Publications by authors named "Kathleen Buchheit"

28 Publications

  • Page 1 of 1

Human airway mast cells proliferate and acquire distinct inflammation-driven phenotypes during type 2 inflammation.

Sci Immunol 2021 Feb;6(56)

Jeff and Penny Vinik Immunology Center, Division of Allergy and Clinical Immunology, Brigham and Women's Hospital, Boston, MA, USA.

Mast cells (MCs) play a pathobiologic role in type 2 (T2) allergic inflammatory diseases of the airway, including asthma and chronic rhinosinusitis with nasal polyposis (CRSwNP). Distinct MC subsets infiltrate the airway mucosa in T2 disease, including subepithelial MCs expressing the proteases tryptase and chymase (MC) and epithelial MCs expressing tryptase without chymase (MC). However, mechanisms underlying MC expansion and the transcriptional programs underlying their heterogeneity are poorly understood. Here, we use flow cytometry and single-cell RNA-sequencing (scRNA-seq) to conduct a comprehensive analysis of human MC hyperplasia in CRSwNP, a T2 cytokine-mediated inflammatory disease. We link discrete cell surface phenotypes to the distinct transcriptomes of CRSwNP MC and MC, which represent polarized ends of a transcriptional gradient of nasal polyp MCs. We find a subepithelial population of CD38CD117 MCs that is markedly expanded during T2 inflammation. These CD38CD117 MCs exhibit an intermediate phenotype relative to the expanded MC and MC subsets. CD38CD117 MCs are distinct from circulating MC progenitors and are enriched for proliferation, which is markedly increased in CRSwNP patients with aspirin-exacerbated respiratory disease, a severe disease subset characterized by increased MC burden and elevated MC activation. We observe that MCs expressing a polyp MC-like effector program are also found within the lung during fibrotic diseases and asthma, and further identify marked differences between MC in nasal polyps and skin. These results indicate that MCs display distinct inflammation-associated effector programs and suggest that in situ MC proliferation is a major component of MC hyperplasia in human T2 inflammation.
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http://dx.doi.org/10.1126/sciimmunol.abb7221DOI Listing
February 2021

Efficacy of dupilumab in patients with aspirin-exacerbated respiratory disease and previous inadequate response to anti-IL-5 or anti-IL-5Rα in a real-world setting.

J Allergy Clin Immunol Pract 2021 Feb 22. Epub 2021 Feb 22.

Division of Allergy and Clinical Immunology, Brigham and Women's Hospital, Boston, MA; Harvard Medical School, Boston, MA. Electronic address:

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http://dx.doi.org/10.1016/j.jaip.2021.02.020DOI Listing
February 2021

The importance of timely diagnosis of aspirin-exacerbated respiratory disease for patient health and safety.

World J Otorhinolaryngol Head Neck Surg 2020 Dec 8;6(4):203-206. Epub 2020 Sep 8.

Department of Medicine, Division of Allergy and Clinical Immunology, Brigham and Women's Hospital, Boston, MA, USA.

Backgroud: Aspirin-exacerbated respiratory disease (AERD) is a difficult-to-treat syndrome where timely diagnosis and initiation of disease-specific therapies are pertinent to improved patient outcomes.

Objective: To characterize the most common timeline for development of the clinical triad [asthma, nasal polyposis, and reactions to nonsteroidal anti-inflammatory drugs (NSAIDs)], identify barriers to prompt diagnosis of AERD, and describe indications for an aspirin challenge to facilitate accurate diagnosis.

Methods: Six hundred ninety-seven patients with diagnosed AERD and history of at least one sinus surgery to remove nasal polyps were identified in the Brigham and Women's Hospital AERD registry. Patient reported age at disease onset of asthma, nasal polyposis, and age of first NSAID reaction were obtained from 2013 to 2019 at enrollment.

Results: Of the 697 patients identified, diagnosis of asthma preceded diagnosis of nasal polyposis and first NSAID reaction, although there was considerable variability between patients.

Conclusions: Prompt diagnosis of AERD is important for patient and provider education and improved care of this difficult-to-treat population of patients. Consider diagnostic aspirin challenge in patients without historical reactions to NSAIDs who have an otherwise compatible clinical history, specifically in patients who take daily low-dose aspirin, leukotriene modifiers, avoid NSAIDs, or who are severely symptomatic at baseline where it would be difficult to identify an acute worsening of symptoms.
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http://dx.doi.org/10.1016/j.wjorl.2020.07.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7729250PMC
December 2020

Aspirin-Exacerbated Respiratory Disease: Association Between Patient-Reported Sinus and Asthma Morbidity.

J Allergy Clin Immunol Pract 2020 Dec 8. Epub 2020 Dec 8.

Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Boston, Mass; Harvard Medical School, Boston, Mass.

Background: The association between sinonasal and pulmonary symptoms in aspirin-exacerbated respiratory disease is not fully established.

Objective: To characterize sinonasal and asthma symptomatology, and to determine whether reported sinonasal symptoms predict asthma severity.

