Eosinophils and helminth infection: protective or pathogenic?

Since the earliest descriptions of this enigmatic cell, eosinophils have been implicated in both protective and pathogenic immune responses to helminth infection. Nevertheless, despite substantial data from in vitro studies, human infections, and animal models, their precise role in helminth infection remains incompletely understood. This is due to a number of factors, including the heterogeneity of the many parasites included in the designation "helminth," the complexity and redundancy in the host immune response to helminths, and the pleiotropic functions of eosinophils themselves. This review examines the consequences of helminth-associated eosinophilia in the context of protective immunity, pathogenesis, and immunoregulation.

Dysregulation of interleukin 5 expression in familial eosinophilia.

BACKGROUND: Familial eosinophilia (FE) is a rare autosomal dominant inherited disorder characterized by the presence of lifelong peripheral eosinophilia (>1500/µL). Mapped to chromosome 5q31-q33, the genetic cause of FE is unknown, and prior studies have failed to demonstrate a primary abnormality in the eosinophil lineage. OBJECTIVE: The aim of this study was to identify the cells driving the eosinophilia in FE. METHODS: Microarray analysis and real-time PCR were used to examine transcriptional differences in peripheral blood mononuclear cells (PBMC), and in purified cell subsets from affected and unaffected family members belonging to a single large kindred. Cytokine levels in serum and PBMC culture supernatants were assessed by suspension array multiplexed immunoassays. RESULTS: Whereas IL-5 mRNA expression was significantly increased in freshly isolated PBMC from affected family members, this was not accompanied by increased mRNA expression of other Th2 cytokines (IL-4 or IL-13). Serum levels of IL-5 and IL-5 receptor α, but not IgE, were similarly increased in affected family members. Of note, IL-5 mRNA expression was significantly increased in purified CD3+ CD4+, CD14+, CD19+, and ILC2 cells from affected family members, as were IL-5 protein levels in supernatants from both stimulated PBMC and ILC2 cultures. CONCLUSIONS: These data are consistent with the hypothesis that the eosinophilia in FE is secondary to dysregulation of IL-5 production in PBMC (and their component subsets).

Clinical features predict responsiveness to imatinib in platelet-derived growth factor receptor-alpha-negative hypereosinophilic syndrome.

BACKGROUND: With the exception of the presence of the FIP1L1-PDGFRA fusion gene, little is known about predictors of imatinib response in clinically-defined hypereosinophilic syndrome (HES). METHODS: Subjects with FIP1L1-PDGFRA-myeloid neoplasm (FP; n =12), PDGFRA-negative HES with ≥4 criteria suggestive of a myeloid neoplasm (MHES; n =10), or steroid-refractory PDGFRA-negative HES with <4 myeloid criteria (SR; n = 5) were enrolled in a prospective study of imatinib therapy (NCT00044304: registered at clinicaltrials.gov). The primary outcome was an eosinophil count <1.5 × 109/L at one month and improvement of clinical symptoms. Clinical, molecular, and bone marrow responses to imatinib were assessed. A retrospective cohort of 18 subjects with clinically-defined HES who received imatinib (300-400 mg daily ≥ 1 month) were classified according to the criteria used in the prospective study. RESULTS: Overall, imatinib response rates were 100% in the FP group (n = 16), 54% in the MHES group (n = 13) and 0% in the SR group (n = 16). The presence of ≥ 4 myeloid features was the sole predictor of response. After ≥ 18 months in complete remission, imatinib was tapered and discontinued in 8 FP and 1 MHES subjects. Seven subjects (6 FP, 1 MHES) remain in remission off therapy for a median of 29 months (range 14-36). CONCLUSIONS: Clinical features of MHES predict imatinib response in PDGFRA-negative HES.

The consequences of not having eosinophils.

Several lines of evidence suggest that deficiency of eosinophils is not associated with any characteristic abnormality. Patients lacking eosinophils, in the setting of immunodeficiency or as a consequence of IgG-mediated eosinophil precursor destruction, do not display any distinguishing abnormalities related to eosinophil reduction. The observation that eosinophil-deficient mice do not display any distinctive syndrome or failure of their health is evidence that, under ordinary laboratory conditions, the eosinophil does not play a critical role in the well-being of mammals. Observations that monoclonal antibodies to interleukin-5 (IL-5) are well tolerated appear unsurprising in light of these findings. For example, patients with the hypereosinophilic syndrome have received mepolizumab, an anti-IL-5 monoclonal antibody, for as long as 6 years and have not developed any characteristic set of adverse events. Safety data for reslizumab, another anti-IL-5 monoclonal antibody, and benralizumab, a monoclonal antibody to the IL-5 receptor α-chain, are comparatively limited, especially for benralizumab, although reports of administration of these antibodies to humans suggest that they are well tolerated. Thus, data to the present suggest that reduction of eosinophils appears to have no characteristic ill effects on normal health, and monoclonal antibodies that deplete eosinophils have the potential to be widely employed in the treatment of eosinophil-associated diseases.

