Prominent Eosinophilic Infiltration Research Articles

Mechanisms of asthma

Asthma is a syndrome of variable airflow obstruction. It is characterized pathologically by bronchial inflammation with prominent eosinophil infiltration, physiologically by bronchial hyper-reactivity, and clinically by variable cough, chest tightness and wheeze. The prevalence of asthma varies geographically; it is particularly common in developed countries, where 10% of children and young adults suffer the disorder. It has many causes; this contribution focuses on atopic asthma, which is the most common.

Allergieassoziierte Kolitis

There is substantial evidence that allergic reactions exist in the gastrointestinal tract (GI). However, patients with food allergy-related enteropathy pose a diagnostic challenge to physicians because the clinical features are variable, unspecific, occur in other gastrointestinal disorders, and specific diagnostic tools are missing. Several recent studies and reviews have focused on the function of eosinophilic granulocytes in GI disease. The role of eosinophils in the pathophysiology of GI hypersensitivity reactions is poorly defined. However, some findings have been reported that imply an involvement of eosinophils in allergic reactions of the gut. The presumptive histology of allergy-associated colitis in colonic and ileal biopsies is based on prominent pure eosinophilic infiltration of a normal lamina propria, submucosa and epithelium with variable degrees of degranulation. An immunoperoxidase stain for eosinophilic peroxidase is supportive in establishing the diagnosis if suspected. Neutrophils or mononuclear infiltrates are not significantly increased and damage to the intestinal tissue is not prominent. Despite characteristic histologic changes in colonic biopsy specimens, a final diagnosis depends on careful clinical examination and exclusion of several differential diagnoses.

Celecoxib-induced acute interstitial nephritis

Data about the nephrotoxicity of selective cyclooxygenase-2 inhibitors are still evolving. Acute interstitial nephritis is a well-described complication of therapy with nonselective nonsteroidal anti-inflammatory drugs. We report a case of biopsy-proven acute interstitial nephritis in a 73-year-old diabetic woman, who had taken celecoxib for more than 1 year before presentation. She presented with clinical findings of subnephrotic proteinuria and acute renal failure that required dialysis. She recovered renal function with cessation of celecoxib therapy after 2 weeks. Other medications were reintroduced safely, without recurrence of renal failure. A kidney biopsy specimen showed acute interstitial nephritis with a prominent eosinophilic infiltrate in the interstitium. This case documents the occurrence of acute interstitial nephritis with celecoxib and emphasizes the need for continued vigilance and care in use of cyclooxygenase-2 inhibitors in high-risk patients. © 2002 by the National Kidney Foundation, Inc.

Acute radiation colitis in patients treated with short-term preoperative radiotherapy for rectal cancer.

The histopathologic features of acute radiation-induced colitis in humans have been described in occasional, >20-year-old studies, but they have not been analyzed in detail. We characterize such findings in 34 patients with rectal cancer who underwent surgery a few days after preoperative irradiation with 25 Gy given over 5-7 days, and we compare the results to the histopathologic features detected in 18 patients treated by a conventional preoperative irradiation protocol consisting of 45 Gy during 5 weeks followed by surgery after a time interval of at least 3 weeks. Short-term preoperative irradiation therapy generally induced severe mucosal inflammation characterized by increased cellularity of the lamina propria, prominent eosinophilic infiltrates, crypt disarray, surface and crypt epithelial damage, nuclear abnormalities, and presence of apoptotic bodies in the crypt epithelium. These histopathologic features were absent or detected only occasionally in the patient group treated according to the long-term preoperative irradiation protocol. Despite acute severe inflammation, none of the patients treated by short-term irradiation developed perioperative complications. These observations indicate that acute radiation colitis may remain clinically silent and resolve spontaneously within a few weeks after irradiation. Given the widening acceptance of short-term preoperative irradiation protocols for rectal cancer, pathologists should be aware of the rather characteristic histologic findings of acute radiation colitis and avoid unnecessary concern of clinicians. The differential diagnosis includes infectious colitis, collagenous and ischemic colitis, nonsteroidal anti-inflammatory drug-associated colitis, and chronic idiopathic inflammatory bowel disease.