Methods: Prospectively collected data from an aspirin-exacerbated respiratory disease registry cohort were included from 2013 to 2018. Sinonasal symptomatology measured by Sino-Nasal Outcomes Test (SNOT) 22-item total scores was used as the predictor variable, with Asthma Control Test (ACT) scores and percent predicted FEV (FEV% predicted) as primary outcomes. All instances of paired data on the same date were used. ACT score was also evaluated with FEV% predicted as the outcome. Mixed effects regression was completed.

Results: From 1065 aspirin-exacerbated respiratory disease registry subjects (mean age, 48.1 ± 12.8 years; 68.0% females, 29.8% males), mean SNOT-22 score was 42.3 ± 24.12 (n = 1307 observations from 869 subjects), mean ACT score was 19.4 ± 5.2 (n = 1511 observations from 931 subjects), and mean FEV% predicted was 82.8 ± 19.6 (n = 777 observations from 307 subjects). SNOT-22 score significantly predicted ACT scores (P < .0001, 1185 paired observations from 845 subjects) and FEV% predicted (P = .018, 485 observations from 246 subjects). Any 10-point increase in SNOT-22 score was associated with a 0.87-point decrease in ACT score and a 0.75% decrease in FEV% predicted. Any 1-point increase in ACT score was associated with a 1.0% increase in FEV% predicted (P < .0001, 616 observations from 269 subjects). The most severe SNOT-22 symptoms were sense of smell/taste and blockage/congestion of nose.

Conclusions: SNOT-22 scores significantly predict ACT scores and FEV% predicted, and ACT scores significantly predict FEV% predicted. This study demonstrates an association between patient-reported rhinosinusitis and asthma symptom severity and subjective and objective measures of asthma severity.
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http://dx.doi.org/10.1016/j.jaip.2020.11.051DOI Listing
December 2020

The role of aspirin desensitization followed by oral aspirin therapy in managing patients with aspirin-exacerbated respiratory disease: A Work Group Report from the Rhinitis, Rhinosinusitis and Ocular Allergy Committee of the American Academy of Allergy, Asthma & Immunology.

J Allergy Clin Immunol 2020 Dec 9. Epub 2020 Dec 9.

Division of Allergy, Asthma, and Immunology, Scripps Clinic, San Diego, Calif.

Aspirin-exacerbated respiratory disease (AERD) is characterized by the clinical triad of chronic rhinosinusitis with nasal polyps, asthma, and an intolerance to medications that inhibit the cycloxgenase-1 enzyme. Patients with AERD on average have more severe respiratory disease compared with patients with chronic rhinosinusitis with nasal polyps and/or asthma alone. Although patients with AERD traditionally develop significant upper and lower respiratory tract symptoms on ingestion of cycloxgenase-1 inhibitors, most of these same patients report clinical benefit when desensitized to aspirin and maintained on daily aspirin therapy. This Work Group Report provides a comprehensive review of aspirin challenges, aspirin desensitizations, and maintenance aspirin therapy in patients with AERD. Identification of appropriate candidates, indications and contraindications, medical and surgical optimization strategies, protocols, medical management during the desensitization, and recommendations for maintenance aspirin therapy following desensitization are reviewed. Also included is a summary of studies evaluating the clinical efficacy of aspirin therapy after desensitization as well as a discussion on the possible cellular and molecular mechanisms explaining how this therapy provides unique benefit to patients with AERD.
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http://dx.doi.org/10.1016/j.jaci.2020.10.043DOI Listing
December 2020

Local immunoglobulin production in nasal tissues: A key to pathogenesis in chronic rhinosinusitis with nasal polyps and aspirin-exacerbated respiratory disease.

Ann Allergy Asthma Immunol 2021 02 13;126(2):127-134. Epub 2020 Oct 13.

Division of Allergy and Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois; Current Affiliation: Type 2 Inflammation and Fibrosis Cluster, Immunology and Inflammation Therapeutic Area, Sanofi, Cambridge, Massachusetts. Electronic address:

Objective: Local activation of B cells and antibody production are important for protective and pathogenic immune responses. Furthermore, there is evidence that local activation of B cells and antibody production are important for pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP) and a severe subset of CRSwNP, aspirin-exacerbated respiratory disease (AERD). This review summarizes these findings and the potential role of B cells and antibodies in disease pathogenesis.

Data Sources: Published literature from PubMed searches.

Study Selections: Studies relevant to B cell development and the roles of B cells and antibodies in the pathogenesis of CRSwNP and AERD.

Results: Formation of tertiary lymphoid structures plays a key role in the local activation of B cells and antibody production. This process is important for fighting infections, but it also contributes to autoimmune disease. Furthermore, there is evidence to support a role for local B cell activation and antibody production in a variety of allergic diseases. Nasal polyp tissues from patients with CRSwNP and AERD have elevated levels of activated B cell subsets and locally produced antibodies. These locally produced antibodies may contribute to disease pathogenesis in a variety of ways, including activation of innate effector cells, whereas locally activated B cells may contribute to pathogenesis through the activation of T cells.

