A focus in our lab has been the study of allergic diseases and mast cell proliferative disorders. Even though much is known about mast cell-derived mediators and their potential contributions to these diseases, the identification of mediators (derived or not from mast cells) and receptors that critically influence certain aspects of the allergic response and mast cell related disorders remains incompletely understood. Some allergic-like reactions in a variety of syndromes such as urticaria are caused by largely unknown antigen-independent mechanisms. An example is vibratory urticaria (VU), a subtype of physical urticaria triggered by sustained vibration against the skin. We demonstrated a pathogenic involvement of mast cells in families with inherited vibratory urticaria and identified a missense mutation in an adhesion G-protein coupled receptor known to bind dermatan sulfate, (ADGRE2 or EMR2) associated with this condition. The findings implicate that mast cells can sense physical stimuli through a membrane receptor, a novel facet to mast cell biology and of relevance to physical urticarias. Our studies using a sequencing based-gene expression analysis approach in patients with food anaphylaxis to lipid transfer protein (LTP), suggested underlying changes in gene expression that predispose to the induction of food induced anaphylaxis. For example, sphingosine-1-phosphate (S1P) signaling was identified as a canonical pathway downregulated in this group of patients. Since S1P is an important lipid mediator for immunity, sensitization to food allergens and recovery from anaphylactic shock, we are investigating the role of S1P and its receptors in mast cells and basophils, and in models of allergic inflammation. Neoplastic accumulation of mast cells in systemic mastocytosis (SM), a mast cell proliferation disorder, associates with activating mutations in the receptor tyrosine kinase KIT. Constitutive activation of tyrosine kinase oncogenes has been linked to imbalances in oxidant/antioxidant mechanisms in other myeloproliferative disorders. However, the impact of KIT mutations on the redox status in SM and the potential therapeutic implications are not well understood. We thus examined the regulation of reactive oxygen species (ROS) and of the antioxidant protein DJ-1 (PARK-7), which increases with cancer progression and acts to lessen oxidative damage to malignant cells, in relationship with SM severity. In less advanced disease, the serum levels of DJ-1 are reduced due to activating KIT mutations in mast cells and continuous production of ROS resulting in DJ-1 oxidation and degradation. However, in patients with high mast cell burden and advanced disease, DJ-1 levels are instead increased due to escalating IL-6 which robustly induces DJ-1 transcription and overcomes DJ-1 depletion. Blockade of IL-6 receptor minimized ROS and DJ-1 dysregulation and retarded the progressive accumulation of mast cells in a mouse model of mastocytosis and thus we suggest that increased DJ-1 may favor mast cell expansion by protecting against oxidative stress. IL-6 blockade could represent an adjunctive therapy in the treatment of patients with advanced mastocytosis, as it would reduce DJ-1 levels, making mutation-positive mast cells vulnerable to oxidative damage.

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Kulinski, Joseph M; Proia, Richard L; Larson, Elisabeth M et al. (2018) S1P? Regulates Passive Systemic Anaphylaxis in Mice but Is Dispensable for Canonical IgE-Mediated Responses in Mast Cells. Int J Mol Sci 19:
Olivera, Ana; Beaven, Michael A; Metcalfe, Dean D (2018) Mast cells signal their importance in health and disease. J Allergy Clin Immunol 142:381-393
Bandara, Geethani; Muñoz-Cano, Rosa; Tobío, Araceli et al. (2018) Targeting Sphingosine Kinase Isoforms Effectively Reduces Growth and Survival of Neoplastic Mast Cells With D816V-KIT. Front Immunol 9:631
Yin, Yuzhi; Bai, Yun; Olivera, Ana et al. (2017) An optimized protocol for the generation and functional analysis of human mast cells from CD34+ enriched cell populations. J Immunol Methods 448:105-111
Muñoz-Cano, Rosa; Pascal, Mariona; Bartra, Joan et al. (2016) Distinct transcriptome profiles differentiate nonsteroidal anti-inflammatory drug-dependent from nonsteroidal anti-inflammatory drug-independent food-induced anaphylaxis. J Allergy Clin Immunol 137:137-146
Boyden, Steven E; Metcalfe, Dean D; Komarow, Hirsh D (2016) Vibratory Urticaria and ADGRE2. N Engl J Med 375:95
Kim, Do-Kyun; Beaven, Michael A; Kulinski, Joseph M et al. (2016) Regulation of Reactive Oxygen Species and the Antioxidant Protein DJ-1 in Mastocytosis. PLoS One 11:e0162831
Taguchi, Yoshimitsu; Allende, Maria L; Mizukami, Hiroki et al. (2016) Sphingosine-1-phosphate Phosphatase 2 Regulates Pancreatic Islet ?-Cell Endoplasmic Reticulum Stress and Proliferation. J Biol Chem 291:12029-38
Kirshenbaum, Arnold S; Cruse, Glenn; Desai, Avanti et al. (2016) Immunophenotypic and Ultrastructural Analysis of Mast Cells in Hermansky-Pudlak Syndrome Type-1: A Possible Connection to Pulmonary Fibrosis. PLoS One 11:e0159177
Desai, Avanti; Jung, Mi-Yeon; Olivera, Ana et al. (2016) IL-6 promotes an increase in human mast cell numbers and reactivity through suppression of suppressor of cytokine signaling 3. J Allergy Clin Immunol 137:1863-1871.e6

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