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Objective: RNA sequencing (transcriptomics) is used to study biological pathways. However, the yield of data depends on comparing well-characterized cohorts. We compared tissue eosinophilia versus nasal polyp (NP) status as the metric to characterize transcriptomic mechanisms at play in eosinophilic and non-eosinophilic chronic rhinosinusitis (CRS) versus controls., Methods: RNA sequencing was conducted on sinonasal tissue samples of CRS and controls. Analyses were conducted based on polyp status [with nasal polyps (CRSwNP) and without nasal polyps (CRSsNP)] as well as tissue eosinophil levels per high power field (eos/hpf)[non-eosinophilic (<10 eos/hpf, neCRS) or eosinophilic (≥10 eos/hpf, eCRS)]. The yield of differentially expressed genes (DEGs) and biological pathways through Ingenuity Pathway Analysis (IPA) were compared., Results: CRS tissue differed from controls by 736 statistically significant DEGs. Both NP status and tissue eosinophilia were effective in differentiating CRS from controls and into two distinct subgroups. Statistically significant DEGs identified when comparing CRS by NP status were 60, whereas 110 DEGs were identified using eosinophil cutoff ≥10 and <10 eos/hpf. Additionally, heatmaps showed greater homogeneity within each CRS subgroup when analyzed by tissue eosinophilia versus NP status. On IPA, the IL-17 signaling pathway was significantly different only by tissue eosinophilia status, not NP status, being higher in CRS <10 eos/hpf., Conclusion: Tissue eosinophilia is superior to an analysis by NP status for the study of CRS transcriptome by RNA sequencing in identifying DEGs. Classification of CRS samples by eosinophil counts agnostic of NP status may offer advantageous insights into CRS pathogenetic mechanisms., Level of Evidence: 3 Laryngoscope, 133:2480-2489, 2023., (© 2023 The American Laryngological, Rhinological and Otological Society, Inc.)

FIP1L1-PDGFRA-positive myeloid neoplasm with eosinophilia (F/P+ MN-eo) is a rare disease: robust epidemiological data are lacking and reported issues are scarce, of low sample-size and limited follow-up. Imatinib mesylate (IM) is highly efficient but no predictive factor of relapse after discontinuation has yet been identified. One hundred and fifty-one patients with F/P+ MN-eo (143 males; mean age at diagnosis 49 years; mean annual incidence: 0.18 case per million population) were included in this retrospective nationwide study involving all French laboratories who perform the search of F/P fusion gene (study period: 2003-2019). The main organs involved included the spleen (44%), skin (32%), lungs (30%), heart (19%) and central nervous system (9%). Serum vitamin B12 and tryptase levels were elevated in 74/79 (94%) and 45/57 (79%) patients, respectively, and none of the 31 patients initially treated with corticosteroids achieved complete hematologic remission. All 148 (98%) IM-treated patients achieved complete hematologic and molecular (when tested, n = 84) responses. Forty-six patients eventually discontinued IM, among whom 20 (57%) relapsed. In multivariate analysis, time to IM initiation (continuous HR: 1,01 [0.99-1,03]; P = .05) and duration of IM treatment (continuous HR: 0,97 [0,95-0,99]; P = .004) were independent factors of relapse after discontinuation of IM. After a mean follow-up of 80 (56) months, the 1, 5- and 10-year overall survival rates in IM-treated patients were 99%, 95% and 84% respectively. In F/P+ MN-eo, prompt initiation of IM and longer treatment durations may prevent relapses after discontinuation of IM., (© 2020 Wiley Periodicals LLC.)