Islet xenograft rejection in absence of CD8 + T cells does not require either interferon-γ or interleukin-5

We recently demonstrated that interleukin-5 and eosinophils mediate rejection of skin allografts when CD8 + T cell-dependent and Th1-type CD4 + T cell-dependent pathways are not functional. The purpose of this study was to determine whether a similar mechanism might be operative during rejection of rat islet xenografts in mice. First, we observed that eosinophils indeed infiltrate rejected islet grafts together with CD4 + and CD8 + T cells. CD8 + T cell depletion significantly enhanced graft survival and a further prolongation of islet function was obtained in combination with interferon-γ neutralization. However, islet rejection characterized by prominent eosinophil and macrophage infiltration still occurred in this setting. Although eosinophil infiltrates were dramatically reduced in interleukin-5 deficient mice, the ability of these animals to reject islet xenografts under CD8 + T cell depletion and interferon-γ neutralization was similar to that of wild-type mice. We conclude that in absence of CD8 + T cells and interferon-γ, macrophages, but not eosinophils, mediate rejection of rat-to-mouse islet xenografts.

Lymphoepithelioma-like carcinoma of the cervix with prominent eosinophilic infiltrate: an HPV-18 associated case

Lymphoepithelioma-like carcinoma of the cervix with prominent eosinophilic infiltrate: an HPV-18 associated case

The 3-week sulphasalazine syndrome strikes again

A 34-year-old lady developed a constellation of dermatitis, fever, lymphadenopathy and hepatitis, beginning on the 17th day of a course of oral sulphasalazine for sero-negative rheumatoid arthritis. Cervical and inguinal lymph node biopsies showed the features of severe necrotising lymphadenitis, associated with erythrophagocytosis and prominent eosinophilic infiltrates, without viral inclusion bodies, suggestive of an adverse drug reaction. A week later, fulminant drug-induced hepatitis, associated with the presence of anti-nuclear autoantibodies (but not with other markers of autoimmunity), and accompanied by multi-organ failure and sepsis, supervened. She subsequently died some 5 weeks after the commencement of her drug therapy. Post-mortem examination showed evidence of massive hepatocellular necrosis, acute hypersensitivity myocarditis, focal acute tubulo-interstitial nephritis and extensive bone marrow necrosis, with no evidence of malignancy. It is thought that the clinico-pathological features and chronology of this case bore the hallmarks of the so-called “3-week sulphasalazine syndrome”, a rare, but often fatal, immunoallergic reaction to sulphasalazine.

Elevated Interleukin-4 and Interleukin-6 in Rats Sensitized with Toluene Diisocyanate.

In order to investigate the cytokine profile in toluene diisocyanate (TDI)-induced occupational asthma, we conducted a quantification of cytokine production in a murine model of respiratory hyperreactivity to TDI. Wistar rats were sensitized with intranasal application of 10% TDI and provoked with 5% TDI to induce airway hypersensitivity. The blood leucocytes were counted, and bronchoalveolar lavage (BAL) was performed and the cellular responses in BAL fluid were analysed. Lung histological examination was performed to investigate the inflammatory status in the airway. The production of IL-2, IL-4, IL-6 and IFN-gamma in serum, BAL fluid and spleen cell were determined with ELISA kits. The cellular results demonstrated that neutrophils and eosinophils in blood were significantly increased and the total cells and each different cell, in particular eosinophils in BAL fluid were markedly increased in TDI sensitized rats. Histological analysis showed that a respiratory inflammation represented by prominent infiltration of eosinophils in central and peripheral airways was present in TDI-sensitized rats. The cytokine assays revealed that in TDI-sensitized rats, IL-4 was predominately secreted in serum, and IL-4 and IL-6 rather than IL-2 and IFN-gamma were predominately secreted in BAL fluid and in spleen cell. These findings suggested that IL-4 and IL-6 are preferentially produced and may have an important role in occupational asthma induced by TDI.

