Eosinophils and Eosinophil Activation in the Pathogenesis of Human Disease

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications & trials

Abstract

Using a cohort of more than 750 subjects with a wide variety of eosinophilic disorders, ranging from benign eosinophilia to eosinophilic leukemia, we have continued to identify and characterize novel subgroups of patients with eosinophilia and to explore responses to targeted therapies with the goal of increasing our understanding of the role of eosinophils in homeostasis and disease pathogenesis. We have also continued our collaborative studies examining the role of eosinophils in the immune response to microbial infections, including M. tuberculosis and Helicobacter pylori, and the role of eosinophils in the clinical manifestations of COVID-19. As the number of therapeutic agents that affect eosinophils, eosinophil migration and eosinophil activation increase, it is becoming increasingly important to understand the mechanisms driving eosinophilia and eosinophil activation in patients presenting with hypereosinophilic syndromes. We have previously shown that the clinical subtype of HES is an important predictor of response to conventional and targeted therapies (Kuang et al. J Allergy Clin Immunol Pract 2018; Khoury et al. J Allergy Clin Immunol Pract 2018). In this regard, lymphocytic variant HES (LHES), a rare disorder characterized by the presence of phenotypically aberrant populations of CD4+ Th2 lymphocytes, has consistently proven to be relatively treatment-refractory as compared to idiopathic and overlap forms of HES. Using multiparameter flow cytometry to analyze lymphocytes in whole blood and stored peripheral blood mononuclear cells from a cohort of 42 untreated and treated patients with LHES, we confirmed prior data demonstrating that the aberrant CD4+ T cell populations in LHES have a Th2 memory phenotype and demonstrated that the tissue homing receptor CCR8 is a dominant surface marker on these cells. Moreover, expanded populations of Foxp3+Helios+CCR8+ regulatory T cells were identified in many patients which correlated with the size of the aberrant T cell population. These data provide further evidence for direct involvement of the aberrant T cell populations in disease pathogenesis in LHES and a rationale for further exploration of T cell-directed therapies (Anderson et al. J Allergy Clin Immunol 2025). The importance of non-eosinophil mechanisms in LHES was highlighted by the increased rate of relapse in these patients on a phase 2 study of benralizumab in HES (Kuang et al. J Allergy Clin Immunol Pract 2025). Our group has a long-standing interest in treatment-refractory hypereosinophilic syndromes. Targeted therapeutics not only provide potentially less toxic, more effective treatment options but contribute to our understanding of underlying pathogenesis. This is perhaps most clearly demonstrated by early studies of imatinib in HES (Klion et al. Blood 2003), which led to the discovery of the FIP1L1::PDGFRA fusion gene and a phase 2 study of benralizumab which showed safety and efficacy in treatment-refractory HES for up to 10 years (Kuang et al. N Engl J Med 2019; Kuang et al. J Allergy Clin Immunol Pract 2025). The latter prompted the initiation of a recently completed multicenter phase 3 study of benralizumab in HES. More recently, we have begun to explore the effects of dupilumab, a monoclonal antibody that blocks the IL-4 receptor, in treatment refractory hypereosinophilic syndromes. Whereas dupilumab has been shown to reduce tissue eosinophilia by inhibiting eotaxin-mediated chemotaxis, this can lead to increased peripheral eosinophilia and rare eosinophilic complications (Wechsler et al. J Allergy Clin Immunol Pract 2022) that may be accentuated in patients with a history of hypereosinophilia (Ezekwe et al. J Allergy Clin Immunol Pract 2025). Ongoing studies of targeted therapies in HES include the use of tyrosine kinase inhibitors (imatinib and ruxolitinib) for the treatment of steroid-refractory HES, a multicenter phase 3 trial of benralizumab for HES, and a new trial exploring the use of dupilumab as add-on therapy for patients with HES in hematologic remission on an eosinophil-lowering biologic but with persistent symptoms. Historically, eosinophils have been viewed as effector cells with primary roles in the response to helminth infection and allergens. Consistent with this, prior studies in our group have focused on the role of eosinophils and eosinophil activation in the clinical manifestations and post-treatment reactions in filariasis (Herrick et al. Clin Infect Dis 2020; Legrand et al. Clin Infect Dis 2017; Legrand et al. Clin Infect Dis 2021). Over the past decade, however, there has been increasing interest in the role of eosinophils in the modulation of responses to non-helminth pathogens. As part of a collaboration with Dr. Katrin Mayer-Barber, we have demonstrated that eosinophils are among the earliest circulating cells to sense and respond to Mtb infection of alveolar macrophages. In contrast to CCR3-mediated recruitment to the lung in allergic pulmonary disease and COVID-19 infection, eosinophil recruitment to the lung in a murine model of Mtb infection was dependent on GPR183 (Bohrer et al. Cell Rep 2022). Current studies include two recently initiated clinical protocols that will examine the interaction between gastric eosinophils and Helicobacter pylori infection.