Kelly Bruton

All Publications

• Type 2-polarized memory B cells hold allergen-specific IgE memory. Science translational medicine Koenig, J. F., Knudsen, N. P., Phelps, A., Bruton, K., Hoof, I., Lund, G., Libera, D. D., Lund, A., Christensen, L. H., Glass, D. R., Walker, T. D., Fang, A., Waserman, S., Jordana, M., Andersen, P. S. 2024; 16 (733): eadi0944

  Abstract

  Allergen-specific immunoglobulin E (IgE) antibodies mediate pathology in diseases such as allergic rhinitis and food allergy. Memory B cells (MBCs) contribute to circulating IgE by regenerating IgE-producing plasma cells upon allergen encounter. Here, we report a population of type 2-polarized MBCs defined as CD23hi, IL-4Rαhi, and CD32low at both the transcriptional and surface protein levels. These MBC2s are enriched in IgG1- and IgG4-expressing cells while constitutively expressing germline transcripts for IgE. Allergen-specific B cells from patients with allergic rhinitis and food allergy were enriched in MBC2s. Furthermore, MBC2s generated allergen-specific IgE during sublingual immunotherapy, thereby identifying these cells as a major reservoir for IgE. The identification of MBC2s provides insights into the maintenance of IgE memory, which is detrimental in allergic diseases but could be beneficial in protection against venoms and helminths.

  View details for DOI 10.1126/scitranslmed.adi0944

  View details for PubMedID 38324637

• Heterogeneity, subsets, and plasticity of T follicular helper cells in allergy JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Grydziuszko, E., Phelps, A., Bruton, K., Jordana, M., Koenig, J. E. 2022; 150 (5): 990-998

  Abstract

  Antibody responses are critical for protection against pathogens. However, diseases such as allergic rhinitis or food allergy result from aberrant production of IgE antibodies against otherwise innocuous environmental antigens. The production of allergen-specific IgE requires interaction between B cells and CD4+ T cells, and a granular understanding of these interactions is required to develop novel therapies for allergic disease. CD4+ T cells are exceptionally heterogeneous in their transcriptional, epigenetic, and proteomic profiles, which poses significant challenges when attempting to define subsets relevant to the study of allergy among a continuum of cells. Defining subsets such as the T follicular helper (TFH) cell cluster provides a shorthand to understand the functions of CD4+ T cells in antibody production and supports mechanistic experimentation for hypothesis-driven discovery. With a focus on allergic disease, this Rostrum article broadly discusses heterogeneity among CD4+ T cells and provides a rationale for subdividing TFH cells into both functional and cytokine-skewed subsets. Further, it highlights the plasticity demonstrated by TFH cells during the primary response and after recall, and it explores the possibility of harnessing this plasticity to reprogram immunity for therapeutic benefit in allergic disease.

  View details for DOI 10.1016/j.jaci.2022.08.023

  View details for Web of Science ID 000898376600003

  View details for PubMedID 36070826

• The Road Toward Transformative Treatments for Food Allergy. Frontiers in allergy Phelps, A., Bruton, K., Grydziuszko, E., Koenig, J. F., Jordana, M. 2022; 3: 826623

  Abstract

  A series of landmark studies have provided conclusive evidence that the early administration of food allergens dramatically prevents the emergence of food allergy. One of the greatest remaining challenges is whether patients with established food allergy can return to health. This challenge is particularly pressing in the case of allergies against peanut, tree nuts, fish, and shellfish which are lifelong in most patients and may elicit severe reactions. The standard of care for food allergy is allergen avoidance and the timely administration of epinephrine upon accidental exposure. Epinephrine, and other therapeutic options like antihistamines provide acute symptom relief but do not target the underlying pathology of the disease. In principle, any transformative treatment for established food allergy would require the restoration of a homeostatic immunological state. This may be attained through either an active, non-harmful immune response (immunological tolerance) or a lack of a harmful immune response (e.g., anergy), such that subsequent exposures to the allergen do not elicit a clinical reaction. Importantly, such a state must persist beyond the course of the treatment and exert its protective effects permanently. In this review, we will discuss the immunological mechanisms that maintain lifelong food allergies and are, consequently, those which must be dismantled or reprogrammed to instate a clinically non-reactive state. Arguably, the restoration of such a state in the context of an established food allergy would require a reprogramming of the immune response against a given food allergen. We will discuss existing and experimental therapeutic strategies to eliminate IgE reactivity and, lastly, will propose outstanding questions to pave the road to the development of novel, transformative therapeutics in food allergy.

