IO, Boumpas DT. Lupus nephritis. Current opinion in rheumatology 1996 Sep; 8(5).
Ji JD, Tassiulas I, Park-Min KH, Aydin A, Mecklenbrauker I, Tarakhovsky A, Pricop L, Salmon JE, Ivashkiv LB. Inhibition of interleukin 10 signaling after Fc receptor ligation and during rheumatoid arthritis. The Journal of experimental medicine 2003 Jun; 197(11).
Ivashkiv LB, Tassiulas I. Can SOCS make arthritis better?. The Journal of clinical investigation 2003 Mar; 111(6).
Boumpas DT, Tassiulas IO, Fleisher TA, Vaughan E, Piscitelli S, Kim Y, Pucino F, Balow JE, Austin HA. A pilot study of low-dose fludarabine in membranous nephropathy refractory to therapy. Clinical nephrology 1999 Aug; 52(2).
Tassiulas I, Duncan SR, Centola M, Theofilopoulos AN, Boumpas DT. Clonal characteristics of T cell infiltrates in skin and synovium of patients with psoriatic arthritis. Human immunology 1999 Jun; 60(6).
Davis JC, Fessler BJ, Tassiulas IO, McInnes IB, Yarboro CH, Pillemer S, Wilder R, Fleisher TA, Klippel JH, Boumpas DT. High dose versus low dose fludarabine in the treatment of patients with severe refractory rheumatoid arthritis. The Journal of rheumatology 1998 Sep; 25(9).
Tassiulas IO, Aksentijevich I, Salmon JE, Kim Y, Yarboro CH, Vaughan EM, Davis JC, Scott DL, Austin HA, Klippel JH, Balow JE, Gourley MF, Boumpas DT. Angiotensin I converting enzyme gene polymorphisms in systemic lupus erythematosus: decreased prevalence of DD genotype in African American patients. Clinical nephrology 1998 Jul; 50(1).
Davis JC, Tassiulas IO, Boumpas DT. Lupus nephritis. Current opinion in rheumatology 1996 Sep; 8(5).