Localized Eosinophil Degranulation Mediates Disease in Tropical Pulmonary Eosinophilia

Abstract

To explore the mechanisms underlying the eosinophil-mediated inflammation of tropical pulmonary eosinophilia (TPE), bronchoalveolar lavage (BAL) fluid, serum, and supernatants from pulmonary and blood leukocytes (WBC) from patients with acute TPE (n ‫؍‬ 6) were compared with those obtained from healthy uninfected individuals (n ‫؍‬ 4) and from patients with asthma (n ‫؍‬ 4) or elephantiasis (n ‫؍‬ 5). Although there were no significant differences in the levels of interleukin-4 (IL-4), IL-5, IL-13, eotaxin, granulocyte-macrophage colony-stimulating factor, RANTES, or eosinophil cationic protein, there was a marked increase in eosinophil-derived neurotoxin (EDN) both systemically and in the lungs of individuals with TPE compared to each of the control groups (P < 0.02). Moreover, there was a compartmentalization of this response, with EDN levels being higher in the BAL fluid than in the serum (P < 0.02). Supernatants from WBC from either whole blood or BAL cells were examined for chemokines, cytokines, eosinophil degranulation products, and arachidonic acid metabolites. Of the many mediators examined-particularly those associated with eosinophil trafficking-only EDN (in BAL fluid and WBC) and MIP-1␣ (in WBC) levels were higher for TPE patients than for the non-TPE control groups (P < 0.02). These data suggest it is the eosinophilic granular protein EDN, an RNase capable of damaging the lung epithelium, that plays the most important role in the pathogenesis of TPE.Tropical pulmonary eosinophilia (TPE), an unusual manifestation of human lymphatic filarial infection, is characterized by an eosinophilic pulmonary inflammatory infiltrate and marked elevations of immunoglobulin E (IgE) and circulating eosinophils in the serum, all felt to be mediated by immunologic hyperreactivity to filarial parasites or their antigens. Although 129 million people worldwide are infected with lymphatic filariasis, Ͻ0.01% develop TPE (20). It is unclear what factors predispose patients to the rare, localized, and profound immune dysregulation associated with TPE.

Allergic Sensitization Underlies Hyperreactive Antigen-Specific CD4+ T Cell Responses in Coincident Filarial Infection

“…In contrast, this marked increase in the Th2-associated IgE levels and eosinophilia driven by filarial antigens in Fil + A + patients has also been implicated in the pathogenesis of some syndromes associated with filarial infections (67–70) including tropical pulmonary eosinophilia (TPE) (68, 71, 72) and the localized hyperreactive dermatitis (sowda) seen in Onchocerca volvulus -infected patients (73–75). Finally, given that IL-10-mediated modulation of Th1/Th2/Th17/Th9 responses (76) has been associated with clinically asymptomatic filarial infection, it is possible that allergic sensitization coincident with these filarial infections results in altering the balance of regulatory and effector responses that could in turn alter the longevity of the parasites in their human hosts.…”

Eosinophilic Pneumonias

“…These are then ingested by mosquitos taking blood meals, followed by subsequent maturation to thirdstage larvae, completing the life cycle of the organism (126). The pathogenesis of TFPE has not been clarified fully, but a strong eosinophilic immunologic response to microfilariae trapped in the lungs likely plays a pivotal role (129,145,202). Interestingly, only a small percentage of patients affected with lymphatic filariasis develop pulmonary manifestations, and there is a strong male predominance in developing TFPE (126,207).…”

Tropical Pulmonary Eosinophilia: A Case Series in a Setting of Nonendemicity

“…These cases further underscore the necessity of early intervention, because chronic TPE may result in permanent, irreversible deficits in pulmonary function, despite treatment with diethylcarbamazine [14]. In fact, it has recently been shown that pulmonary eosinophils in TPE degranulate and release toxic oxygen radicals long after treatment with diethylcarbamazine [19], increasing damage initiated during the acute stages of disease. When TPE is recognized and treated early, patients often have a dramatic and rapid response to diethylcarbamazine.…”