Background: Siglec-7 is an inhibitory receptor (IR) expressed on human blood eosinophils. Whereas activation of other IRs, including Siglec-8 and CD300a, has been shown to downregulate eosinophil function, little is known about the role of Siglec-7 on human eosinophils., Objective: To examine Siglec-7 expression and function in eosinophils from normal (ND) and eosinophilic (EO) donors., Methods: Eosinophil expression of Siglec-7 was quantified by flow cytometry and quantitative PCR. Soluble Siglec-7 (sSiglec-7) levels were measured by ELISA in serum. The effect of Siglec-7 on eosinophil viability and degranulation was assessed in vitro by AnnexinV-FITC/7-AAD staining and by measuring GM-CSF-induced mediator release in culture supernatants. Signal transduction was studied by Western blot., Results: Siglec-7 was expressed ex vivo on blood eosinophils from all eosinophilic and normal individuals studied. Siglec-7 surface, but not SIGLEC-7mRNA expression, was correlated with absolute eosinophil count (AEC). Siglec-7 was upregulated on purified eosinophils after in vitro stimulation with GM-CSF or IL-5. Serum sSiglec-7 was detectable in 133/144 subjects tested and correlated with AEC. Siglec-7 cross-linking inhibited GM-CSF-induced release of eosinophil peroxidase, TNF-α, and IL-8 (n = 7-8) but did not promote eosinophil apoptosis (n = 5). Finally, Siglec-7 cross-linking on GM-CSF-activated eosinophils induced phosphorylation of SHP-1 and de-phosphorylation of ERK1/2 and p38., Conclusions: Siglec-7 is constitutively expressed on human eosinophils and downmodulates eosinophil activation. Targeting of Siglec-7 on eosinophils might enhance treatment efficacy in eosinophil-driven disorders. Conversely, therapeutic interventions that inhibit Siglec-7 could have unanticipated consequences and promote eosinophilic inflammation., (© 2019 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Background: Although current American guidelines distinguish proton pump inhibitor-responsive oesophageal eosinophilia (PPI-REE) from eosinophilic oesophagitis (EoE), these entities are broadly similar. While two microarray studies showed that they have similar transcriptomes, more extensive RNA sequencing studies have not been done previously., Aim: To determine whether RNA sequencing identifies genetic markers distinguishing PPI-REE from EoE., Methods: We retrospectively examined 13 PPI-REE and 14 EoE biopsies, matched for tissue eosinophil content, and 14 normal controls. Patients and controls were not PPI-treated at the time of biopsy. We did RNA sequencing on formalin-fixed, paraffin-embedded tissue, with differential expression confirmation by quantitative polymerase chain reaction (PCR). We validated the use of formalin-fixed, paraffin-embedded vs RNAlater-preserved tissue, and compared our formalin-fixed, paraffin-embedded EoE results to a prior EoE study., Results: By RNA sequencing, no genes were differentially expressed between the EoE and PPI-REE groups at the false discovery rate (FDR) ≤0.01 level. Compared to normal controls, 1996 genes were differentially expressed in the PPI-REE group and 1306 genes in the EoE group. By less stringent criteria, only MAPK8IP2 was differentially expressed between PPI-REE and EoE (FDR = 0.029, 2.2-fold less in EoE than in PPI-REE), with similar results by PCR. KCNJ2, which was differentially expressed in a prior study, was similar in the EoE and PPI-REE groups by both RNA sequencing and real-time PCR., Conclusion: Eosinophilic oesophagitis and PPI-REE have comparable transcriptomes, confirming that they are part of the same disease continuum., (© 2018 John Wiley & Sons Ltd.)

