Eosinophils and Eosinophil Activation in the Pathogenesis of Human Disease

National Institute Of Allergy And Infectious Diseases

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Abstract

Using a cohort of more than 650 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 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). This is perhaps most evident in eosinophilic myeloid neoplasms, including those associated with FIP1L1::PDGFRA (Khoury et al. Allergy 2016). A major obstacle to early institution of targeted therapy is the insensitivity of commercially available diagnostic tests. Retrospective analysis of our cohort of patients with PDGFRA-associated myeloid neoplasms identified 39 patients with who had undergone commercial testing using fluorescence in situ hybridization (FISH) as well as testing using nested PCR at NIH (Pongdee et al. Acta Haematologica 2023). Eight of the 20 patients positive for FIP1L1::PDFGRA by PCR were negative by FISH, resulting in a significant delay in institution of imatinib therapy and adverse clinical outcomes. Targeted therapies not only provide new options for patients but provide insight into the effects of eosinophil depletion in humans and the mechanisms driving eosinophilia and eosinophil activation in HES. Ongoing studies include the use of tyrosine kinase inhibitors (imatinib and ruxolitinib) for the treatment of steroid-refractory HES, a single site study of mepolizumab for the treatment of episodic angioedema and eosinophilia, a multicenter phase 3 trial of benralizumab for HES, as well as long-term followup studies of HES patients enrolled on investigator-initiated trials of benralizumab and dexpramipexole. We have previously described the results of our single center phase 2 placebo-controlled study of benralizumab that demonstrated efficacy of this agent in patients with treatment-refractory PDGFRA-negative HES, including patients with gastrointestinal involvement (Kuang et al. N Engl J Med 2019; Kuang et al. J Allergy Clin Immunol Pract 2022). These results were instrumental in the initiation of an ongoing multicenter phase 3 study of benralizumab in HES and a recently published phase 2 study of benralizumab for eosinophilic gastritis (Kliewer et al. Lancet Gastroenterol Hepatol 2023). Whereas eosinophils were depleted in the blood and gastric tissue in most of the patients in this small placebo-controlled study, other histologic features and patient-reported symptoms were not significantly improved. Our group has recently begun to explore the roles of sex, race, and ethnicity on susceptibility to and diagnosis of varied eosinophilic disorders. PDGFR-associated myeloid neoplasms show an extreme male predominance (Klion et al. Blood 2003) despite the location of the genetic abnormality on chromosome 4. Since tumor suppressors on the X chromosome have been shown to influence sex predominance in other neoplastic disorders, we performed whole genome sequencing on eosinophils from 11 patients with PDGFR-associated myeloid neoplasms prior to imatinib therapy and on peripheral blood mononuclear cells from the same patients in durable remission to identify genetic features that might explain the extreme male predominance in this disorder (Rheinbay et al. Blood Advances 2023). Although no obvious genetic feature was identified, this study showed that PDGFR-rearranged HES has simple genomics that could explain the nearly universal sustained remission with imatinib therapy. We are also beginning to examine factors that contribute to apparent differences in the epidemiology of eosinophilic gastrointestinal disorders (Sabet et al. J Allergy Clin Immunol Pract 2021, Chehade et al. Therapeut Adv Rare Dis 2023). Historically, eosinophils have been viewed as effector cells with primary roles in the response to helminth infection and allergens. Consistent with this, recent 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. To address this issue, we initiated a collaboration with Dr. Katrin Mayer-Barber to examine the role of eosinophils in the host immune response to pulmonary infection with Mycobacterium tuberculosis (Mtb) and, more recently, SARS-CoV2. To date, our data has demonstrated that eosinophils are recruited to the lungs within the first few weeks of infection in a CCR3-independent, GPR183-dependent manner (Bohrer et al. Cell Rep 2022) and that these pulmonary eosinophils may play a key role in orchestrating the early pulmonary innate immune response after Mtb infection (Bohrer et al. J Exp Med 2021). Ongoing studies in murine models and in humans suggest that pulmonary eosinophilia is also a feature of COVID-19 infection but that recruitment occurs via a different mechanism.