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Nora Amanda Barrett
Associate Physician, Brigham and Women's Hospital
Assistant Professor of Medicine, Harvard Medical School

Brigham and Women's Hospital
Department of Medicine
Rheumatology, Immunology
75 Francis Street
Boston, MA 02115


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Research Narrative:

Allergic asthma is characterized by an exuberant Th2 immune response against innocuous environmental antigens, but the innate signaling pathways activated by inhaled antigens to trigger this response are not well defined.  We have identified Dectin-2, a myeloid C-type lectin, as a dendritic cell (DC) receptor for glycans in allergen extracts from the house dust mites Dermatophagoides farinae (Df) and Dermatophagoides pteronyssinus (Dp), and from the mold Aspergillus fumigatus (Af).  Activation of Dectin-2 in DCs stimulates the generation of both lipid mediators such as cysteinyl leukotrienes (cys-LTs) and pro-inflammatory cytokines such as TNF-α and IL-6, via an FcRγ and Syk-dependent signaling pathway.  Lentiviral knockdown of Dectin-2 in bone marrow-derived dendritic cells (BMDCs) inhibits their ability to sensitize naïve recipients to Df and administration of an anti-Dectin-2 blocking antibody to mice dramatically reduces Df-elicited Th2 and Th17 pulmonary inflammation.  Further studies using leukotriene C4 synthase (LTC4S)-deficient mice or type 1 cys-LT receptor (CysLT1R)-deficient mice identify DC cys-LTs as the germane Dectin-2-derived mediators of Th2 pulmonary inflammation to Df.  Thus, the innate Dectin-2/cys-LT signaling pathway is a critical link between allergen recognition and Th2 immunity. 

Respiratory Immunology Laboratory


Education:
University of Virginia School of Medicine, 2000, MD

Publications (Pulled from Harvard Catalyst Profiles):

1. Liu T, Barrett NA, Kanaoka Y, Buchheit K, Laidlaw TM, Garofalo D, Lai J, Katz HR, Feng C, Boyce JA. Cysteinyl leukotriene receptor 2 drives lung immunopathology through a platelet and high mobility box 1-dependent mechanism. Mucosal Immunol. 2019 Jan 21.

2. Bankova LG, Dwyer DF, Yoshimoto E, Ualiyeva S, McGinty JW, Raff H, von Moltke J, Kanaoka Y, Frank Austen K, Barrett NA. The cysteinyl leukotriene 3 receptor regulates expansion of IL-25-producing airway brush cells leading to type 2 inflammation. Sci Immunol. 2018 Oct 05; 3(28).

3. Ordovas-Montanes J, Dwyer DF, Nyquist SK, Buchheit KM, Vukovic M, Deb C, Wadsworth MH, Hughes TK, Kazer SW, Yoshimoto E, Cahill KN, Bhattacharyya N, Katz HR, Berger B, Laidlaw TM, Boyce JA, Barrett NA, Shalek AK. Allergic inflammatory memory in human respiratory epithelial progenitor cells. Nature. 2018 08; 560(7720):649-654.

4. Liu T, Barrett NA, Kanaoka Y, Yoshimoto E, Garofalo D, Cirka H, Feng C, Boyce JA. Type 2 Cysteinyl Leukotriene Receptors Drive IL-33-Dependent Type 2 Immunopathology and Aspirin Sensitivity. J Immunol. 2018 02 01; 200(3):915-927.

5. von Moltke J, O'Leary CE, Barrett NA, Kanaoka Y, Austen KF, Locksley RM. Leukotrienes provide an NFAT-dependent signal that synergizes with IL-33 to activate ILC2s. J Exp Med. 2017 01; 214(1):27-37.

6. Lee MJ, Yoshimoto E, Saijo S, Iwakura Y, Lin X, Katz HR, Kanaoka Y, Barrett NA. Phosphoinositide 3-Kinase d Regulates Dectin-2 Signaling and the Generation of Th2 and Th17 Immunity. J Immunol. 2016 07 01; 197(1):278-87.

7. Bankova LG, Lai J, Yoshimoto E, Boyce JA, Austen KF, Kanaoka Y, Barrett NA. Leukotriene E4 elicits respiratory epithelial cell mucin release through the G-protein-coupled receptor, GPR99. Proc Natl Acad Sci U S A. 2016 May 31; 113(22):6242-7.

8. Dwyer DF, Barrett NA, Austen KF. Expression profiling of constitutive mast cells reveals a unique identity within the immune system. Nat Immunol. 2016 Jul; 17(7):878-87.

9. Sloane D, Govindarajulu U, Harrow-Mortelliti J, Barry W, Hsu FI, Hong D, Laidlaw T, Palis R, Legere H, Bunyavanich S, Breslow R, Wesemann D, Barrett N, Brennan P, Chong HJ, Liu A, Fernandez J, Fanning L, Kyin T, Cahill K, Bankova L, Lynch A, Berlin S, Campos S, Fuchs C, Mayer R, Matulonis U, Castells M. Safety, Costs, and Efficacy of Rapid Drug Desensitizations to Chemotherapy and Monoclonal Antibodies. J Allergy Clin Immunol Pract. 2016 May-Jun; 4(3):497-504.

10. Barrett NA, Austen KF. Licensed to Ill: IL-9 Generation in Immature Mast Cells Permits Food-Elicited Anaphylaxis. Immunity. 2015 Oct 20; 43(4):626-8.