Background: Exposure to aeroallergens induces eosinophilic airway inflammation in patients with asthma and allergic airway diseases. The circulating number of eosinophils in peripheral blood is relatively small, leading us to hypothesize that bone marrow needs to be engaged quickly to meet the demands of the tissues., Methods: To investigate the communication between the lungs and bone marrow, we used acute allergen exposure and airway inflammation models in mice. Gene-deficient mice and cytokine reporter mice as well as in vitro cell culture models were used to dissect the mechanisms., Results: Naïve BALB/c mice produced increased numbers of eosinophil precursors and mature eosinophils in the bone marrow when their airways were exposed to a common fungal allergen, Alternaria alternata. Expression of IL-5 and IL-33 increased rapidly in the lungs, but not in the bone marrow. Sera from allergen-exposed mice promoted eosinophilopoiesis in bone marrow cells from naïve mice, which was blocked by anti-IL-5 antibody. Mice deficient in the IL-33 receptor ST2 (i.e., Il1rl1(-/-) mice) were unable to increase their serum levels of IL-5 and allergen-induced eosinophilopoiesis in the bone marrow after allergen exposure. Finally, group 2 innate lymphoid cells (ILC2s) in the lungs showed robust expression of IL-5 after Alternaria exposure., Conclusions: These finding suggests that lung IL-33, through innate activation of ILC2s and their production of IL-5, plays a key role in promoting acute reactive eosinophilopoiesis in the bone marrow when naïve animals are exposed to airborne allergens. Therefore, bone marrow eosinophilopoiesis may be affected by atmospheric environmental conditions., Competing Interests: The authors declare that they have no conflicts of interest., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: The molecular basis and effects of proton pump inhibitor (PPI) therapy on PPI-responsive oesophageal eosinophilia (PPI-REE) and eosinophilic oesophagitis (EoE) remain unknown., Aim: To compare symptom-histological and cytokine gene expression in PPI-REE and EoE patients, at baseline and after specific treatment., Methods: In consecutive adult patients with an EoE phenotype (dysphagia/food impaction, typical endoscopic findings and > 15 eos/HPF), gene expression of eotaxin-3, IL-13, and IL-5 were determined in distal and proximal oesophagus, at baseline and after omeprazole 40 mg b.d. for 8 weeks. PPI-REE was defined by clinicohistological response. PPI nonresponders (EoE) were offered treatment with topical steroids., Results: Fifty three patients were re-evaluated on PPI therapy. 23 patients (43%) had PPI-REE and 30 patients (57%) had EoE. At baseline, eotaxin-3/IL-13/IL-5 gene expression was indistinguishable between EoE and PPI-REE, excepting increased IL-5 expression in proximal oesophagus (12.54 vs. 57, P = 0.029). PPI therapy significantly decreased eotaxin-3/IL-13 in PPI-REE, at both oesophageal sites (P ≤ 0.008), and IL-5 in distal (P = 0.016), but not in proximal oesophagus. Patients with steroid-responsive EoE also showed a significant decrease in eotaxin-3/IL-5 expression at both oesophageal sites. In EoE patients, initial PPI trial significantly decreased distal oesophageal eosinophilia (63.78 to 41.79 eos/HPF, P = 0.025) and led to symptom remission in 16%, but did not influence Th2 markers., Conclusions: Baseline cytokine gene expression in PPI-REE was nearly indistinguishable from EoE. PPI therapy significantly downregulated oesophageal eotaxin-3/Th2-cytokine gene expression in PPI-REE, similarly to that seen in steroid-responsive EoE. A subset of EoE patients showed clinicohistological improvement on PPI therapy., (© 2014 John Wiley & Sons Ltd.)

Background: Polymorphisms of genes controlling cytokine production have not been studied in the genetic susceptibility to cutaneous adverse drug reactions (CADR)., Objectives: The objective was to determine whether polymorphisms in nine cytokine genes were associated to the occurrence of drug reaction with eosinophilia and systemic symptoms (DRESS) compared to drug-induced maculopapular eruption or urticaria and to controls without drug intolerance., Methods: Results from 118 patients with a well-defined CADR were compared to 236 controls without drug intolerance living in the same area of France. We assessed nine polymorphisms: interleukin (IL)1-alpha-889C>T (rs 1800587), IL1-beta-511C>T (rs 16944), IL1-RN intron-2-VNTR (rs2234663), IL2-330T>G (rs 2069762), IL4-33C>T (rs 2070874), IL5-745C>T (rs 2069812), IL10-592C>A (rs 1800872), IL16-295T>C (rs 4778889) and tumour necrosis factor-alpha-308G>A (rs 1800629)., Results: Three polymorphisms exhibited a significant association with CADR (P < 0.05). The combination of the IL1-RN-A2 and IL1-beta-511C alleles was statistically different between cases and controls (P = 0.007) and the A2C haplotype was associated with susceptibility to CADR, particularly in drug reaction with eosinophilia and systemic symptoms (DRESS) patients (odds ratio = 3.22; 95% confidence interval = 1.23-8.41; P = 0.016). The frequency of the IL10-592A allele was higher in DRESS patients than in controls (dominant model CC vs. CA + AA: P = 0.035). These abnormalities were not evident in maculopapular eruptions or urticaria., Conclusions: This is the first study showing that IL1-cluster polymorphisms and haplotypes and the IL10-592A allele (a low IL10 producer) are associated with DRESS. These gene variants may decrease drug tolerance and promote herpes virus reactivation., (© 2013 The Authors Journal of the European Academy of Dermatology and Venereology © 2013 European Academy of Dermatology and Venereology.)

