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Medical Journal Reviews

The International Eosinophil Society (IES) selects articles on a monthly basis for their importance to scientists and clinicians interested in the eosinophil. We welcome Medical Journal Review submissions from IES Members for consideration. Your review should be clear, compelling, and appeal to our international membership.

Click here to submit your review and download the submission guidelines here.

July 2024

EoE True Culprits: Beyond Eosinophils - Back to the Drawing Board

Article: Eosinophil Depletion with Benralizumab for Eosinophilic Esophagitis
Rothenberg ME, Dellon ES, Collins MH, Bredenoord AJ, Hirano I, Peterson KA, Brooks L, Caldwell JM, Fjällbrant H, Grindebacke H, Ho CN. New England Journal of Medicine. 2024 Jun 27;390(24):2252-63

Reviewed by Mario Ynga-Durand, MD, PhD, Cincinnati Children's Hospital Medical Center, Ohio, United States

Eosinophilic esophagitis (EoE) is a chronic, immune-mediated esophageal disease characterized by eosinophil accumulation, causing inflammation and difficulty swallowing. The recent MESSINA trial investigated benralizumab, an eosinophil-depleting anti-interleukin-5 receptor α monoclonal antibody, for treating EoE. This phase 3 trial included active EoE patients randomly assigned to receive either subcutaneous benralizumab or placebo. The primary goals were to observe histologic response (eosinophil reduction) and symptom relief measured by the Dysphagia Symptom Questionnaire (DSQ). Results were striking: 87.4% of the benralizumab group achieved near complete eosinophil depletion compared to only 6.5% in the placebo group (P<0.001). However, this success in reducing eosinophil counts did not translate into significant symptom relief, with DSQ scores showing no meaningful difference between the two groups. Importantly, few changes in the expression of genes associated with EoE were observed relative to baseline in the benralizumab group as compared with placebo, including CLC and CCR3, both highly expressed by eosinophils.

The MESSINA trial reveals a critical insight: eosinophils, traditionally blamed as the primary culprits in EoE might not be the main drivers of the disease. While benralizumab effectively reduces eosinophil counts the lack of symptom improvement suggests a more complex underlying pathophysiology. This discrepancy indicates that other cells and mechanisms are likely involved in EoE's progression and symptoms. This work should prompt us to rethink our definition and concept of EoE. What truly is the role of eosinophils? Should we redefine the disease itself based on transcriptional and clinical changes akin to atopic dermatitis? Should we refocus on the overarching nature of the dysregulation of esophageal immunity, including neuroimmune cross-talk and epithelial responses to cytokines? Furthermore, could eosinophils have a beneficial effect as remodelers or damage-controlling cells? Understanding the true drivers of EoE, and potentially redefining eosinophils' role within the broader context of immune regulation will be key to developing more effective treatments and ultimately improving the quality of life for those affected by this complex disease. This disease may also give us a glimpse into the real nature of allergy extending beyond traditional type 2 responses and pushing us back to the drawing board.

Mario Ynga-Durand, MD, PhD, is a Research Associate in the Rothenberg CURED Lab at Cincinnati Children's Hospital Medical Center and a Pew Charitable Trust Latin American Fellow in the Biomedical Sciences. He is a member of the Outreach & Diversity Committee of the International Eosinophil Society. After training as a pediatric immunologist in Mexico, he was engaged in the clinical care of patients with allergies before transitioning into biomedical research. Following his doctoral studies in viral immunology at the Helmholtz Center for Infection Research in Germany, Mario has focused his primary interest on understanding the immunologic determinants of the pathogenesis of eosinophilic esophagitis. Ultimately, his research aims to bring advanced research closer to clinical applications.

June 2024

Subsets of sputum eosinophils in asthma exacerbations

Article: Activated sputum eosinophils associated with exacerbations in children on mepolizumab
Gabriella E. Wilson, MD, James Knight, PhD, Qing Liu, MD, PhD, Ashish Shelar, PhD, Emma Stewart, BS, Xiaomei Wang, MD, et al.:
J Allergy Clin Immunol 2024

Reviewed by Jakub Novosad, MD, PhD, Institute of Clinical Immunology and Allergy, University Hospital, Hradec Kralove, Czech Republic

Despite extensive research, the mutual relationship between asthma and eosinophils is a complex and multifaceted topic that has yet to be fully understood. The current understanding of eosinophil biology suggests the existence of different functional subsets, each associated with distinct cytokine production and phenotype. This concept was first observed in the murine model of asthma by Abdala-Valencia in 2016 (Allergy 2016) and later confirmed in human asthma patients by Mesnil (J Clin Invest 2016). The model of regulatory (rEos) and inflammatory (iEos) eosinophils, with different expression of CD62L (CD62hi in rEos / CD62low in iEos), was proposed. This approach has been further explored in asthma patients treated with mepolizumab by Vultaggio (Allergy 2023). In the reviewed paper, Wilson et al. cross-sectionally analyzed sputum eosinophils in severe asthma children patients from a MUPPITS-2 study (n=53) (Jackson, The Lancet 2022), treated either by an ad on mepolizumab (n=22) or placebo (n=31) for 12 months. Induced sputum cells were analyzed using mass cytometry (CyTOF). The authors confirmed decreased sputum eosinophils in mepolizumab-treated patients (P=0.04). They also assessed a relative abundance of sputum eosinophils concerning a history of exacerbations (no exacerbation vs ≥1 exacerbation) and treatment arm. The authors observed no difference in the placebo arm; however, in mepolizumab-treated patients, the absence of exacerbations associated with lower relative counts of eosinophils (P=0.08). Moreover, clustering analysis identified three subpopulations of sputum eosinophils based on CD62L expression (CD62Llow, CD62Lint and CD62Lhi). CD62Lint and CD62Lhi eosinophils exhibited significantly elevated activation markers and eosinophil peroxidase expression, respectively and were more abundant in mepolizumab-treated patients with exacerbations. The authors suggest that these eosinophil subpopulations may contribute to asthma exacerbations despite mepolizumab treatment. The study's strengths include its well-defined patient subpopulations, thorough cytological analysis of induced sputum and multidimensional immune profiling using CyTOF analysis. The weakness is the relatively low study sample size and its cross-sectional design. The study raises new questions regarding the role of eosinophil subsets in asthma and its exacerbation pathogenesis. Surface CD62L expression is a promising way to differentiate between distinct subpopulations. However, the results are controversial. The elevated activation status of CD62Lhi eosinophils seems contradictory to previous findings (Johansson, Frontiers in Medicine 2017), necessitating further research.

