Major Areas of Research
- Identification and characterization of mediators, receptors, and signaling pathways critically involved in allergic inflammation and mast cell-related disorders, with particular emphasis in the lipid mediator sphingosine-1-phosphate and its receptors
Mast cells are innate cells present in tissues involved in the induction of the allergic response and the pathology of certain myeloproliferative disorders. Mast cells express a variety of receptors and thus can respond to a number of environmental cues, including allergens, by releasing substances that are important for the induction and/or regulation of allergic inflammation. Even though much is known about mast cell-derived mediators and their potential contributions to allergy, the identification of intercellular mediators (derived or not from mast cells) that critically influence certain aspects of the allergic responses and mast cell-related disorders remains incompletely understood. The identification and characterization of those mediators affecting tissue responses and inflammation are key to the understanding of the underlying pathology and in the identification of therapeutic alternatives.
Associated with this effort is the study of signals that intrinsically modify the function of human mast cells. Allergens (or antigens) stimulate mast cells by binding the high-affinity IgE receptor in individuals that present IgE antibodies to that particular antigen (or are “sensitized”). The interaction of antigen-specific IgE with antigen on the mast-cell surface leads to a cascade of signaling events that trigger mast-cell responses. These signaling events can be modified by engagement of other receptors in the mast cell. Despite the importance for allergic reactions, critical signaling pathways triggered by the IgE receptor alone or in combination with signals from other receptors remain poorly understood. Furthering this understanding could provide new strategies for the prevention of allergic diseases.
The bioactive lipid sphingosine-1-phosphate (S1P) exemplifies the two aspects of this initiative. S1P is a mediator that can be released by mast cells and other cells and affect tissue responses during allergic and inflammatory responses, but it is also a modifier of mast-cell signaling. S1P is a generated inside mast cells after allergen exposure, and the formation of this lipid is critical for mediating mast-cell responses. Furthermore, increases in the amount of S1P in the tissue environment can alter the phenotype of mast cells, predisposing them to an enhanced responsiveness to an allergen. A better understanding of S1P, its precursors, and its receptors in proliferative and allergic disorders provides insights into the mechanisms for the dysregulated function of mast cells in these diseases.
Dr. Olivera received a doctorate of philosophy from the Universidad Complutense de Madrid, Spain, for research on the signaling mechanisms that mediate the contraction of glomerular mesangial cells induced by adenosine. In 1990, she started a postdoctoral fellowship in the laboratory of Dr. Sarah Spiegel and became a research assistant professor in the department of biochemistry and molecular biology of Georgetown University. There, she studied the role of breakdown products of sphingolipids (ceramide, sphingosine, and sphingosine-1-phosphate) in cell signaling, cellular proliferation, apoptosis, and cell motility. In 2002, she joined Dr. Juan Rivera’s group in the Laboratory of Molecular Immunology of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, where she was appointed staff scientist. In this lab, she investigated the role of sphingosine-1-phosphate in the mechanisms governing mast-cell activation and allergic hypersensitivity. In 2013, Dr. Olivera joined the Mast Cell Biology Section as a staff scientist, where she continues her interest in the role of mast cells in inflammation.
Hox V, Desai A, Bandara G, Gilfillan AM, Metcalfe DD*, Olivera A*. Estrogen increases the severity of anaphylaxis in female mice through enhanced endothelial nitric oxide synthase expression and nitric oxide production. J Allergy Clin Immunol. 2015 Mar;135(3):729-36.e5. *Authors contributed equally.
Muñoz-Cano R, Pascal M, Bartra J, Picado C, Valero A, Kim DK, Brooks S, Ombrello M, Metcalfe DD, Rivera J, Olivera A.Distinct transcriptome profiles differentiate nonsteroidal anti-inflammatory drug-dependent from nonsteroidal anti-inflammatory drug-independent food-induced anaphylaxis. J Allergy Clin Immunol. 2015 Jul 17. Epub ahead of print.
Cruse G, Metcalfe DD, Olivera A. Functional deregulation of KIT: link to mast cell proliferative diseases and other neoplasms.Immunol Allergy Clin North Am. 2014 May;34(2):219-237.
Olivera A, Eisner C, Kitamura Y, Dillahunt S, Allende L, Tuymetova G, Watford W, Meylan F, Diesner SC, Li L, Schnermann J, Proia RL, Rivera J. Sphingosine kinase 1 and sphingosine-1-phosphate receptor 2 are vital to recovery from anaphylactic shock in mice. J Clin Invest. 2010 May;120(5):1429-40.
Olivera A, Mizugishi K, Tikhonova A, Ciaccia L, Odom S, Proia RL, Rivera J. The sphingosine kinase-sphingosine-1-phosphate axis is a determinant of mast cell function and anaphylaxis. Immunity. 2007 Mar;26(3):287-97.
Olivera A, Spiegel S. Sphingosine-1-phosphate as second messenger in cell proliferation induced by PDGF and FCS mitogens.Nature. 1993 Oct 7;365(6446):557-60.