Conclusion: More studies are needed to determine the role of B cells and antibodies in driving disease in these patients. However, targeting the processes that drive local B cell activation and antibody production may provide new therapeutic approaches and could help to reduce chronic inflammation.
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http://dx.doi.org/10.1016/j.anai.2020.09.016DOI Listing
February 2021

Allergic contact dermatitis in a wastewater treatment worker: The role of sodium hypochlorite.

Contact Dermatitis 2020 Dec 19;83(6):533-535. Epub 2020 Oct 19.

Harvard Medical School, Boston, Massachusetts, USA.

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http://dx.doi.org/10.1111/cod.13707DOI Listing
December 2020

Challenges in skin testing for progestogen hypersensitivity.

Ann Allergy Asthma Immunol 2021 01 7;126(1):100-102. Epub 2020 Sep 7.

Division of Allergy and Clinical Immunology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.

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http://dx.doi.org/10.1016/j.anai.2020.09.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726057PMC
January 2021

Leukotriene-Associated Rash in Aspirin-Exacerbated Respiratory Disease.

J Allergy Clin Immunol Pract 2020 Oct 29;8(9):3170-3171. Epub 2020 Jul 29.

Department of Medicine, Harvard Medical School, The Division of Allergy and Clinical Immunology, Brigham and Women's Hospital, Boston, Mass.

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http://dx.doi.org/10.1016/j.jaip.2020.06.061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554182PMC
October 2020

SARS-CoV-2 Receptor ACE2 Is an Interferon-Stimulated Gene in Human Airway Epithelial Cells and Is Detected in Specific Cell Subsets across Tissues.

Cell 2020 05 27;181(5):1016-1035.e19. Epub 2020 Apr 27.

Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Program in Immunology, Harvard Medical School, Boston, MA 02115, USA; Division of Gastroenterology, Hepatology, and Nutrition, Boston Children's Hospital, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA. Electronic address:

There is pressing urgency to understand the pathogenesis of the severe acute respiratory syndrome coronavirus clade 2 (SARS-CoV-2), which causes the disease COVID-19. SARS-CoV-2 spike (S) protein binds angiotensin-converting enzyme 2 (ACE2), and in concert with host proteases, principally transmembrane serine protease 2 (TMPRSS2), promotes cellular entry. The cell subsets targeted by SARS-CoV-2 in host tissues and the factors that regulate ACE2 expression remain unknown. Here, we leverage human, non-human primate, and mouse single-cell RNA-sequencing (scRNA-seq) datasets across health and disease to uncover putative targets of SARS-CoV-2 among tissue-resident cell subsets. We identify ACE2 and TMPRSS2 co-expressing cells within lung type II pneumocytes, ileal absorptive enterocytes, and nasal goblet secretory cells. Strikingly, we discovered that ACE2 is a human interferon-stimulated gene (ISG) in vitro using airway epithelial cells and extend our findings to in vivo viral infections. Our data suggest that SARS-CoV-2 could exploit species-specific interferon-driven upregulation of ACE2, a tissue-protective mediator during lung injury, to enhance infection.
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http://dx.doi.org/10.1016/j.cell.2020.04.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7252096PMC
May 2020

A retrospective analysis of bronchiectasis in patients with aspirin-exacerbated respiratory disease.

J Allergy Clin Immunol Pract 2020 Sep 21;8(8):2799-2801. Epub 2020 Apr 21.

Brigham and Women's Hospital, Division of Allergy and Clinical Immunology, Jeff and Penny Vinik Center for Allergic Diseases Research, Boston, Mass; Harvard Medical School, Boston, Mass. Electronic address:

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http://dx.doi.org/10.1016/j.jaip.2020.04.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484005PMC
September 2020

IL-5Rα marks nasal polyp IgG4- and IgE-expressing cells in aspirin-exacerbated respiratory disease.

J Allergy Clin Immunol 2020 06 19;145(6):1574-1584. Epub 2020 Mar 19.

Department of Medicine, Harvard Medical School, Boston, Mass; Division of Allergy and Clinical Immunology, Brigham and Women's Hospital, Boston, Mass. Electronic address:

Background: The cause of severe nasal polyposis in aspirin-exacerbated respiratory disease (AERD) is unknown. Elevated antibody levels have been associated with disease severity in nasal polyps, but upstream drivers of local antibody production in nasal polyps are undetermined.

Objective: We sought to identify upstream drivers and phenotypic properties of local antibody-expressing cells in nasal polyps from subjects with AERD.

Methods: Sinus tissue was obtained from subjects with AERD, chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP), CRS without nasal polyps, and controls without CRS. Tissue antibody levels were quantified via ELISA and immunohistochemistry and were correlated with disease severity. Antibody-expressing cells were profiled with single-cell RNA sequencing, flow cytometry, and immunofluorescence, with IL-5Rα function determined through IL-5 stimulation and subsequent RNA sequencing and quantitative PCR.