Comparative analysis of paracrine immunotherapy in experimental brain tumors

Local delivery of cytokines has been shown to have a potent antitumor activity against a wide range of malignant brain tumors. In this study, the authors examined the efficacy of treating central nervous system (CNS) tumors by transfecting poorly immunogenic B16/F10 melanoma cells with interleukin (IL)-2, IL-4, or granulocytemacrophage-colony stimulating factor (GM-CSF) gene, and using these cells to deliver the cytokine locally at the site of the CNS tumor. The object was to determine which cytokine would possess the greatest antitumor activity and to further elucidate its mechanism of action. The transfected B16/F10 cells were irradiated to prevent replication and injected intracranially into C57BL/6 mice (10 mice per group) along with nonirradiated, nontransfected B16/F10 (wild-type) melanoma cells. Sixty percent of mice treated with IL-2 (p < 0.001 compared with control) and 10% treated with IL-4 (median survival = 31 days, p < 0.001 compared with control) were long term survivors (> 120 days). The median survival for animals treated with GM-CSF was 22 days with no long term survivors (p = 0.01 compared with control). Control animals that received only wild-type cells had a median survival of 18 days (range 15-20 days). Histopathological examination of brains from animals killed at different times showed minimal infiltration of tumor cells in the IL-2 group, moderate infiltration of tumor cells in the IL-4 group, and gross tumor invasion and tissue necrosis in the GM-CSF group. Animals treated with IL-2 showed a strong CD8 T cell-mediated response, whereas IL-4 evoked a prominent eosinophilic infiltrate in the area of the tumor. High levels of locally expressed IL-2 rather than IL-4 or GM-CSF stimulate a strong immunological cytotoxic antitumor response that leads to significant prolongation of survival in mice challenged with B16/F10 intracranial melanoma tumor cells. Consequently, IL-2 may be a superior candidate for use in paracrine immunotherapy.

Induction of Apoptosis in Bronchial Eosinophils: Beneficial or Harmful?

Background: Prominent eosinophil infiltration takes place in asthmatic bronchi, and damages bronchial epithelial cells. Aim: This study was designed to investigate whether induction of apoptosis in infiltrated cells in the airways is beneficial or harmful. Methods: A/J mice, which are genetically predisposed to be hyperresponsive to acetylcholine, were immunized with ovalbumin (OA) and alum. Thereafter, they were subjected to a 2-week regimen of OA inhalation, during which they were also administered either hamster anti-mouse Fas monoclonal antibody or hamster IgG (sham control) intranasally. Pulmonary function was then analyzed using whole-body plethysmography. Results: Inhalation of OA increased both airway responsiveness to acetylcholine and infiltration of eosinophils. Administration of anti-Fas antibody induced apoptosis in the infiltrating eosinophils and abolished the increase in airway responsiveness to acetylcholine. Conclusion: Induction of apoptosis in eosinophils infiltrating asthmatic bronchi has a beneficial effect on airway hyperresponsiveness.

Exaggerated arthropod-bite lesions in patients with chronic lymphocytic leukemia: A clinical, histopathologic, and immunopathologic study of eight patients

Background: Unusual papulovesicular lesions resembling arthropod bites have been described in patients with chronic lymphocytic leukemia (CLL). Objective: Our purpose was to describe and characterize further the clinical, histopathologic, and immunopathologic features of these lesions. Methods: Eight patients were identified retrospectively who had CLL and characteristic skin lesions. Clinical and histologic features were recorded. Skin biopsy specimens were analyzed immunohistochemically for eosinophil granule major basic protein, eosinophil-derived neurotoxin, neutrophil elastase, and mast cell tryptase. Results: The clinical features, including the lesional distribution, suggested arthropod bites, although most patients could not recall having been bitten. Mixed T- and B-cell lymphoid cell infiltrates were present within lesions, along with prominent eosinophil infiltration and eosinophil granule protein deposition. Conclusion: Exuberant papulovesicular lesions develop in patients with CLL apparently as an exaggerated response to arthropod bites. Prominent eosinophil infiltration and degranulation within these lesions likely contribute to the severity of symptoms. (J Am Acad Dermatol 1998;39:27-35.)

Spontaneous myocarditis in DBA/2 mice. Light microscopic study with transmission and X-ray analytical electron microscopic studies.

