Eosinophilia (see text box
), defined as a peripheral blood eosinophil count greater than 450 cells per microliter, is associated with numerous disorders including allergies, drug reactions, helminth infections, Churg-Strauss syndrome [glossary], some malignancies and metabolic disorders, eosinophilic gastrointestinal disorders, and hypereosinophilic syndrome. Eosinophils are bone marrow-derived leukocytes that are normally less than 5% of leukocytes in the blood, but can be found in higher numbers in tissues such as the bone marrow and gastrointestinal. Recruitment of activated eosinophils from the bloodstream into tissues can occur under a variety of conditions and lead to the release of preformed and newly synthesized products, including cytokines, chemokines, lipid mediators and cytotoxic granule proteins, that can initiate, quickly escalate and sustain local inflammatory and remodeling responses.
Text Box- Blood and Tissue Eosinophilia
Eosinophilia, more than normal numbers of eosinophils, can be found in both the peripheral blood and/or tissues in a variety of disorders, including helminthic parasite infections, atopic and allergic diseases, and adverse drug reactions163,168–170
. In the peripheral blood, eosinophilia can be characterized as mild (450–1500 eosinophils per microliter), moderate (1500–5000 eosinophils per microliter) or severe (greater than 5000 eosinophils per microliter). Hypereosinophilia refers to blood eosinophils level greater than 1500 eosinophils per microliter. In general, blood eosinophilia results from enhanced eosinophilopoiesis (i.e. increased production of eosinophils in the bone marrow). Peripheral blood eosinophilia can be further categorized as primary, secondary and idiopathic. Primary eosinophilia usually occurs in the context of hematologic malignancies and proliferative disorders that result in increased numbers of progenitors leading to increased numbers of eosinophils in the bone marrow and blood. Secondary eosinophilia is the most common form of eosinophilia and often occurs in response to other primary disease processes such as overproduction of the cytokine IL-5 (often by T-cell lymphocytes) leading to elevated production of eosinophils. Idiopathic eosinophilia is often associated with moderate to severe eosinophilia with no identifiable cause.
In a healthy individual, tissue eosinophils normally can be found primarily in the bone marrow and gastrointestinal tract, but can also be found in smaller numbers in the thymus. The number of eosinophils that normally reside in tissues can vary dramatically, even within the same organ system. For instance, in a healthy gastrointestinal tract eosinophils can be found in increasing numbers from the stomach to the colon, but no eosinophils are present in the normal esophagus. Tissue eosinophilia usually results from increased recruitment of activated eosinophils from the bloodstream. Once recruited into the tissues, activated eosinophils have the capability to cause tissue damage and dysfunction. Tissue eosinophilia does not always correlate with blood eosinophilia. Blood eosinophil numbers can be normal, but increased migration of activated eosinophils from the blood results in significantly increased eosinophil numbers in organs, as is found in patients with eosinophilic esophagitis and eosinophilic pneumonias. In contrast, blood eosinophilia can occur without any evidence of increased tissue eosinophilia likely due to the absence of activating signals in the blood stream.
Eosinophil-rich inflammation has long been associated with parasitic infestation and allergic inflammation. A body of evidence including clinical studies and animal models of asthma has demonstrated a causal role for eosinophils in asthma pathogenesis including airway hyper-reactivity, elevated mucus production and airway remodeling. These studies include elegant experiments in eosinophil-lineage-deficient mice that have protection against features of asthma, although not in all cases1,2
. Clinical studies have revealed an important role for eosinophils in asthma exacerbations3,4
. Recent evidence also supports a broader role for eosinophils in health and disease with their emerging role in malignancy and in regulating antibody production5,6
. In addition, eosinophils can frequently be found surrounding solid tumors6,7
and can participate in tumor immune surveillance influencing the incidence of tumor formation8,9
. Recent studies have proposed a role for eosinophils in humoral immunity as an important source of pro-survival factors for long-lived plasma cells in the bone marrow10,11
. In autoimmune disease in which plasma cells have a pathologic role via autoantibody production, eosinophils may prove to be an attractive therapeutic target. Thus, treatments that specifically target eosinophils are likely to be effective in controlling a number of important and prevalent diseases in the fields of allergy, infectious disease, autoimmunity and malignancy. The increasing incidence of eosinophil-associated disorders, including eosinophilic gastrointestinal disorders and asthma, in high income and low income countries highlights the important and expanding need for eosinophil-targeted therapies12,13
There have traditionally been two major approaches to drug development for eosinophilic diseases: blocking recruitment of eosinophils into organs and impairing the survival of mature eosinophils. As discussed below, innovative new strategies for future drug development include blocking eosinophil production in the bone marrow and inhibiting eosinophil activation.