  View details for DOI 10.3389/falgy.2022.826623

  View details for PubMedID 35386642

• Peanut allergy: Beyond the oral immunotherapy plateau CLINICAL AND TRANSLATIONAL ALLERGY Bruton, K., Spill, P., Chu, D. K., Waserman, S., Jordana, M. 2021; 11 (6): e12046

  Abstract

  There are a lack of disease-modifying treatments for peanut allergy, which is lifelong in most instances. Oral immunotherapy has remained at the forefront of prospective treatments, though its efficacy is consistently undermined by the risk of adverse reactions and meager sustained effects.This review discusses the current state of oral immunotherapy, its strengths and limitations, and the future of therapeutics for the treatment of peanut allergy.The persistence of peanut allergy is currently attributed to reservoirs of peanut-specific memory B cells and Th2 cells, though the cellular and molecular interplay that facilitates the replenishment of peanut-specific IgE remains elusive. Uncovering these events will prove critical for identification of novel targets as we forge ahead to a new age of peanut allergy treatment with biotherapeutics.

  View details for DOI 10.1002/clt2.12046

  View details for Web of Science ID 000690767000002

  View details for PubMedID 34429871

  View details for PubMedCentralID PMC8361810

• Interrupting reactivation of immunologic memory diverts the allergic response and prevents anaphylaxis JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Bruton, K., Spill, P., Vohra, S., Baribeau, O., Manzoor, S., Gadkar, S., Davidson, M., Walker, T. D., Koenig, J. E., Ellenbogen, Y., Florescu, A., Wen, J., Chu, D. K., Waserman, S., Jimenez-Saiz, R., Epelman, S., Robbins, C., Jordana, M. 2021; 147 (4): 1381-1392

  Abstract

  IgE production against innocuous food antigens can result in anaphylaxis, a severe life-threatening consequence of allergic reactions. The maintenance of IgE immunity is primarily facilitated by IgG+ memory B cells, as IgE+ memory B cells and IgE+ plasma cells are extremely scarce and short-lived, respectively.Our aim was to investigate the critical requirements for an IgE recall response in peanut allergy.We used a novel human PBMC culture platform, a mouse model of peanut allergy, and various experimental readouts to assess the IgE recall response in the presence and absence of IL-4Rα blockade.In human PBMCs, we have demonstrated that blockade of IL-4/IL-13 signaling aborted IgE production after activation of a recall response and skewed the cytokine response away from a dominant type 2 signature. TH2A cells, identified by single-cell RNA sequencing, expanded with peanut stimulation and maintained their pathogenic phenotype in spite of IL-4Rα blockade. In mice with allergy, anti-IL-4Rα provided long-lasting suppression of the IgE recall response beyond antibody treatment and fully protected against anaphylaxis.The findings reported here advance our understanding of events mediating the regeneration of IgE in food allergy.

  View details for DOI 10.1016/j.jaci.2020.11.042

  View details for Web of Science ID 000647154500003

  View details for PubMedID 33338539

• Memory Generation and Re-Activation in Food Allergy IMMUNOTARGETS AND THERAPY Koenig, J. E., Bruton, K., Phelps, A., Grydziuszko, E., Jimenez-Saiz, R., Jordana, M. 2021; 10: 171-184

  Abstract

  Recent evidence has highlighted the critical role of memory cells in maintaining lifelong food allergies, thereby identifying these cells as therapeutic targets. IgG+ memory B cells replenish pools of IgE-secreting cells upon allergen exposure, which contract thereafter due to the short lifespan of tightly regulated IgE-expressing cells. Advances in the detection and highly dimensional analysis of allergen-specific B and T cells from allergic patients have provided insight on their phenotype and function. The newly identified Th2A and Tfh13 populations represent a leap in our understanding of allergen-specific T cell phenotypes, although how these populations contribute to IgE memory responses remains poorly understood. Within, we discuss the mechanisms by which memory B and T cells are activated, integrating knowledge from human systems and fundamental research. We then focus on memory reactivation, specifically, on the pathways of secondary IgE responses. Throughout, we identify areas of future research which will help identify immunotargets for a transformative therapy for food allergy.