Disease Overview: The eosinophilias encompass a broad range of nonhematologic (secondary or reactive) and hematologic (primary, clonal) disorders with potential for end-organ damage., Diagnosis: Hypereosinophilia (HE) has generally been defined as a peripheral blood eosinophil count greater than 1,500/mm(3) and may be associated with tissue damage. After exclusion of secondary causes of eosinophilia, diagnostic evaluation of primary eosinophilias relies on a combination of morphologic review of the blood and marrow, standard cytogenetics, fluorescent in situ hybridization, flow immunocytometry, and T-cell clonality assessment to detect histopathologic or clonal evidence for an acute or chronic myeloid or lymphoproliferative disorder., Risk Stratification: Disease prognosis relies on identifying the subtype of eosinophilia. After evaluation of secondary causes of eosinophilia, the 2008 World Health Organization establishes a semimolecular classification scheme of disease subtypes including "myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1', chronic eosinophilic leukemia, not otherwise specified" (CEL, NOS), lymphocyte-variant HE, and idiopathic hypereosinophilic syndrome (HES), which is a diagnosis of exclusion., Risk-Adapted Therapy: The goal of therapy is to mitigate eosinophil-mediated organ damage. For patients with milder forms of eosinophilia (e.g., <1,500/mm(3)) without symptoms or signs of organ involvement, a watch and wait approach with close-follow-up may be undertaken. Identification of rearranged PDGFRA or PDGFRB is critical because of the exquisite responsiveness of these diseases to imatinib. Corticosteroids are first-line therapy for patients with lymphocyte-variant HE and HES. Hydroxyurea and interferon-alpha have demonstrated efficacy as initial treatment and steroid-refractory cases of HES. In addition to hydroxyurea, second-line cytotoxic chemotherapy agents and hematopoietic cell transplant have been used for aggressive forms of HES and CEL with outcomes reported for limited number of patients. Although clinical trials have been performed with anti-IL-5 (mepolizumab) and anti-CD52 (alemtuzumab) antibodies, their therapeutic role in primary eosinophilic diseases and HES has yet to be established., (Copyright © 2014 Wiley Periodicals, Inc.)

Background: Recent advances in eosinophilic oesophagitis (EoE) have confirmed the existence of a new disease phenotype, proton pump inhibitor (PPI)-responsive oesophageal eosinophilia (PPI-REE)., Aim: To summarise evidence supporting the use of PPI therapy in patients with suspected EoE (oesophageal dysfunction plus >15 eos/HPF in oesophageal biopsies)., Methods: A literature search was conducted through MEDLINE, using the MeSH search terms 'eosinophilic oesophagitis', 'proton pump inhibitors' and 'oesophageal eosinophilia'. Relevant articles and their reference lists were identified through manual review., Results: Ten articles, including 258 patients with suspected EoE (152 children, 106 adults) undergoing clinico-histological re-evaluation after PPI therapy, were identified. In children, clinical response ranged from 78% to 86% and histological remission from 23% to 40%. In adults, symptom response ranged from 25% to 80% and histological remission from 33% to 61%. Among PPI-REE patients with oesophageal pH-monitoring, 35 showed pathological and 10 normal studies. PPI-REE was significantly commoner with documented gastro-oesophageal reflux disease (GERD) when compared to patients with negative pH monitoring (70% vs. 29%, P < 0.001). Symptom improvement/resolution occurred in 50-85% of patients without histological remission on PPI therapy. Six PPI-REE patients demonstrated clinico-histological relapse on PPI therapy., Conclusions: At least one third of patients with suspected EoE achieve clinico-histological remission on PPI therapy. Response is more limited in children compared with that in adults. pH monitoring does not accurately predict response to PPI therapy, albeit histological remission is significantly higher, up to 70%, upon documented GERD. Symptom improvement is common with PPI therapy despite persistent eosinophilic infiltration., (© 2013 John Wiley & Sons Ltd.)