Serum biomarkers are similar in Churg-Strauss syndrome and hypereosinophilic syndrome.

RATIONALE: Churg-Strauss syndrome (CSS) and hypereosinophilic syndrome (HES) overlap considerably in clinical presentation. A reliable means of distinguishing between these groups of patients is needed, especially in the setting of glucocorticoid therapy. METHODS: A retrospective chart review of 276 adult subjects referred for evaluation of eosinophilia > 1500/µl was performed, and subjects with a documented secondary cause of eosinophilia or a PDGFR -positive myeloproliferative neoplasm were excluded. The remaining subjects were assessed for the presence of American College of Rheumatology (ACR) criteria. Laboratory and clinical parameters were compared between subjects with biopsy-proven vasculitis (CSS; n = 8), ≥4 ACR criteria (probable CSS; n = 21), HES with asthma and/or sinusitis without other CSS-defining criteria (HESwAS; n = 20), HES without asthma or sinusitis (HES; n = 18), and normal controls (n = 8). Serum biomarkers reported to be associated with CSS were measured using standard techniques. RESULTS: There were no differences between the subjects with definite or probable CSS or HES with respect to age, gender, or maintenance steroid dose. Serum CCL17, IL-8, and eotaxin levels were significantly increased in eosinophilic subjects as compared to normal controls, but were similar between the eosinophilic groups. Serum CCL17 correlated with eosinophil count (P < 0.0001, r = 0.73), but not with prednisone dose. CONCLUSIONS: In patients with a history of asthma and sinusitis, distinguishing between ANCA-negative CSS and PDGFR-negative HES is difficult because of significant overlap in clinical presentation and biomarker profiles.

CD2 identifies a monocyte subpopulation with immunoglobulin E-dependent, high-level expression of Fc epsilon RI.

BACKGROUND: Fc epsilon RI expression by monocytes can affect monocyte function via multiple mechanisms, thereby potentially influencing the generation of allergic inflammation. Previous studies on the in vivo regulation of monocyte Fc epsilon RI expression by ambient IgE have yielded conflicting results. OBJECTIVE: We hypothesized that monocyte Fc epsilon RI expression is limited to a specific monocyte subset, and that within that subset Fc epsilon RI surface expression is correlated to serum IgE. METHODS: Study 1: Blood was obtained from non-allergic subjects (n=14) and subjects with allergic asthma (n=18), hypereosinophilic syndrome (n=2), hyper-IgE syndrome (n=6), and helminth infection (n=4). Study 2: Blood was obtained from allergic subjects in a clinical trial of omalizumab before and during study drug treatment. Monocyte surface Fc epsilon RI expression was measured using flow cytometry. RESULTS: Fc epsilon RI expression was significantly greater in the CD2(high) vs. CD2(low) monocyte subsets (31% vs. 1.9% median Fc epsilon RI+, respectively). In asthmatic and non-atopic healthy control subjects, CD2(low) monocytes expressed little or undetectable Fc epsilon RI. In study 1, Fc epsilon RI expression was highly correlated to serum IgE in the CD2(high), but not in the CD2(low) monocyte subpopulation (R values of 0.67 and 0.41, respectively). In study 2, omalizumab, but not placebo, caused a significant and sustained decline in Fc epsilon RI expression within the CD2(high) monocyte subset. CONCLUSIONS: CD2 defines a monocyte subset with high Fc epsilon RI expression, whose magnitude is highly correlated to serum IgE. As such, this new description of CD2(high) monocytes as Fc epsilon RI-bearing cells suggests that they may be potential targets of anti-IgE immunomodulatory therapies.

Platelet-derived growth factor receptor-alpha-associated hypereosinophilic syndrome and lymphomatoid papulosis.

Fip1-like 1/platelet-derived growth factor receptor-alpha (FIP1L1/PDGFRA)-positive hypereosinophilic syndrome is a rare disorder with a poor prognosis if untreated and for which treatment with imatinib mesilate is highly effective. A 33-year-old man presented with recurrent papular skin lesions and marked peripheral eosinophilia. Skin biopsy revealed proliferation of CD30(+) T cells consistent with lymphomatoid papulosis (LyP), whereas molecular analysis of peripheral blood mononuclear cells demonstrated the presence of the FIP1L1/PDGFRA fusion gene. As the presence of this gene has important prognostic and therapeutic implications, this report underscores the importance of molecular testing in the evaluation of patients with LyP and peripheral eosinophilia.

"Pseudo-conduction block" in a patient with vasculitic neuropathy.