DBA/2 inbred mice spontaneously develop myocarditis and a unique form of subepicardial inflammation of the right ventricle characterized by a prominent eosinophilic infiltrate with calcinosis. We studied this myocarditis using light microscopy and both transmission and analytical X-ray electron microscopy, paying particular attention to eosinophil-associated cardiocyte injury. At 5 weeks of age, many eosinophils and mononuclear cells (MNCs) were seen in the subepicardium of the right ventricle. Electron microscopy showed that cardiocytes underwent degenerative changes, including myofibrillar lysis, accumulation of Z-band material and mitochondrial inclusions, and rupture of plasma membranes. The infiltrating eosinophils appeared to be activated, and cells with cytoplasmic vacuoles, suggestive of degranulation, were noted. The myocardial injury was most severe in the 7th week and healed with myocardial fibrosis and calcinosis by the 8th week. Analytical X-ray electron microscopy showed that the calcinosis was initiated in mitochondrial inclusions of injured cardiocytes. The peripheral eosinophil count did not increase during the course of the disease, but there was a positive correlation between the ratio of eosinophils to infiltrated white blood cells (Eo/WBCs) in the right ventricle and the severity of myocardial damage. Eosinophils may play a significant part in subepicardial cardiocyte injury seen in DBA/2 mice.

Author reply

We appreciate the attention of Dr. Nakamura et al. to our article1 and simply apologize for the fact that we unfortunately did not refer to their article,2 although it mainly dealt with gastric B-cell lymphoma, especially mucosa-associated lymphoid tissue (MALT) lymphoma. However, to our surprise, "the detailed clinicopathologic features of gastric T-cell lymphoma" that they mentioned were comprised only of histologic classification, MIB-1 index, and overall survival rate. We believe clinicopathologic features of a certain type of lymphoma should include patient age and gender, and a description of the macroscopic and histologic features of the gastric lesions with either the study of frozen section immunohistochemistry or DNA analysis. These features should have included the birthplace and viral status of the patients because as we pointed out in our article, the southwestern part of Japan is an endemic region for human T-lymphotropic virus type 1 (HTLV-1). The objective of our article was not simply to describe clinicopathologic features of gastric T-cell lymphoma as a whole, but to document two types of gastric T-cell lymphoma associated with or without HTLV-1. We found that HLTV-1 negative T-cell lymphoma mainly is comprised of a distinct type of lymphoma with a natural killer (NK) cell phenotype accompanied by the prominent infiltration of eosinophils. We believe that the future studies of gastric T-cell lymphoma should cite this information, referring HTLV-1 status and NK cell phonotype. Motoko Shimada-Hiratsuka M.D.*, Masashi Fukayama M.D.

Electron microscopic study on the outer membrane of chronic subdural hematoma.

We studied the electron microscopic features of the outer membrane of chronic subdural hematoma to explore the mechanism of growth of chronic subdural hematoma. Ultrastructurally, the outer membrane consisted of bundles of collagen fibrils and cellular elements such as fibroblasts, mast cells, migrating erythrocytes, platelets and eosinophils. A large number of proliferating macrocapillaries coursed among them. Such general characteristics of the endothelial cells with proliferating macrocapillaries as gap junctions and thinness or absence of the basement membrane suggested that they be very fragile and susceptible to bleeding. The number and extent of endothelial gap junctions indicated that they could account for most of the leakage not only into the tissue of the outer membrane but also into the hematoma cavity. The outer membranes had a prominent infiltration of eosinophils. Plasminogen secreted by the eosinophils inhibits the formation of platelet thrombus within the lumen and also dissolves fibrinoid substance, which reinforces fragile endothelial walls or edematous interstitium. These features possibly contribute to the recurring hemorrhage from the vessels in the outer membrane and the resultant enlargement of the hematoma.

Churg-Strauss Syndrome Presenting with Pulmonary Capillaritis and Diffuse Alveolar Hemorrhage: CASE REPORT

Churg-Strauss syndrome (CSS) is a rare disorder characterized by the histopathological triad of systemic necrotizing vasculitis, extravascular granuloma, and eosinophilic infiltrate, occurring in individuals with asthma or a history of allergy. We report a case of CSS with rare presentation of diffuse pulmonary hemorrhage. A transbronchial lung biopsy showed necrotizing vasculitis, pulmonary capillaritis, and prominent eosinophilic infiltrate. At autopsy, necrotizing granuloma and diffuse alveolar hemorrhage were found in the lungs. Laboratory data showed hypereosinophilia, disseminated intravascular coagulopathy, and positive anti-proteinase 3 antineutrophil cytoplasmic antibody (ANCA). This case emphasize that CSS should be considered in the differential diagnosis of ANCA-positive vasculitis with diffuse alveolar hemorrhage.