Disease Overview: The eosinophilias encompass a broad range of non-hematologic (secondary or reactive) and hematologic (primary, clonal) disorders with potential for end-organ damage., Diagnosis: Hypereosinophilia has generally been defined as a peripheral blood eosinophil count greater than 1,500/mm(3) and may be associated with tissue damage. After exclusion of secondary causes of eosinophilia, diagnostic evaluation of primary eosinophilias relies on a combination of morphologic review of the blood and marrow, standard cytogenetics, fluorescent in situ-hybridization, flow immunocytometry, and T-cell clonality assessment to detect histopathologic or clonal evidence for an acute or chronic myeloid or lymphoproliferative disorder., Risk Stratification: Disease prognosis relies on identifying the subtype of eosinophilia. After evaluation of secondary causes of eosinophilia, the 2008 World Health Organization establishes a semi-molecular classification scheme of disease subtypes including myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1, chronic eosinophilic leukemia, not otherwise specified (CEL, NOS), lymphocyte-variant hypereosinophilia, and idiopathic hypereosinophilic syndrome (HES), which is a diagnosis of exclusion., Risk-Adapted Therapy: The goal of therapy is to mitigate eosinophil-mediated organ damage. For patients with milder forms of eosinophilia (e.g. < 1,500/mm(3) ) without symptoms or signs of organ involvement, a watch and wait approach with close-follow-up may be undertaken. Identification of rearranged PDGFRA or PDGFRB is critical because of the exquisite responsiveness of these diseases to imatinib. Corticosteroids are first-line therapy for patients with lymphocyte-variant hypereosinophilia and HES. Hydroxyurea and interferon-alpha have demonstrated efficacy as initial treatment and steroid-refractory cases of HES. In addition to hydroxyurea, second line cytotoxic chemotherapy agents and hematopoietic cell transplant have been used for aggressive forms of HES and CEL with outcomes reported for limited numbers of patients. Although clinical trials have been performed with anti IL-5 (mepolizumab) and anti-CD52 (alemtuzumab) antibodies, their therapeutic niche in primary eosinophilic diseases and HES have yet to be established., (Copyright © 2011 Wiley-Liss, Inc.)

Chromosome 8p11.2 translocations result in diverse oncogenic fusion genes involving FGFR1 or MYST3. Among 24,262 unique patient cytogenetic studies performed at the Mayo Clinic, 8p11.2 translocations were identified in 14 cases ( approximately 0.06%). FISH analysis was performed in 13 patients (12 had myeloid neoplasms) and revealed abnormalities of MYST3 (n = 4) or FGFR1 (n = 4) in eight patients. MYST3 abnormalities were associated with acute myeloid leukemia (AML), M4 in three and M6 in one. Three of the four FGFR1-rearranged cases were associated with myeloproliferative neoplasms but none, including the two with sole 8p11.2, displayed the typical phenotype for stem cell leukemia/lymphoma (SCLL) and only one had eosinophilia; the fourth case had AML-M4. FISH did not reveal FGFR1 involvement in the one patient with SCLL. We conclude that neither the SCLL phenotype nor blood eosinophilia is a consistent feature of FGFR1-associated 8p11.2 translocations; conversely, FISH might not always reveal FGFR1 involvement in typical SCLL.