A 63-year-old man presented with progressive asymmetric weakness and numbness in his hands of 2 weeks duration. Nerve conduction studies showed low amplitude motor evoked potentials of both median nerves. The right ulnar, left tibial and peroneal nerves had normal potentials on distal stimulation with markedly decreased amplitudes proximally, suggestive of "conduction block". Three weeks later, amplitudes were decreased throughout. The patient was diagnosed with vasculitis. The acute ischemic injury presumably resulted in axonal damage between the distal and proximal stimulation sites, with subsequent Wallerian degeneration.

Onchocerciasis in a nonendemic population: clinical and immunologic assessment before treatment and at the time of presumed cure.

Although suppressive therapy for onchocerciasis with intermittent ivermectin prevents the development of pathology in endemic populations, the clinical and immunologic effects of therapy in the absence of continued exposure are unknown. To address this question, 14 patients treated with ivermectin for onchocerciasis acquired >10 years ago during temporary residence in Africa were reevaluated. None had evidence of continued infection or pathology at follow-up. Although eosinophilia, serum IgE, and antifilarial antibody levels decreased after ivermectin therapy, none of these parameters was useful in predicting the resolution of symptoms in infected patients. Peripheral blood mononuclear cells isolated from patients at follow-up were more responsive to parasite antigen in vitro, which is as assessed by proliferation and production of interferon-gamma and interleukin (IL)-5. In contrast, antigen-induced levels of IL-10 were significantly decreased at follow-up, consistent with diminished down-regulatory factors rather than a switch from type 2 to type 1 immune responses.

The relationship between serum IgE and surface levels of FcepsilonR on human leukocytes in various diseases: correlation of expression with FcepsilonRI on basophils but not on monocytes or eosinophils.

BACKGROUND: Expression of receptors for IgE (FcepsilonR) have been mainly studied on mast cells and blood basophils in the context of allergic disease. Some reports have noted limited expression of FcepsilonR on other leukocytes, including blood monocytes and eosinophils in certain patients. An association between human blood basophil expression of FcepsilonRIalpha and serum IgE has been noted among allergic subjects. OBJECTIVE: Recent evidence supports regulation of FcepsilonRIalpha by free IgE on both mast cells and basophils. We hypothesized that this relationship would exist across an extremely wide range of IgE levels for human basophils, irrespective of underlying disease. We further examined whether a similar relationship existed between serum IgE and FcepsilonRIalpha or FcepsilonRII (CD23) expression on monocytes and eosinophils in these same subjects. METHODS: Blood was obtained from nonallergic subjects (n = 3) and subjects with allergic asthma (n = 5), atopic dermatitis (n = 3), hypereosinophilic syndromes (n = 7), hyper-IgE syndrome (n = 6), helminth infestation (n = 6), or IgE myeloma (n = 1). Levels of serum IgE were determined by using RIA and ranged from 3 to 4.7 mg/mL. Levels of cell surface FcepsilonRIalpha, FcepsilonRII, and IgE were measured by using immunofluorescence and flow cytometry. RESULTS: Basophil surface IgE density and FcepsilonRIalpha expression correlated with serum IgE levels (r = 0. 67 and r = 0.46, respectively; P <.01; n = 31) regardless of the disease state. In contrast, monocyte FcepsilonRIalpha expression did not correlate with serum IgE (r = 0.09, P >.5, n = 29), and low-level eosinophil FcepsilonRIalpha expression was only detected in a single asthmatic subject. CD23 expression was not detected on basophils or eosinophils, except for the eosinophils from the donor with IgE myeloma. CD23 was present on monocytes from some donors but did not correlate with serum IgE levels. CONCLUSIONS: In a variety of disease states, FcepsilonRIalpha expression by basophils, but not monocytes or eosinophils, correlated with serum IgE levels across a 6-log range of IgE. These data support the concept of in vivo regulation of FcepsilonRIalpha on basophils by serum IgE and further demonstrate that this is independent of allergic disease per se.

Albendazole therapy for loiasis refractory to diethylcarbamazine treatment.

Although diethylcarbamazine is curative in approximately 60% of patients who acquire loiasis as long-term visitors to an endemic area, some individuals continue to have signs and symptoms of infection despite multiple courses of diethylcarbamazine. On the basis of a study of albendazole treatment of loiasis in microfilaremic patients that suggested a macrofilaricidal effect of the drug, we treated three patients who had symptomatic loiasis refractory to more than four courses of diethylcarbamazine with albendazole. At the time of treatment, all patients had persistent symptoms despite decreasing titers of antifilarial antibodies and normal eosinophil counts. Symptoms resolved in all three patients following albendazole therapy. In one patient, nonspecific symptoms recurred 2 years later, but unlike her symptoms before albendazole therapy, they were not accompanied by the appearance of subcutaneous nodules containing adult worms. The other two patients have been symptom-free in the 8 years after albendazole treatment. In summary, albendazole may be useful for the treatment of loiasis when diethylcarbamazine is ineffective or cannot be used.