Results: Tissue IgE and IgG4 levels were elevated in AERD compared with in controls (P < .01 for IgE and P < .001 for IgG4 vs CRSwNP). Subjects with AERD whose nasal polyps recurred rapidly had higher IgE levels than did subjects with AERD, with slower regrowth (P = .005). Single-cell RNA sequencing revealed increased IL5RA, IGHG4, and IGHE in antibody-expressing cells from patients with AERD compared with antibody-expressing cells from patients with CRSwNP. There were more IL-5Rα plasma cells in the polyp tissue from those with AERD than in polyp tissue from those with CRSwNP (P = .026). IL-5 stimulation of plasma cells in vitro induced changes in a distinct set of transcripts.

Conclusions: Our study identifies an increase in antibody-expressing cells in AERD defined by transcript enrichment of IL5RA and IGHG4 or IGHE, with confirmed surface expression of IL-5Rα and functional IL-5 signaling. Tissue IgE and IgG4 levels are elevated in AERD, and higher IgE levels are associated with faster nasal polyp regrowth. Our findings suggest a role for IL-5Rα antibody-expressing cells in facilitating local antibody production and severe nasal polyps in AERD.
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http://dx.doi.org/10.1016/j.jaci.2020.02.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7282948PMC
June 2020

Biologics in chronic rhinosinusitis with nasal polyposis.

Ann Allergy Asthma Immunol 2020 04 9;124(4):326-332. Epub 2019 Dec 9.

Department of Medicine, Harvard Medical School, the Division of Allergy and Clinical Immunology, Brigham and Women's Hospital, and the Jeff and Penny Vinik Center, Boston, Massachusetts.

Objective: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a common and heterogeneous inflammatory condition, for which the drivers of the underlying inflammation are not yet fully understood. The use of biologic therapies to target specifically relevant effector cells or cytokines in CRSwNP is a growing field of interest. The objectives of this review are to provide an update on the existing studies of biologics in CRSwNP and to identify potential future areas for further research.

Data Sources: An initial literature review of biologic therapies in CRS was performed through publications gathered from a PubMed search for title/abstract containing "biologic" and "chronic rhinosinusitis." Further manuscripts describing scientific premise for each biologic were then reviewed.

Study Selections: A detailed review of all studies describing biologic therapies targeting inflammation in CRSwNP was performed.

Results: Biologic therapies targeting interleukin (IL)-4Rα, IL-5, IL-5Rα, IL-33, immunoglobulin (Ig)E, and thymic stromal lymphopoietin (TSLP) have all been developed and have been investigated for treatment in CRSwNP, or current research suggests that they may have utility in this area. Only dupilumab, which inhibits IL-4Rα, has gained Food and Drug Administration approval for the treatment of adults with inadequately controlled CRSwNP.

Conclusion: Recent advances in our understanding of the fundamental drivers of the chronic respiratory inflammation in CRSwNP has led to the identification of several potential therapeutic targets for this disease. Future clinical success will rely on the availability of biomarker-based endotyping and responder analyses so that clinicians can precisely match each patient to the appropriate biologic, thereby optimizing the proper treatment strategy.
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http://dx.doi.org/10.1016/j.anai.2019.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7113089PMC
April 2020

Presentation and natural history of progestogen hypersensitivity.

Ann Allergy Asthma Immunol 2019 02 26;122(2):156-159. Epub 2018 Oct 26.

Jeff and Penny Vinik Center for Allergic Diseases Research, Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Boston, Massachusetts; Department of Medicine, Harvard Medical School, Boston, Massachusetts. Electronic address:

Objective: To review the published medical literature on the clinical presentation, risk factors, and natural history of hypersensitivity reactions to progestogens.

Data Sources: Through the use of PubMed, we conducted a review of allergy, dermatology, and obstetric literature for cases and case series of patients with hypersensitivity reactions to exogenous or endogenous progestogens. There are no longitudinal, prospective studies related to progestogen hypersensitivity.

Study Selections: Publications were selected that described cases that were clinically consistent with progesterone hypersensitivity and positive test results or clear symptoms with exposure to progestogens to confirm the diagnosis.

Results: Progestogen hypersensitivity symptoms can be triggered by endogenous progesterone or exogenous progestins used for contraception or fertility treatments. Symptoms are varied and include dermatitis, urticaria, asthma, and anaphylaxis.

Conclusion: Although the medical literature on progestogen hypersensitivity is limited to case reports and small case series, significant heterogeneity exists in clinical presentation among patients.
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http://dx.doi.org/10.1016/j.anai.2018.10.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6497082PMC
February 2019

Cysteinyl leukotriene receptor 2 drives lung immunopathology through a platelet and high mobility box 1-dependent mechanism.

Mucosal Immunol 2019 05 21;12(3):679-690. Epub 2019 Jan 21.

Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, MA, USA.