Blood eosinophilia signifies either a cytokine-mediated reactive phenomenon (secondary) or an integral phenotype of an underlying haematological neoplasm (primary). Secondary eosinophilia is usually associated with parasitosis in Third World countries and allergic conditions in the West. Primary eosinophilia is operationally classified as being clonal or idiopathic, depending on the respective presence or absence of a molecular, cytogenetic or histological evidence for a myeloid malignancy. The current communication features a comprehensive clinical summary of both secondary and primary eosinophilic disorders with emphasis on recent developments in molecular pathogenesis and treatment.

Background: Intermediate phenotypes are often measured as a proxy for asthma. It is largely unclear to what extent the same set of environmental or genetic factors regulate these traits., Objective: Estimate the environmental and genetic correlations between self-reported and clinical asthma traits., Methods: A total of 3,073 subjects from 802 families were ascertained through a twin proband. Traits measured included self-reported asthma, airway histamine responsiveness (AHR), skin prick response to common allergens including house dust mite (Dermatophagoides pteronyssinus [D. pter]), baseline lung function, total serum immunoglobulin E (IgE) and eosinophilia. Bivariate and multivariate analyses of eight traits were performed with adjustment for ascertainment and significant covariates., Results: Overall 2,716 participants completed an asthma questionnaire and 2,087 were clinically tested, including 1,289 self-reported asthmatics (92% previously diagnosed by a doctor). Asthma, AHR, markers of allergic sensitization and eosinophilia had significant environmental correlations with each other (range: 0.23-0.89). Baseline forced expiratory volume in 1 s (FEV(1)) showed low environmental correlations with most traits. Fewer genetic correlations were significantly different from zero. Phenotypes with greatest genetic similarity were asthma and atopy (0.46), IgE and eosinophilia (0.44), AHR and D. pter (0.43) and AHR and airway obstruction (-0.43). Traits with greatest genetic dissimilarity were FEV(1) and atopy (0.05), airway obstruction and IgE (0.07) and FEV(1) and D. pter (0.11)., Conclusion: These results suggest that the same set of environmental factors regulates the variation of many asthma traits. In addition, although most traits are regulated to great extent by specific genetic factors, there is still some degree of genetic overlap that could be exploited by multivariate linkage approaches.

The BCR-ABL-negative chronic myeloproliferative disorders (CMPD) and myelodysplastic/myeloproliferative diseases (MDS/MPD) are a spectrum of related conditions for which the molecular pathogenesis is poorly understood. Translocations that disrupt and constitutively activate the platelet-derived growth factor receptor beta(PDGFRB) gene at chromosome band 5q33 have been described in some patients, the most common being the t(5;12)(q33;p13). An accurate molecular diagnosis of PDGFRB-rearranged patients has become increasingly important since recent data have indicated that they respond very well to imatinib mesylate therapy. In this study, we have tested nine patients with a CMPD or MDS/MPD and a translocation involving 5q31-33 for disruption of PDGFRB by two-colour fluorescence in situ hybridization (FISH) using differentially labelled, closely flanking probes. Normal control interphase cells gave a false positive rate of 3% (signals more than one signal width apart). Six patients showed a pattern of one fused signal (from the normal allele) and one pair of signals separated by more than one signal width in > 85% of interphase cells, indicating that PDGFRB was disrupted. These individuals had a t(1;5)(q21;q33), t(1;5)(q22;q31), t(1;3;5)(p36;p21;q33), t(2;12;5)(q37;q22;q33), t(3;5) (p21;q31) and t(5;14)(q33;q24) respectively. The remaining three patients with a t(1;5)(q21;q31), t(2;5)(p21;q33) and t(5;6)(q33;q24-25) showed a normal pattern of hybridization, with > or = 97% interphase cells with two fusion signals. We conclude that two-colour FISH is useful to determine the presence of a PDGFRB rearrangement, although, as we have shown previously, this technique may not detect subtle complex translocations at this locus. Our data indicate that several PDGFRB partner genes remain to be characterized.