Jakub Novosad, MD, PhD, is a clinical immunologist and allergologist at the Institute of Clinical Immunology and Allergy in the University Hospital in Hradec Kralove in the Czech Republic. He finished his PhD on the immunobiology of intracellular parasitism. He currently focuses on clinical and laboratory research on immunobiology and biomarkers of eosinophilic asthma, and he is particularly interested in the clinical outcomes of biological treatment. He is a member of the National Centre for Severe Asthma in the Czech Republic, the European Academy for Allergology and Clinical Immunology (EAACI), the International Eosinophil Society (IES), the Website / Social Media Committee, and the Website Content Subcommittee.

April 2024

Eosinophils potentiate anti-bacterial immunity

Article: Eosinophils promote CD8+ T cell memory generation to potentiate anti-bacterial immunity
Zhou, J., Liu, J., Wang, B. et al.
Signal Transduction and Targeted Therapy, Article No. 43, 28 Feb. 2024

Reviewed by Roopa Hebbandi Nanjundappa, MSc, PhD, Dalhousie University, Halifax, Canada

The generation of memory T cell responses against infections is considered a hallmark of protective immunity. The generation of CD8+ T cell memory relies on several factors including cytokine milieu in the microenvironment, initial CD4+ T cell responses, and the presence of macrophages (Cullen et al., 2019; Son et al., 2021; Lobby et al., 2022). The precise role of eosinophils in CD8+ T cell responses during infections has remained unclear. Therefore, a recent study by Zhou et al. aimed to elucidate the contribution of eosinophils to the generation of memory CD8+ T cell responses using an OVA-expressing Listeria monocytogenes (L.m) infection model via intraperitoneal injections. The study employed both in vitro culture techniques and a mouse model deficient in eosinophils (ΔdblGATA-1) to investigate the role of eosinophils in the generation of L.m-specific memory CD8+ T cells in spleen and mesenteric lymph nodes (MLNs). The findings revealed that eosinophils play a crucial role in enhancing the generation of CD8+ T cell memory to L.m infection, in the spleens but not in the MLNs, thereby providing resistance to reinfection in mice. Mechanistically, eosinophil-derived IL-4 was found to rescue L.m infection-induced JNK/Caspase-3 dependent apoptosis of CD8+ T cells, thus facilitating the establishment of immunological memory against bacterial infection. The involvement of IL-4 was confirmed through both in vitro culture assays and adoptive transfer experiments involving wildtype and IL-4 deficient eosinophils into ΔdblGATA-1 mice.

A major strength of the study lies in the authors' exploration of the previously undefined role of eosinophils in potentiating CD8+ T cell immunological memory in the context of L.m infection. Furthermore, this study opens up new questions: (1) Do transgenic IL-5 mice, which harbor increased eosinophil levels, show heightened CD8+ T cell immunological memory against L.m? (2) Does L.m. infection via oral routes induce similar memory in the gastrointestinal tract (GI), given that eosinophils are abundant in the GI tract lining? (3) Does a similar mechanism exist for other bacterial, viral, and fungal infections? (4) Are there any susceptibilities or compromises in patients receiving eosinophil-depleting therapies to secondary bacterial infections or responses to vaccinations?

Roopa Hebbandi Nanjundappa, MSc, PhD, is an AAI postdoctoral fellow at Dalhousie University. She earned her PhD in Immunology from the University of Calgary, where her research focused on understanding how a gut microbial molecular mimic of pancreatic beta-cell auto-antigen can protect the host from inflammatory bowel disease. Currently, she is investigating the roles of mast cells and eosinophils in Respiratory Syncytial Virus (RSV) infection under the mentorship of Dr. Jean Marshall.

Past Reviews

March 2024

Nourishing insights: diet-driven adaptation of eosinophils
Reviewed by Krishan Chhiba, MD, PhD, Northwestern University, Chicago, United States

February 2024

Eosinophils identified as a major contributor to bone homeostasis via eosinophil peroxidase activity
Reviewed by Nana-Fatima Haruna, PhD Candidate, Northwestern University, Chicago, United States

January 2024

Transcriptomic profiling of the acute mucosal response to local food injections in adults with eosinophilic esophagitis
Reviewed by Eva Gruden, Pharmacist, Medical University of Graz, Austria

December 2023

Bordetella spp. block eosinophil recruitment to suppress the generation of early mucosal protection
Reviewed by Rachael FitzPatrick, PhD Candidate, Reynolds Laboratory at the University of Victoria, Canada

October 2023

Neuromedin U programs eosinophils to promote mucosal immunity of the small intestine
Reviewed by Beth Jacobson, PhD with input from Marc Rothenberg, MD, PhD

Chronic HDM exposure shows time-of-day and sex-based differences in inflammatory response associated with lung circadian clock disruption
Reviewed by Julia Teppan, MSc.Ph.D.Student

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