Cysteinyl leukotrienes (cysLTs) facilitate eosinophilic mucosal type 2 immunopathology, especially in aspirin-exacerbated respiratory disease (AERD), by incompletely understood mechanisms. We now demonstrate that platelets, activated through the type 2 cysLT receptor (CysLTR), cause IL-33-dependent immunopathology through a rapidly inducible mechanism requiring the actions of high mobility box 1 (HMGB1) and the receptor for advanced glycation end products (RAGE). Leukotriene C (LTC) induces surface HMGB1 expression by mouse platelets in a CysLTR-dependent manner. Blockade of RAGE and neutralization of HMGB1 prevent LTC-induced platelet activation. Challenges of AERD-like Ptges mice with inhaled lysine aspirin (Lys-ASA) elicit LTC synthesis and cause rapid intrapulmonary recruitment of platelets with adherent granulocytes, along with platelet- and CysLTR-mediated increases in lung IL-33, IL-5, IL-13, and bronchoalveolar lavage fluid HMGB1. The intrapulmonary administration of exogenous LTC mimics these effects. Platelet depletion, HMGB1 neutralization, and pharmacologic blockade of RAGE eliminate all manifestations of Lys-ASA challenges, including increase in IL-33, mast cell activation, and changes in airway resistance. Thus, CysLTR signaling on platelets prominently utilizes RAGE/HMGB1 as a link to downstream type 2 respiratory immunopathology and IL-33-dependent mast cell activation typical of AERD. Antagonists of HMGB1 or RAGE may be useful to treat AERD and other disorders associated with type 2 immunopathology.
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http://dx.doi.org/10.1038/s41385-019-0134-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6462243PMC
May 2019

A retrospective analysis of esophageal eosinophilia in patients with aspirin-exacerbated respiratory disease.

J Allergy Clin Immunol Pract 2019 04 25;7(4):1338-1340. Epub 2018 Sep 25.

Harvard Medical School, Boston, Mass; Brigham and Women's Hospital, Jeff and Penny Vinik Center for Allergic Diseases Research, Boston, Mass; Vanderbilt University Medical Center, Nashville, Tenn. Electronic address:

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http://dx.doi.org/10.1016/j.jaip.2018.09.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6433551PMC
April 2019

Allergic inflammatory memory in human respiratory epithelial progenitor cells.

Nature 2018 08 22;560(7720):649-654. Epub 2018 Aug 22.

Institute for Medical Engineering and Science (IMES), Massachusetts Institute of Technology, Cambridge, MA, USA.

Barrier tissue dysfunction is a fundamental feature of chronic human inflammatory diseases. Specialized subsets of epithelial cells-including secretory and ciliated cells-differentiate from basal stem cells to collectively protect the upper airway. Allergic inflammation can develop from persistent activation of type 2 immunity in the upper airway, resulting in chronic rhinosinusitis, which ranges in severity from rhinitis to severe nasal polyps. Basal cell hyperplasia is a hallmark of severe disease, but it is not known how these progenitor cells contribute to clinical presentation and barrier tissue dysfunction in humans. Here we profile primary human surgical chronic rhinosinusitis samples (18,036 cells, n = 12) that span the disease spectrum using Seq-Well for massively parallel single-cell RNA sequencing, report transcriptomes for human respiratory epithelial, immune and stromal cell types and subsets from a type 2 inflammatory disease, and map key mediators. By comparison with nasal scrapings (18,704 cells, n = 9), we define signatures of core, healthy, inflamed and polyp secretory cells. We reveal marked differences between the epithelial compartments of the non-polyp and polyp cellular ecosystems, identifying and validating a global reduction in cellular diversity of polyps characterized by basal cell hyperplasia, concomitant decreases in glandular cells, and phenotypic shifts in secretory cell antimicrobial expression. We detect an aberrant basal progenitor differentiation trajectory in polyps, and propose cell-intrinsic, epigenetic and extrinsic factors that lock polyp basal cells into this uncommitted state. Finally, we functionally demonstrate that ex vivo cultured basal cells retain intrinsic memory of IL-4/IL-13 exposure, and test the potential for clinical blockade of the IL-4 receptor α-subunit to modify basal and secretory cell states in vivo. Overall, we find that reduced epithelial diversity stemming from functional shifts in basal cells is a key characteristic of type 2 immune-mediated barrier tissue dysfunction. Our results demonstrate that epithelial stem cells may contribute to the persistence of human disease by serving as repositories for allergic memories.
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http://dx.doi.org/10.1038/s41586-018-0449-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6133715PMC
August 2018

COX-1 mediates IL-33-induced extracellular signal-regulated kinase activation in mast cells: Implications for aspirin sensitivity.

J Allergy Clin Immunol 2019 03 12;143(3):1047-1057.e8. Epub 2018 Jul 12.

Department of Medicine, Harvard Medical School, Boston, Mass; Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Boston, Mass. Electronic address:

Background: Classical FcεRI-induced mast cell (MC) activation causes synthesis of arachidonic acid (AA)-derived eicosanoids (leukotriene [LT] C, prostaglandin [PG] D, and thromboxane A), which mediate vascular leak, bronchoconstriction, and effector cell chemotaxis. Little is known about the significance and regulation of eicosanoid generation in response to nonclassical MC activation mechanisms.