Abnormal clones of clusters of differentiation (CD)3(-)CD4(+) or CD3(+)CD4(-)CD8(-) phenotypically abnormal lymphocytes have been identified in some patients who have the idiopathic hypereosinophilic syndrome. This report illustrates the disparate clinical courses of six eosinophilic patients with evidence of abnormal T-cell clones based on the finding of a T-cell receptor gene rearrangement. The data suggest that molecular genetics testing for T-cell receptor gene rearrangements should be included in the routine work-up of patients with idiopathic eosinophilia., (Copyright 2001 Wiley-Liss, Inc.)

We report a therapy-related MDS (RAEB) patient with eosinophilia, unbalanced translocation der(7)t(1;7) (q12;q22) and lung cancer. We observed no increase in cytokine levels in serum or in the conditioned medium (CM) of peripheral T cells cultured with or without IL-2. When bone marrow (BM) cells were cultured with GM-CSF, IL-3 and SCF in a semisolid system, the colonies were exclusively eosinophilic. Cytogenetic analysis of the colony cells identified the same chromosome abnormality in all metaphases to that of BM cells. Suspension and clonogenic colony assay of BM cells cultured with various cytokines showed predominant eosinophilic growth and differentiation with GM-CSF, but not with the other cytokines examined. These findings, together with mild morphological abnormalities of eosinophils, indicate clonal involvement of eosinophils in the myelodysplastic syndrome (MDS) clone, and that the eosinophilia was derived from the neoplastic clone with the translocation and was not associated with the patient's lung cancer.

We describe a patient with eosinophilia and an abnormal CD(3+)4-(8-) alpha beta+ T-cell population. Chromosomal analysis of sorted CD(3+)4-(8-) cells revealed abnormal karyotypes on chromosome 16. In the presence of IL-2 the production of IL-5 from CD(3+)4-(8-) cells was higher than that from CD(3+)4-(8-) cells. Eosinophil survival-enhancing activity in the patient serum was inhibited by a combination of anti-IL-5 and anti-GM-CSF monoclonal antibodies. These data suggest that increased production of IL-5 and GM-CSF from the abnormal CD(3+)4-(8-) cells might cause eosinophilia.

A t(5;12)(q33;p13) translocation has been detected in two patients with myeloid disorder and eosinophilia. Six other patients with haematological disease with eosinophilia with similar translocation have been published previously. The existence of a new entity, a myeloproliferative disorder with eosinophilia and t(5;12) (q31-q33;p12-p13), is suggested by the results of the present study.

A chromosomally abnormal clone characterized by a translocation, t(5;12)(q31;q13), was detected in the marrow of a child with myelodysplasia and associated eosinophilia which included a generalized skin infiltration. Combined immunophenotyping and fluorescence in situ hybridization on interphase bone marrow cells showed that the chromosomal rearrangement was restricted to the granulocyte lineage but was not present in the eosinophils. If the chromosome rearrangement is important in the overproduction of eosinophils in this case, the lineage restriction found suggests that its effect must be indirect.

A 72-year-old male who was admitted to our hospital with severe anemia was diagnosed as refractory anemia with ring sideroblasts (RARS), according to the French-American-British (FAB) classification of myelodysplastic syndromes (MDS). The patient showed persistent eosinophilia with no definite signs of either allergy or a parasitic infection. Chromosomal analysis of bone marrow cells revealed inv(16)(p13q22), a known characteristic of M4Eo acute myeloid leukemia (AML) in the FAB classification. This patient didn't exhibit leukemic transformation during his 20-month clinical course, nor was any found at autopsy. Therefore, this is the first case of RARS to speculate that the chromosomal characteristic inv(16)(p13q22) might be specific for eosinophilia rather than AML.