  View details for DOI 10.2147/ITT.S284823

  View details for Web of Science ID 000663387100001

  View details for PubMedID 34136419

  View details for PubMedCentralID PMC8200165

• Perturbations to Homeostasis in Experimental Models Revealed Innate Pathways Driving Food Allergy FRONTIERS IN IMMUNOLOGY Bruton, K., Koenig, J. E., Phelps, A., Jordana, M. 2020; 11: 603272

  Abstract

  While type 2 immunity has been conventionally viewed as beneficial against helminths, venoms, and poisons, and harmful in allergy, contemporary research has uncovered its critical role in the maintenance of homeostasis. The initiation of a type 2 immune response involves an intricate crosstalk between structural and immune cells. Structural cells react to physical and chemical tissue perturbations by secreting alarmins, which signal the innate immune system to restore homeostasis. This pathway acts autonomously in the context of sterile injury and in the presence of foreign antigen initiates an adaptive Th2 response that is beneficial in the context of venoms, toxins, and helminths, but not food allergens. The investigation of the triggers and mechanisms underlying food allergic sensitization in humans is elusive because sensitization is a silent process. Therefore, the central construct driving food allergy modeling is based on introducing perturbations of tissue homeostasis along with an allergen which will result in an immunological and clinical phenotype that is consistent with that observed in humans. The collective evidence from multiple models has revealed the pre-eminent role of innate cells and molecules in the elicitation of allergic sensitization. We posit that, with the expanding use of technologies capable of producing formidable datasets, models of food allergy will continue to have an indispensable role to delineate mechanisms and establish causal relationships.

  View details for DOI 10.3389/fimmu.2020.603272

  View details for Web of Science ID 000601273200001

  View details for PubMedID 33362786

  View details for PubMedCentralID PMC7758527

• HIT-COVID, a global database tracking public health interventions to COVID-19 SCIENTIFIC DATA Zheng, Q., Jones, F. K., Leavitt, S., Ung, L., Labrique, A. B., Peters, D. H., Lee, E. C., Azman, A. S., HIT-COVID Collaboration 2020; 7 (1): 286

  Abstract

  The COVID-19 pandemic has sparked unprecedented public health and social measures (PHSM) by national and local governments, including border restrictions, school closures, mandatory facemask use and stay at home orders. Quantifying the effectiveness of these interventions in reducing disease transmission is key to rational policy making in response to the current and future pandemics. In order to estimate the effectiveness of these interventions, detailed descriptions of their timelines, scale and scope are needed. The Health Intervention Tracking for COVID-19 (HIT-COVID) is a curated and standardized global database that catalogues the implementation and relaxation of COVID-19 related PHSM. With a team of over 200 volunteer contributors, we assembled policy timelines for a range of key PHSM aimed at reducing COVID-19 risk for the national and first administrative levels (e.g. provinces and states) globally, including details such as the degree of implementation and targeted populations. We continue to maintain and adapt this database to the changing COVID-19 landscape so it can serve as a resource for researchers and policymakers alike.

  View details for DOI 10.1038/s41597-020-00610-2

  View details for Web of Science ID 000566937400002

  View details for PubMedID 32855428

  View details for PubMedCentralID PMC7453020

• Follicular T cells: From stability to failure ALLERGY Jimenez-Saiz, R., Bruton, K., Jordana, M. 2020; 75 (4): 1006-1007

  View details for DOI 10.1111/all.14167

  View details for Web of Science ID 000529134100042

  View details for PubMedID 31883377

• <it>TAK1</it> ng aim at mechanisms of allergic inflammation: contribution of TAK1 activity in allergen-mediated mast cell activation Watson, C., Maguire, A., Rouillard, M., Crozier, R., Yousef, M., Bruton, K., Fajardo, V., MacNeil, A. WILEY. 2020

  View details for DOI 10.1096/fasebj.2020.34.s1.05566

  View details for Web of Science ID 000546023102411

• TAK1 signaling activity links the mast cell cytokine response and degranulation in allergic inflammation JOURNAL OF LEUKOCYTE BIOLOGY Watson, C. F., Maguire, A. R., Rouillard, M. M., Crozier, R. E., Yousef, M., Bruton, K. M., Fajardo, V. A., MacNeil, A. J. 2020; 107 (4): 649-661

