Eosinophil Knockout Humans: Uncovering the Role of Eosinophils Through Eosinophil-Directed Biological Therapies

Abstract

The enigmatic eosinophil has emerged as an exciting component of the immune system, involved in a plethora of homeostatic and inflammatory responses. Substantial progress has been achieved through experimental systems manipulating eosinophils in vivo, initially in mice and more recently in humans. Eosinophil knockout mice have identified a contributory role for eosinophils in basal and inflammatory processes and protective immunity. Primarily fueled by the purported proinflammatory role of eosinophils in eosinophil-associated diseases, a series of anti-eosinophil therapeutics have emerged as a new class of drugs. These agents, which dramatically deplete eosinophils, provide a valuable opportunity to characterize the consequences of eosinophil knockout humans. Herein, we comparatively describe mouse and human eosinophil knockouts. We put forth the view that human eosinophils negatively contribute to a variety of diseases and, unlike mouse eosinophils, do not yet have an identified role in physiological health; thus, clarifying all roles of eosinophils remains an ongoing pursuit. Expected final online publication date for the Annual Review of Immunology, Volume 39 is April 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Eosinophils and Chronic Respiratory Diseases in Hospitalized COVID-19 Patients

“…Eosinophils recognize and react against viruses through indirect mechanisms such as pattern recognition receptors (toll-like receptors, nucleotide-binding oligomerization domain-like receptors, and he receptor for advanced glycation end products), high mobility group box 1 (HMGB1) receptor expression, and participation in antigen presentation, and through direct mechanisms such as the release of preformed eosinophil-derived neurotoxin and eosinophil cationic protein and extracellular traps ( 14 ). Dysregulation of eosinophils contributes to many eosinophil-associated diseases as idiopathic hypereosinophilic syndrome, severe eosinophilic asthma, chronic rhinosinusitis with nasal polyposis (CRSwNP), eosinophilic esophagitis, eosinophilic granulomatosis with polyangiitis, bullous pemphigoid, and atopic dermatitis ( 15 ). Under certain conditions, eosinophils migrate to target tissues such as the respiratory tract, where the presence of degranulated eosinophils in lung tissue is associated with the pathogenesis of bronchial smooth muscle hyperreactivity ( 16 ).…”

Initiation and Pathogenesis of Severe Asthma with Fungal Sensitization

“…While SAFS is generally nonresponsive to corticosteroids, the advent of anti-eosinophilic biologics has led to better management of asthma severity in SAFS patients [169]. The knowledge that eosinophils play a host-protective role during virus infections [142,170], including IAV infections [91,141,171] and possibly SARS-CoV-2 infection [172], raises the question of whether fungal allergen-induced eosinophilia has some benefit, at least seasonally, and if so, what the possible long-term complications may be of eliminating eosinophils in SAFS patients [173]. Much remains to be discovered on the immune pathogenesis of fungal allergies and the consequences of fungal allergic disease on immune responses to subsequent or concomitant infectious stimuli.…”

Eosinophils and eosinophil-associated disorders: immunological, clinical, and molecular complexity

“…Eosinophils express a unique composition of cell surface receptors relevant to adhesion, homing, and migration in tissues [ 4 , 5 , 59 – 69 ]. Some of these receptors contribute to the transmigration of eosinophils across endothelial monolayers and thus to the homing of eosinophils and their precursor cells in tissues, which is critical for the development of tissue HE found in patients with HE-related organ damage.…”

“…Eosinophils produce an array of proinflammatory mediators and cytokines, including interleukins, chemokines, and other compounds [ 1 – 5 , 81 – 85 ]. Several of these molecules, such as the chemokines, can recruit and/or activate leukocytes in affected organ sites.…”

“…During the past decades, our knowledge on eosinophils, their products, eosinophil-rich neoplasms, and the mechanisms underlying HE and HES-specific organ damage has improved considerably [ 5 – 19 ]. Moreover, a number of proposals for the classification of HE, HES, and related syndromes have been published [ 7 – 11 , 14 – 19 ].…”