We studied two patients with a leukaemic T cell lymphoma who presented with a marked increase in blood eosinophilia. To investigate the mechanism of the eosinophilia, supernatants of peripheral blood cells containing more than 80% lymphoma cells were tested by biological assays for the presence of colony stimulating factors (CSF). In one case supernatants stimulated the growth of granulocyte-macrophage (GM), erythroid and eosinophil colonies. These effects were neutralized by anti-GM-CSF antibodies; anti-IL5 antibodies slightly decreased eosinophil colony formation. Supernatants derived from the second patient cells stimulated the same lineages. Neutralizing experiments demonstrated that in addition to GM-CSF it contained interleukin 3 (IL-3) and interleukin 5 (IL-5). In agreement with the biological data, RNA studies using the polymerase chain reaction showed that cells from the first patient expressed GM-CSF transcripts; IL-5 transcripts were also detected in very low amounts. GM-CSF, IL-3 and IL-5 transcripts were detected in cells from the second patient. Thus eosinophilia associated with some T cell lymphoma is likely due to secretion of different combinations of cytokines by malignant cells.

In 4 inbred strains of guinea pig the tendency to develop peripheral high-eosinophilia was shown to be genetically controlled. The development of eosinophilia with age and following immunization was examined in high- and low-eosinophilic parental strains, in F1-hybrids and in backcross offspring. The results show that probably only one or a very few segregating genes control eosinophilia, and they also indicate that different genes are involved in the determination of spontaneous (age-related) and immunization-induced eosinophilia.

Development of eosinophilia was studied in four strains of guinea pigs (gp), selectively bred for either high or low respiratory anaphylactic reactivity. One high-asthma strain (IMM/S 209) and one low-asthma strain (IMM/R 203) developed spontaneous high blood eosinophilia. The 2 other gp strains - one high-asthma strain (IMM/S 740) and one low-asthma strain (IMM/R 201-16) - maintained normal low levels of eosinophilic granulocytes (eos). The levels of eos in various tissues showed similar differences between the gp strains. Following immunization with ovalbumin/Al(OH)3 the levels of blood eos increased significantly only in gp of strain 209. The blood eos levels in gp of all 4 strains decreased significantly following immunization with ovalbumin in Freund's complete adjuvant (FCA).

Two children are described who presented at the age of 5 and 7 months with anaemia, a high white cell count with eosinophilia and thrombocytopenia. Both children had an identical balanced translocation t(1;5)(q23;q33) and no evidence of a constitutional abnormality. The response to treatment of one child was poor, the other remains well on therapy. This translocation has not been previously reported and is likely to represent a subclass of myeloproliferative disorder analogous to the monosomy 7 syndrome, although less common. The previous literature of acquired chromosome abnormalities involving chromosomes 1 and 5 is reviewed.

A cytogenetic analysis was carried out on bone marrow cells from 11 patients who presented with hypereosinophilia and the clinical features of the idiopathic hypereosinophilic syndrome. One of these patients was found to have trisomy 8 affecting the myeloid series, including eosinophils. In this patient, marrow eosinophils also showed asynchrony of nuclear-cytoplasmic maturation, and there were increased numbers of myeloid progenitor cells in the blood. Six months later, blast cell transformation occurred, and he died soon afterwards. These findings show that abnormalities in the karyotype of bone marrow cells and culture of blood progenitor cells may help to identity eosinophilic leukaemia among patients who present with features of the idiopathic hypereosinophilic syndrome.

Two siblings, a 38-year-old woman and a 33-year-old man, developed eosinophilic fasciitis within a period of 6 months. They were found to have identical HLA-A, B, DR, and DQ antigens, raising the possibility of a genetic influence in the development of this disease. No common environmental factors close to the time of onset were identified; however, the possibility of a common, remote environmental factor cannot be discounted.

Four patients representing a spectrum of haematological malignancies are reported. Two patients had Philadelphia chromosome negative myeloproliferative disorders, one had acute lymphoblastic leukaemia and one had eosinophilic leukaemia. In each case eosinophilia was present and demonstrated to be part of the malignancy by the association of clonally abnormal metaphases with eosinophil granules. Abnormalities involving the short arm of chromosome 12 (12p13) were a constant feature in all four cases and therefore a nonrandom association between this chromosome region and malignant eosinophil proliferation is proposed.