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Joshua A. Boyce, MD
Associate Physician, Brigham and Women's Hospital
Professor of Pediatrics, 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:

This laboratory focuses on the mechanisms by which allergic pulmonary inflammation is controlled by lipid mediators of inflammation, their cellular sources, and their receptors. We use transgenic mice, RNA interference in primary cells, and benchside approaches with cells and tissues obtained from carefully characterized human subjects. We have shown that leukotiene E4, the most abundant metabolite of the cysteinyl leukotrienes (cys-LTs), is a potent inducer/amplifier of pulmonary eosinophil recruitment by a pathway that is independent of the known receptors for cys-LTs (CysLT1R and CysLT2R), but instead depends on the present of platelets and the P2Y12 receptor for adenosine diphosphate (ADP). LTE4 is very abudant in the urine of subjects with aspirin-exacerbated respiratory disease (AERD), a distinctive asthma phenotype that is associated with marked tissue eosinophilia, severe nasal polyposis, and difficult-to-control asthma. We have recently found that platelet adherent leukocytes are markedly increased in the circulation and nasal polyp tissue of patients with AERD. These adherent platelets express leukotriene C4 synthase, and account for ~60% of the capacity of granulocytes to generate cys-LTs in AERD. These observations imply a "feed forward" system in which platelets are both effectors of and sources of cys-LTs. In collaboration with our pulmonary colleagues, we conducting a placebo controlled trial of a P2Y12 receptor antagonist as a potential therapy for AERD.

We are also interested in the prostaglandin E2 (PGE2) system and its role in maintaining homeostatic control over the extent of the inflammatory response in the lung. Epigenetic modifications in the genes encoding the synthetic enzymes (cyclooxygenase 2, microsomal PGE2 synthase-1 (mPGES-1) and the E prostanoid (EP)2 receptor may be associated with AERD. We are using epithelial cells, granulocytes, and fibroblasts from well-characterized patient populations to determine the extents to which chromatin remodeling, methylation variants, and micro RNA regulate the expressions and functions of COX-2, mPGES-1, and EP2 receptors. We have also demonstrated that deletion of the ptges locus in mice confers a phenotype that is strikingly similar to AERD in mice, with distinct and key roles for platelet-adherent leukocytes, the thromboxane receptor, and mast cells. The mouse and human inform thus each other, faciltating the identification of disease-causing mechanisms and identification of potential treatments.  

 

 


Education:
U. of Massachusetts Medical School , 1985, MD

Honors/Awards:
American Academy of Allergy Asthma and Immunology 2012 Special Recognition Award
MERIT (R37) Award NIAID 2013
Albert L. Sheffer Professor of Medicine in the Field of Allergic Diseases

Lab Members:
Tao Liu, Ph.D, Instructor in Medicine
Anya Cutler, Research Assistant
Denise Garofalo, Research Assistant
Laura Fanning, M.D., Instructor in Medicine
Tanya M. Laidlaw, M.D., Assistant Professor of Medicine
Catherine Kahill, M.D., Instructor in Medicine
Chunli Feng, M.D., Research Assistant
Kathleen Buchheit, M.D., Research Fellow
Sachin Sumachiwal, Ph.D., Research Fellow
Dingxin Pan, Ph.D., Research Fellow

Collaborators:
Benjamin Raby, M.D., Channing Lab, Scientific Collaborator

Matthew Meyerson, M.D., Ph.D., Broad Institute, Scientific Collaborator

Elliot Israel, M.D., Brigham and Womens Hospital, Scientific Collaborator

Barbara Balestrieri, M.D., Brigham and Womens Hospital, Scientific Collaborator

Yoshihide Kanoka, M.D., Ph.D., Brigham and Womens Hospital, Scientific Collaboratory


Courses Taught:
2004-present, HMS, Immunology 202


Other Professional Activities:
Member, American Board of Allergy and Immunology , ABAI
Member, Allergy, Immunology and Transplantation Review Committee, NIH/NIAID

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. Cahill KN, Murphy K, Singer J, Israel E, Boyce JA, Laidlaw TM. Plasma tryptase elevation during aspirin-induced reactions in aspirin-exacerbated respiratory disease. J Allergy Clin Immunol. 2019 Feb; 143(2):799-803.e2.

3. Bankova LG, Boyce JA. A new spin on mast cells and cysteinyl leukotrienes: Leukotriene E4 activates mast cells in vivo. J Allergy Clin Immunol. 2018 Oct; 142(4):1056-1057.

4. 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.

5. Pan D, Buchheit KM, Samuchiwal SK, Liu T, Cirka H, Raff H, Boyce JA. COX-1 mediates IL-33-induced extracellular signal-regulated kinase activation in mast cells: Implications for aspirin sensitivity. J Allergy Clin Immunol. 2019 Mar; 143(3):1047-1057.e8.

6. Laidlaw TM, Cahill KN, Cardet JC, Murphy K, Cui J, Dioneda B, Kothari P, Raby BA, Israel E, Boyce JA. A trial of type 12 purinergic (P2Y12) receptor inhibition with prasugrel identifies a potentially distinct endotype of patients with aspirin-exacerbated respiratory disease. J Allergy Clin Immunol. 2019 Jan; 143(1):316-324.e7.

7. Samuchiwal SK, Boyce JA. Role of lipid mediators and control of lymphocyte responses in type 2 immunopathology. J Allergy Clin Immunol. 2018 Apr; 141(4):1182-1190.

8. 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.

9. Yamaguchi M, Samuchiwal SK, Quehenberger O, Boyce JA, Balestrieri B. Macrophages regulate lung ILC2 activation via Pla2g5-dependent mechanisms. Mucosal Immunol. 2018 05; 11(3):615-626.

10. Cahill KN, Boyce JA, Israel E. Novel Treatments for Airway Disease. N Engl J Med. 2017 08 10; 377(6):597.