Objectives: We sought to determine the regulation and significance of MC-derived eicosanoids synthesized in response to IL-33, a cytokine critical to innate type 2 immunity.

Methods: We used an ex vivo model of mouse bone marrow-derived mast cells and an IL-33-dependent in vivo model of aspirin-exacerbated respiratory disease (AERD).

Results: IL-33 potently liberates AA and elicits LTC, PGD, and thromboxane A production by bone marrow-derived mast cells. Unexpectedly, the constitutive function of COX-1 is required for IL-33 to activate group IVa cytosolic phospholipase A with consequent AA release for synthesis of all eicosanoids, including CysLTs. In contrast, COX-1 was dispensable for FcεRI-driven CysLT production. Inhibition of COX-1 prevented IL-33-induced phosphorylation of extracellular signal-related kinase, an upstream effector of cytosolic phospholipase A, which was restored by exogenous PGH, implying that the effects of COX-1 required its catalytic function. Administration of a COX-1-selective antagonist to mice completely prevented the generation of both PGD and LTC in a model of AERD in which MC activation is IL-33 driven.

Conclusions: MC-intrinsic COX-1 amplifies IL-33-induced activation in the setting of innate type 2 immunity and might help explain the phenomenon of therapeutic desensitization to aspirin by nonselective COX inhibitors in patients with AERD.
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http://dx.doi.org/10.1016/j.jaci.2018.06.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6330164PMC
March 2019

A retrospective analysis of mepolizumab in subjects with aspirin-exacerbated respiratory disease.

J Allergy Clin Immunol Pract 2018 May - Jun;6(3):1045-1047. Epub 2018 Mar 6.

Brigham and Women's Hospital, Division of Rheumatology, Immunology, and Allergy, Boston, Mass; Harvard Medical School, Boston, Mass.

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http://dx.doi.org/10.1016/j.jaip.2018.01.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5997393PMC
October 2019

Progestogen Hypersensitivity.

Curr Allergy Asthma Rep 2018 01 19;18(1). Epub 2018 Jan 19.

Department of Internal Medicine, Division of Immunology/Allergy Section, University of Cincinnati College of Medicine, 231 Albert Sabin Way, ML #563, Cincinnati, OH, 45267-0563, USA.

Purpose Of Review: Progestogen hypersensitivity (PH) is a rare disorder which usually occurs in women of childbearing age with symptoms ranging from urticaria with or without angioedema, multiple organ involvement consistent with allergic anaphylaxis, to a spectrum of other non-evanescent skin eruptions. In this review, we present a clinical vignette of PH and discuss the clinical presentation and proposed pathomechanisms, diagnosis, and treatment of PH.

Recent Findings: The hypersensitivity symptoms are associated with exogenous progestin exposure (e.g., contraceptive medicines, in vitro fertilization therapy) or endogenous progesterone from progesterone surges during the luteal phase of the menstrual cycle and pregnancy. Recognition of this condition can be challenging to the clinician due to its heterogeneous clinical presentation. It has been recently proposed to use the new term "progestogen hypersensitivity" to replace "autoimmune progesterone dermatitis" due to the lack of evidence supporting an autoimmune mechanism for this disorder. In addition, diagnostic and treatment algorithms are now available that can lead to successful management of this condition. More new developments of Progesterone desensitization protocols are now available which appear to be the safest and most effective long-term treatment option for PH. With the extensive use of oral contraceptives and increased use of supra-physiologic doses of progesterone to support pregnancy in in vitro fertilization, there is likely to be a higher prevalence of PH in the future than currently recognized. Therefore, the allergist-immunologist will be required to collaborate with gynecologists and reproductive endocrinologists to diagnose and treat this condition.
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http://dx.doi.org/10.1007/s11882-018-0758-xDOI Listing
January 2018

Progestogen Hypersensitivity: An Evidence-Based Approach to Diagnosis and Management in Clinical Practice.

Immunol Allergy Clin North Am 2017 11 23;37(4):773-784. Epub 2017 Aug 23.

Department of Medicine, Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Department of Medicine, Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, 60 Fenwood Road, Boston, MA 02115, USA.

Heterogeneous presentations of disease pose particular diagnostic and management challenges to the clinician. Progestogen hypersensitivity (PH) classically consists of hypersensitivity symptoms to endogenous progesterone during the luteal phase of the menstrual cycle. However, with the rise of assisted fertility and the exponential growth in the use of exogenous progestins for contraception, PH's prevalence and symptom heterogeneity have increased. In this article, we focus on the clinical approach to PH diagnosis with an emphasis on key elements of the history, physical, and testing modalities. We also review the current evidence for successful management and treatment across a broad range of patients.
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http://dx.doi.org/10.1016/j.iac.2017.07.006DOI Listing
November 2017

Progestogen Hypersensitivity: Heterogeneous Manifestations with a Common Trigger.

