Contributions of Eosinophils to Human Health and Disease

Abstract

The human eosinophil has long been thought to favorably influence innate mucosal immunity but at times has also been incriminated in disease pathophysiology. Research into eosinophil biology has uncovered a number of interesting contributions by eosinophils to health and disease. However, it appears that not all eosinophils from all species are created equal. It remains unclear, for example, exactly how having eosinophils benefits the human host when helminth infections in the developed world have become scarce. This review focuses on our current state of knowledge as it relates to human eosinophils. When information is lacking, we discuss lessons learned from mouse studies that may or may not directly apply to human biology and disease. It is an exciting time to be an "eosinophilosopher" because the use of biologic agents that selectively target eosinophils provides an unprecedented opportunity to define the contribution of this cell to eosinophil-associated human diseases.

Keywords: biologic agents; biomarkers; cytokines; eosinophil; eosinophil-related diseases; function; hematopoiesis; hypereosinophilic syndrome; phenotype; treatments.

Figure 1.

Development of the eosinophil lineage in the context of normal human hematopoiesis. In the current paradigm, hematopoietic stem cells (HSC) give rise directly to eosinophil/mast cell progenitors (EoMP), from which IL-5R⁺ eosinophil progenitors (EoPs) develop and terminally differentiate into mature eosinophils. EoMPs also differentiate into basophil progenitors (BaP) and mast cells. Expression of GATA-1 versus Flt3 distinguishes between early multipotent progenitors that give rise to EoMP and megakaryocyte/erythroid progenitors (MEP) versus common lymphoid progenitors (CLP) and neutrophil/macrophage progenitors (NMP) (formerly GMP). Both NMP and MEP arise from a common myeloid progenitor (CMP) distinct from the EoMP population.

Figure 2.

Surface molecules expressed on human eosinophils. There is some overlap among categories for some of these proteins. Common names for chemokine (CC and CXC) receptors, toll-like receptors (TLRs), and others are used here instead of the CD names because of the greater use and familiarity of the former among most readers. The asterisk indicates molecules expressed on activated eosinophils. Abbreviations used: CRTh2, chemoattractant receptor-homologous molecule expressed on Th2 cells; CysLT, cysteinyl leukotriene; EMR1, EGF-like module-containing mucin-like hormone receptor-like 1; fMLP; N-Formyl-methionyl-leucyl-phenylalanine; IFN, interferon; IL, interleukin; KIR2DL3, Killer Cell Immunoglobulin Like Receptor, Two Ig Domains And Long Cytoplasmic Tail 3; LIF, Leukemia inhibitory factor; LIR, Leukocyte immunoglobulin-like receptor; Mac-2, epsilon binding protein; NOD, nucleotide-binding oligomerization domain; OXE, Oxoeicosanoid; P2X and P2Y, ATP-gated purinoreceptors; PAF, platelet activating factor; LTB, leukotriene B; PAR, Protease activated receptor; PIR, paired Ig-like receptor; RAGE, receptor for advanced glycation end products; SCF, stem cell factor; Siglec, sialic acid-binding, immunoglobulin-like lectin; TLR, toll-like receptor; TNF, tumor necrosis factor; Trk, Tropomyosin-receptor-kinase; TSLP, Thymic stromal lymphopoietin. Updated from (143) with permission.

Figure 3.

Mechanisms involved in eosinophil extravasation during inflammation. Roles of adhesion molecules, chemoattractants and other molecules during the process of eosinophil migration from the circulation into tissues. Shown are the contributions of sets of leukocyte, endothelial, and tissue molecules during the steps of tethering, rolling, firm adhesion, transendothelial migration (diapedesis) and localization within tissues. Note that in addition to other adhesion molecules, PECAM-1 on both the leukocyte and the endothelium is uniquely involved in diapedesis.

Figure 4.

Examples of stimuli, drugs and intracellular molecules that enhance or reduce eosinophil survival. Abbreviations used: BAX, bcl-2-like protein 4; bcl-2, B-cell lymphoma 2; BCL2L, bcl-2-like protein; BIM, bcl-2-like protein 4; CDK, cyclin-dependent kinase; cIAP-2, cellular inhibitor of apoptosis 2; IFN, interferon; IL, interleukin; MCL1, myeloid cell leukemia 1; Siglec, sialic acid-binding, immunoglobulin-like lectin; TNF, tumor necrosis factor.

Figure 5.

Roles of eosinophils in normal tissue and metabolic homeostasis in health. Major functions of the eosinophilic leukocyte include the maintenance of tissue microenvironments during normal organismal development, along with the establishment and regulation of host innate and adaptive immune responses. Findings from mouse models that have yet to be confirmed in humans are denoted with “*”. Abbreviations used: ECM, extracellular matrix protein; M2 macrophage, an alternatively activated macrophage that arises in response to exposure to Th2-type cytokines Treg, T regulatory cells.

Figure 6.

Roles of eosinophils in disease pathogenesis. Contributions of eosinophils to complications of various diseases as separated by organ involvement that can occur independent of underlying disease pathogenesis.

Figure 7.

Histologic findings in EGID, EGPA and bullous pemphigoid. Panels a and b: hematoxylin and eosin stained section of a biopsy from a patient with eosinophilic esophagitis, at both lower and higher power magnification, showing increased intraepithelial eosinophils, epithelial spongiosis and basal cell hyperplasia; Panels c and d: hematoxylin and eosin stained section of a biopsy from a patient with eosinophilic gastritis, at both lower and higher power magnification, showing increased eosinophils in the gastric lamina propria; Panel e: hematoxylin and eosin stained section of a lung biopsy from a patient with EGPA showing a dense interstitial infiltrate rich in eosinophils, lymphocytes and plasma cells involving a vessel wall with focal fibrinous changes; Panel f: hematoxylin and eosin stained section of a skin biopsy from a patient with bullous pemphigoid showing a sub-epidermal blister with numerous eosinophils aligned along the cutaneous basement membrane zone. Also present is significant epidermal edema (spongiosis) with a few intraepithelial eosinophils.

Figure 8.

Bone marrow and cytopathologic findings in HES. Giemsa-stained bone marrow aspirate and hematoxylin and eosin-stained bone marrow biopsy from a patient with idiopathic hypereosinophilic syndrome (Panels a and b, respectively) and FIP1L1-PDGFRA positive myeloid neoplasm (Panels c and d, respectively); Panel e: an example of a dysplastic eosinophil seen on a peripheral blood smear from a patient with HES that was accidentally mis-identified as a neutrophil in an electronic differential blood count.