  Abstract

  Mast cells drive the inappropriate immune response characteristic of allergic inflammatory disorders via release of pro-inflammatory mediators in response to environmental cues detected by the IgE-FcεRI complex. The role of TGF-β-activated kinase 1 (TAK1), a participant in related signaling in other contexts, remains unknown in allergy. We detect novel activation of TAK1 at Ser412 in response to IgE-mediated activation under SCF-c-kit potentiation in a mast cell-driven response characteristic of allergic inflammation, which is potently blocked by TAK1 inhibitor 5Z-7-oxozeaenol (OZ). We, therefore, interrogated the role of TAK1 in a series of mast cell-mediated responses using IgE-sensitized murine bone marrow-derived mast cells, stimulated with allergen under several TAK1 inhibition strategies. TAK1 inhibition by OZ resulted in significant impairment in the phosphorylation of MAPKs p38, ERK, and JNK; and mediation of the NF-κB pathway via IκBα. Impaired gene expression and near abrogation in release of pro-inflammatory cytokines TNF, IL-6, IL-13, and chemokines CCL1, and CCL2 was detected. Finally, a significant inhibition of mast cell degranulation, accompanied by an impairment in calcium mobilization, was observed in TAK1-inhibited cells. These results suggest that TAK1 acts as a signaling node, not only linking the MAPK and NF-κB pathways in driving the late-phase response, but also initiation of the degranulation mechanism of the mast cell early-phase response following allergen recognition and may warrant consideration in future therapeutic development.

  View details for DOI 10.1002/JLB.2A0220-401RRR

  View details for Web of Science ID 000516869500001

  View details for PubMedID 32108376

• Human BCR analysis of single-sorted, putative IgE(+) memory B cells in food allergy JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Jimenez-Saiz, R., Ellenbogen, Y., Bruton, K., Spill, P., Sommer, D. D., Lima, H., Waserman, S., Patil, S. U., Shreffler, W. G., Jordana, M. 2019; 144 (1): 336-+

  Abstract

  R. Jimenez-Saiz, Y. Ellenbogen and K. Bruton et al. developed a method to identify bona fide IgE+ MBCs in humans, demonstrated their extreme rarity in circulation and cautioned against the clinical utility of their assessment.

  View details for DOI 10.1016/j.jaci.2019.04.001

  View details for Web of Science ID 000473432800042

  View details for PubMedID 30959060

  View details for PubMedCentralID PMC7010227

• IgG1(+) B-cell immunity predates IgE responses in epicutaneous sensitization to foods ALLERGY Jimenez-Saiz, R., Ellenbogen, Y., Koenig, J. E., Gordon, M. E., Walker, T. D., Rosace, D., Spill, P., Bruton, K., Kong, J., Monteiro, K., Wen, J., Tuomanen, E. I., Kolbeck, R., Chu, D. K., Waserman, S., Jordana, M. 2019; 74 (1): 165-175

  Abstract

  The generation of IgE-mediated food allergy in humans is silent and only diagnosed upon manifestation of clinical symptoms. While experimental models have been used to investigate some mechanisms of allergic sensitization, the generation of humoral immunity and memory remains to be elucidated. Here, we defined the evolution of allergen-specific B-cell responses during epicutaneous sensitization to foods.Wild-type and genetic knockout animals, and drug or antibody strategies for cell depletion and immunoglobulin signaling blockade were used to investigate epicutaneous sensitization and disease progression; we analyzed allergen-specific germinal centers and IgG1+ memory B cells by flow cytometry, evaluated humoral responses, and determined clinical reactivity (anaphylaxis).Epicutaneous sensitization caused microscopic skin damage, inflammation, and recruitment of activated dendritic cells to the draining lymph nodes. This process generated allergen-specific IgG1+ germinal center B cells, serum IgG1, and anaphylaxis that was mediated by the alternative pathway. Whether we used peanut and/or ovalbumin from the egg white for sensitization, the allergen-specific IgG1+ memory compartment predominantly exhibited an immature, pro-germinal center phenotype (PDL-2- CD80- CD35+ CD73+ ). Subsequent subclinical exposures to the allergen induced IgE+ germinal center B cells, serum IgE, and likely activated the classical pathway of anaphylaxis.Our data demonstrate that IgG1+ B-cell immunity against food allergens in epicutaneous sensitization precedes the generation of IgE responses. Therefore, the assessment of allergen-specific cellular and humoral IgG1+ immunity may help to identify individuals at risk of developing IgE-mediated food allergy and hence provide a window for therapeutic interventions.

  View details for DOI 10.1111/all.13481

  View details for Web of Science ID 000459664100016

  View details for PubMedID 29790165

• The IgE memory reservoir in food allergy JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Jimenez-Saiz, R., Bruton, K., Koenig, J. E., Waserman, S., Jordana, M. 2018; 142 (5): 1441-1443

  View details for DOI 10.1016/j.jaci.2018.08.029

  View details for Web of Science ID 000449429800006

  View details for PubMedID 30201515