J Allergy Clin Immunol Pract 2017 May - Jun;5(3):566-574

Department of Internal Medicine, Division of Immunology/Allergy Section, University of Cincinnati College of Medicine, Cincinnati, Ohio. Electronic address:

Hypersensitivity to progestogen, previously known as autoimmune progesterone dermatitis, is an increasingly recognized clinical entity that presents specific diagnostic and treatment challenges. Clinical presentations are heterogeneous, but can consist of hypersensitivity symptoms associated with the progesterone surge during the luteal phase of the menstrual cycle or after exposure to exogenous progestins. With the increasing use of exogenous progesterone for contraception and fertility, more cases of hypersensitivity to exogenous progestins have been described. Here we will review proposed pathomechanisms for progestogen hypersensitivity (PH) as well as the clinical presentation of PH, testing strategies to aid in diagnosis, and treatment options for patients with hypersensitivity to progestogens.
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http://dx.doi.org/10.1016/j.jaip.2017.01.019DOI Listing
February 2018

Update on the Management of Aspirin-Exacerbated Respiratory Disease.

Allergy Asthma Immunol Res 2016 Jul;8(4):298-304

Department of Medicine, Harvard Medical School, Boston, MA, USA.

Aspirin-exacerbated respiratory disease (AERD) is an adult-onset upper and lower airway disease consisting of eosinophilic nasal polyps, asthma, and respiratory reactions to cyclooxygenase 1 (COX-1) inhibitors. Management includes guideline-based treatment of asthma and sinus disease, avoidance of COX-1 inhibitors, and for some patients aspirin desensitization followed by high-dose aspirin therapy. Despite this, many patients have inadequately controlled symptoms and require multiple sinus surgeries. In this review, we discuss the current standard approaches to the management of AERD, and we introduce several therapeutics under development that may hold promise for the treatment of AERD.
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http://dx.doi.org/10.4168/aair.2016.8.4.298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4853506PMC
July 2016

Progestogen Hypersensitivity in 24 Cases: Diagnosis, Management, and Proposed Renaming and Classification.

J Allergy Clin Immunol Pract 2016 Jul-Aug;4(4):723-9. Epub 2016 Apr 16.

Division of Rheumatology, Immunology and Allergy, Department of Medicine, BWH, Harvard Medical School, Boston, Mass. Electronic address:

Background: Autoimmune progesterone dermatitis is a poorly recognized syndrome associated with a hypersensitivity to progestogens. Symptoms present heterogeneously, which may complicate diagnosis. Management has generally centered on symptomatic control with medication. Recently, an increasing number of cases have been reported with in vitro fertilization (IVF). Desensitization to progestogens is suggested as an approach to tolerate fertility treatments and provide symptom control.

Objectives: To describe the diagnosis and management of progestogen hypersensitivity (PH) and to detail the use of desensitization. We also propose a new terminology of progestogen hypersensitivity instead of autoimmune progesterone dermatitis, and a classification system based on exogenous and endogenous progestogen triggers to facilitate diagnosis and management.

Methods: Twenty-four cases of PH were evaluated retrospectively. Symptom presentation, diagnostic modalities, desensitization protocols, and outcomes were analyzed.

Results: Symptom onset was classified as a reaction to either endogenous progesterone (42%) or exogenous progestogens (58%). Symptoms were heterogeneous and included cyclical dermatitis, urticaria, angioedema, asthma, and anaphylaxis. Triggers were also heterogenous and included progesterone as well as progestins. Eleven patients underwent intramuscular (27%) or oral (73%) desensitization. Desensitization resulted in symptom control in 8 patients, IVF medication tolerance in 3 patients, and 2 pregnancies.

Conclusions: This is the largest case series of patients with PH with successful treatment outcomes. The new terminology progestogen hypersensitivity more accurately represents the diversity of presentations to endogenous or exogenous progestogens. We demonstrate that progestogen desensitization is successful in multiple patients and can result in symptom control and fertility. Women with cyclical allergic symptoms, including those undergoing IVF, should be evaluated for PH.
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http://dx.doi.org/10.1016/j.jaip.2016.03.003DOI Listing
October 2017

Thymic stromal lymphopoietin controls prostaglandin D2 generation in patients with aspirin-exacerbated respiratory disease.

J Allergy Clin Immunol 2016 05 12;137(5):1566-1576.e5. Epub 2015 Dec 12.

Department of Medicine, Harvard Medical School, Boston, Mass; Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Boston, Mass.

Background: Prostaglandin (PG) D2 is the dominant COX product of mast cells and is an effector of aspirin-induced respiratory reactions in patients with aspirin-exacerbated respiratory disease (AERD).

Objective: We evaluated the role of the innate cytokine thymic stromal lymphopoietin (TSLP) acting on mast cells to generate PGD2 and facilitate tissue eosinophilia and nasal polyposis in patients with AERD.

