Senior Research associate - School of Pharmacy, The Hebrew University of Jerusalem (Advisor: Prof. Francesca Levi-Schaffer, 11/2016-present)
Returning Scientist - School of Pharmacy, The Hebrew University of Jerusalem (Advisor: Prof. Francesca Levi-Schaffer, 2015-2016)
Instructor of Medicine - BIDMC, Harvard Medical School (2006-2010)
Postdoctoral fellow - BIDMC, Harvard Medical School (Advisor: Prof. Peter F. Weller 2006-2010)
PhD - Weizmann Institute of Science (Advisor: Prof. Ronen Alon 2001-2006)
Eosinophils are innate immune granulocytes known for their cytotoxic effector functions against parasites and their involvement in host tissues damage in allergic diseases. Many of their functions arise from the unique capacity of eosinophils, unlike other immune cells, to store preformed cytotoxic proteins, enzymes, cytokines, chemokines and growth factors in their cytoplasmic granules, available for immediate release or degranulation. Having this preformed ammunition stored in granules allows eosinophils to contribute at the very beginning of the immune response before induced adaptive immunity is initiated, as well as at later time points during inflammation.
Deposition of released eosinophil granule proteins has been demonstrated in diseased tissues, such as airways, heart, small intestine mucosa and skin from patients with acute and chronic eosinophilic disorders, such as, asthma, allergic rhinitis, hypereosinophilic syndromes, Churg-Strauss syndrome, atopic dermatitis, food sensitivity, eosinophilic gastroenteritis and eosinophilic esophagitis to name a few.
Mechanisms of granule protein secretion: The principal process of secretion from intracellular granules (pink ovals, Fig.1) is by means of piecemeal degranulation (PMD), in which intact eosinophils can mobilize and selectively secrete their preformed granule proteins by transporting small packets within granule-derived secretory vesicles (black dots, Fig. 1) to the cell surface. In addition to secretion by PMD, eosinophils have the capacity to release intact granules on cytolysis (Fig.1). Cytolysis is characterized by plasma membrane rupture and the extracellular liberation of intact membrane-bound granules. The presence of intact extracellular eosinophil granules in tissues and fluids has previously been documented in guinea pigs, mice, as well as human tissues in association with diverse disorders, including allergic asthma and rhinitis, dermatitis, helminth infections, eosinophilic esophagitis, and urticaria.
Although critical roles of these eosinophil-driven proteins in host defense and in allergy pathology have been known for decades, the mechanisms that regulate their specific secretion are not well understood. Current therapies concentrate on non-specific blockers of the immune system, such as glucocorticoids or immunosuppressors and have significant adverse side effects. Newer potential therapies are currently concentrating on broadly blocking Th2-mediated inflammation, eosinophil migration and/or survival, rather than modulating eosinophil secretion/degranulation.
Interestingly, studies by me and colleagues indicated that these eosinophil-derived cell-free granules, from human and murine origin, express functional chemokine and cytokine receptors and secrete their content in response to physiological stimuli.
Main research aims
- Understanding the contribution of adhesion molecules as well as cytoskeletal machinery in eosinophil degranulation.
- Understand the implication of isolated granules in allergic inflammation.
This project is funded by EU FP7-MC-CIG-630897 grant.