Lymphatic filariasis in a hyperendemic region: a ten-year, follow-up panel survey.

The present study is a long-term panel survey of a population living in a previously identified Wuchereria bancrofti-endemic area of Benin. Unexpectedly, a marked decrease in the prevalence of microfilaremia (from 9.4% to 0.48%; P < 0.001) occurred over a 10-year period in the absence of chemotherapy or vector control measures. The percentage of patients with chronic pathology remained stable during the study period. The decrease in the prevalence of parasitemia could not be explained by environmental or sociologic changes in the region, or by differences between the two study populations. These data suggest that the epidemiology of lymphatic filariasis in an endemic region may change independently of recognized modulating factors.

OvGalBP, a filarial antigen with homology to vertebrate galactoside-binding proteins.

The increased incidence of "allergic" symptomatology and clinical complications seen in non-endemic individuals with loiasis, as compared to natives of endemic areas, is thought to reflect a heightened immune response to filarial antigens. To identify antigens involved in this hyperresponsiveness, a cDNA library constructed from adult female RNA from the related filarial parasite, Onchocerca volvulus, was screened with serum from a North American who acquired loiasis in West Africa. Sequence analysis of one of the identified clones, OvGalBP, revealed significant homology to the vertebrate S-type lectins, a family of thiol-dependent, metal-independent galactoside binding lectins, which includes an IgE-binding protein thought to be involved in IgE regulation. The 1100-bp insert of OvGalBP contains the entire protein coding region and has a 3' poly(A) tail. The two amino acid consensus sequences (WGxExR and HFNPRF) found in all of the S-type lectins are present. Purified recombinant protein expressed as a fusion with glutathione-S-transferase (OvGalBP-GST) was recognized by sera from a majority of filaria-infected patients but not by putatively immune individuals from an endemic area or by unexposed endemic and non-endemic controls. Interestingly, OvGalBP-GST specifically bound IgE (and not IgG) in a lactose-inhibitable manner, suggesting a potential role for this protein in the pathophysiology of human filarial infection.

Ceftazidime-related nonconvulsive status epilepticus.

The third-generation cephalosporin, ceftazidime, is widely used for the treatment of serious gram-negative infections. As is true of cephalosporins in general, reported adverse effects have been few. We report a case of ceftazidime-induced status epilepticus in a patient with Pseudomonas aeruginosa meningitis and compare the clinical manifestations of this case with those of two previously described cases of ceftazidime-related encephalopathy. This diagnosis should be entertained and an electroencephalogram should be obtained in all patients with myoclonus and/or altered mental status while they are receiving ceftazidime therapy.

Effectiveness of diethylcarbamazine in treating loiasis acquired by expatriate visitors to endemic regions: long-term follow-up.

Although successful treatment of loiasis with diethylcarbamazine (DEC) has been reported, little is known about the long-term success rate of therapy or the predisposing factors for treatment failure. To address these questions, 32 patients were followed 2-15 years (median, 4.5) after DEC treatment; all had acquired infection while expatriate visitors to endemic areas of Africa. Using a strict definition of successful treatment, 12 (38%) appeared to be cured after one course of therapy and 5(16%) after two courses. Of the remaining 15 patients, 3 continued to be symptomatic despite more than four courses of treatment. Although 12 of the 17 patients who relapsed did so within 1 year of treatment, several had relatively long asymptomatic periods (2-8 years). There was no predictive difference in clinical or laboratory parameters (including eosinophilia and specific filarial serology) between patients requiring one or more courses of therapy.

Albendazole in human loiasis: results of a double-blind, placebo-controlled trial.

To assess the filaricidal activity and clinical safety of albendazole in human loiasis, a double-blind, placebo-controlled study was conducted in an endemic area in Benin, Africa. Twenty-three men with microfilaremia (100-30,000/mL) were randomly assigned to receive albendazole (200 mg; n = 11) or placebo (n = 12) twice daily for 21 days; 1 patient from each group withdrew from the study. There were no clinical adverse effects and no observed hepatotoxicity, renal toxicity, or hematologic abnormalities attributable to the drug. In the albendazole group, microfilarial levels began to decrease at day 14 after treatment and by 6 months had fallen to a geometric mean of 20% of pretreatment levels (vs. 84.8% in the placebo group). Blood eosinophil levels and anti-filarial IgG and IgG4 also fell significantly in response to albendazole. Taken together, these data suggest that albendazole has a primary (possibly embryotoxic) effect on the adult parasite, resulting in a slow decrease in microfilaremia.