Methods: Urinary eicosanoid levels were measured in aspirin-tolerant control subjects and patients with AERD. Nasal polyp specimens from patients with AERD and chronic rhinosinusitis were analyzed by using quantitative PCR, Western blotting, and immunohistochemistry. Human cord blood-and peripheral blood-derived mast cells were stimulated with TSLP in vitro to assess PGD2 generation.

Results: Urinary levels of a stable PGD2 metabolite (uPGD-M) were 2-fold higher in patients with AERD relative to those in control subjects and increased further during aspirin-induced reactions. Peak uPGD-M levels during aspirin reactions correlated with reductions in blood eosinophil counts and lung function and increases in nasal congestion. Mast cells sorted from nasal polyps expressed PGD2 synthase (hematopoietic PGD2 synthase) mRNA at higher levels than did eosinophils from the same tissue. Whole nasal polyp TSLP mRNA expression correlated strongly with mRNA encoding hematopoietic PGD2 synthase (r = .75), the mast cell-specific marker carboxypeptidase A3 (r = .74), and uPGD-M (r = 0.74). Levels of the cleaved active form of TSLP were increased in nasal polyps from patients with AERD relative to those in aspirin-tolerant control subjects. Recombinant TSLP induced PGD2 generation by cultured human mast cells.

Conclusions: Our study demonstrates that mast cell-derived PGD2 is a major effector of type 2 immune responses driven by TSLP and suggests that dysregulation of this innate system contributes significantly to the pathophysiology of AERD.
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http://dx.doi.org/10.1016/j.jaci.2015.10.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4860132PMC
May 2016

Aspirin-Exacerbated Diseases: Advances in Asthma with Nasal Polyposis, Urticaria, Angioedema, and Anaphylaxis.

Curr Allergy Asthma Rep 2015 Dec;15(12):69

Division of Rhematology, Immunology, and Allergy, Department of Medicine, Brigham and Women's Hospital/Harvard Medical School, 1 Jimmy Fund Way, Smith Building Room 638, Boston, MA, 02115, USA.

Aspirin-exacerbated diseases are important examples of drug hypersensitivities and include aspirin-exacerbated respiratory disease (AERD), aspirin- or non-steroidal anti-inflammatory drug (NSAID)-induced urticaria/angioedema, and aspirin- or NSAID-induced anaphylaxis. While each disease subtype may be distinguished by unique clinical features, the underlying mechanisms that contribute to these phenotypes are not fully understood. However, the inhibition of the cyclooxygenase-1 enzyme is thought to play a significant role. Additionally, eosinophils, mast cells, and their products, prostaglandins and leukotrienes, have been identified in the pathogenesis of AERD. Current diagnostic and treatment strategies for aspirin-exacerbated diseases remain limited, and continued research focusing on each of the unique hypersensitivity reactions to aspirin is essential. This will not only advance the understanding of these disease processes, but also lead to the subsequent development of novel therapeutics that patients who suffer from aspirin-induced reactions desperately need.
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http://dx.doi.org/10.1007/s11882-015-0569-2DOI Listing
December 2015

Aspirin-Exacerbated Respiratory Disease Involves a Cysteinyl Leukotriene-Driven IL-33-Mediated Mast Cell Activation Pathway.

J Immunol 2015 Oct 4;195(8):3537-45. Epub 2015 Sep 4.

Department of Medicine, Harvard Medical School, Boston, MA 02115; Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, MA 02115; Jeff and Penny Vinik Center for Allergic Disease Research, Boston, MA 02115; Department of Pediatrics, Harvard Medical School, Boston, MA 02115

Aspirin-exacerbated respiratory disease (AERD), a severe eosinophilic inflammatory disorder of the airways, involves overproduction of cysteinyl leukotrienes (cysLTs), activation of airway mast cells (MCs), and bronchoconstriction in response to nonselective cyclooxygenase inhibitors that deplete homeostatic PGE2. The mechanistic basis for MC activation in this disorder is unknown. We now demonstrate that patients with AERD have markedly increased epithelial expression of the alarmin-like cytokine IL-33 in nasal polyps, as compared with polyps from aspirin-tolerant control subjects. The murine model of AERD, generated by dust mite priming of mice lacking microsomal PGE2 synthase (ptges(-/-) mice), shows a similar upregulation of IL-33 protein in the airway epithelium, along with marked eosinophilic bronchovascular inflammation. Deletion of leukotriene C4 synthase, the terminal enzyme needed to generate cysLTs, eliminates the increased IL-33 content of the ptges(-/-) lungs and sharply reduces pulmonary eosinophilia and basal secretion of MC products. Challenges of dust mite-primed ptges(-/-) mice with lysine aspirin induce IL-33-dependent MC activation and bronchoconstriction. Thus, IL-33 is a component of a cysLT-driven innate type 2 immune response that drives pathogenic MC activation and contributes substantially to AERD pathogenesis.
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http://dx.doi.org/10.4049/jimmunol.1500905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4592820PMC
October 2015