FGFR1 is fused with a novel zinc-finger gene, ZNF198, in the t(8;13) leukaemia/lymphoma syndrome.

Various histological subtypes of leukaemia and lymphoma are associated with diagnostic chromosome translocations, and substantial strides have been made in determining the specific oncogenes targetted by those translocations. We report the cloning of a novel fusion oncogene associated with a unique leukaemia/lymphoma syndrome. Patients afflicted with this syndrome present with lymphoblastic lymphoma and a myeloproliferative disorder, often accompanied by pronounced peripheral eosinophilia and/or prominent eosinophilic infiltrates in the affected bone marrow, which generally progress to full-blown acute myelogenous leukaemia within a year of diagnosis. A specific chromosome translocation, t(8;13)(p11;q11-12), is found in both lymphoma and myeloid leukaemia cells from these patients, supporting bi-lineage differentiation from a transformed stem cell. We find that the 8p11 translocation breakpoints, in each of four patients, interrupt intron 8 of the fibroblast growth factor receptor 1 gene (FGFR1). These translocations are associated with aberrant transcripts in which four predicted zinc-finger domains, contributed by a novel and widely expressed chromosome-13 gene (ZNF198), are fused to the FGFR1 tyrosine-kinase domain. Transient expression studies show that the ZNF198-FGFR1 fusion transcript directs the synthesis of an approximately 87-kD polypeptide, localizing predominantly to the cytoplasm. Our studies demonstrate an FGFR1 oncogenic role and suggest a tumorigenic mechanism in which ZNF198-FGFR1 activation results from ZNF198 zinc-finger-mediated homodimerization.

Eosinophilia and intracranial worm recovery in interleukin-5 transgenic and interleukin-5 receptor α chain-knockout mice infected with Angiostrongylus cantonensis

We infected interleukin-5 (IL-5)-transgenic (IL-5-Tg) and IL-5 receptor alpha knockout (IL-5R alpha -/-) mice with Angiostrongylus cantonensis to determine the possible roles of IL-5 and eosinophils in A. cantonensis infection in mice. IL-5-Tg mice demonstrated significantly higher eosinophilia in bone marrow, blood and cerebrospinal fluid (CSF), lower intracranial worm recovery and smaller female worms than naive C3H/HeN mice. Both IL-5-Tg and C3H/HeN mice evoked antigen-specific serum and CSF IgA antibody responses as early as days 5 and 7 postinfection, respectively. Prominent eosinophil infiltration was noted around intracranial worms in the subarachnoid spaces of the mouse brains; eosinophils adhering to the worm surface were degranulated. In contrast, IL-5R alpha -/- mice yielded a higher worm recovery than wild-type or heterozygous mice at day 20 postinfection and failed to provoke CSF eosinophilia. These findings indicate that A. cantonensis infection in the mouse causes IL-5 production and subsequent CSF eosinophilia, the latter probably being involved in the killing of intracranial worms.

Primary mucoepidermoid carcinoma of the thyroid gland: A report of six cases and a review of the literature of a follicular epithelial-derived tumor

Primary mucoepidermoid carcinomas of the thyroid gland are uncommon tumors of low-grade malignant potential. We report six cases of thyroid mucoepidermoid carcinoma, four occurred in women and two in men with an age range of 29 to 57 (median, 46 years). The clinical presentation was that of a painless mass. Radiographic studies showed a single, solid, “cold” nodule in either the right or left lobe, or isolated to the isthmus. There was no history of a mucoepidermoid carcinoma developing in more typical locations (eg, salivary gland) in any of the patients. Histologically, the tumors were characterized by an intimate admixture of squamoid/epidermoid cells and mucocytes. The tumors were delineated but not encapsulated with prominent cyst formation and a variable amount of associated fibrosis. The squamoid component showed horny pearl formation, individual cell keratinization and/or the presence of intercellular bridges. Intracytoplasmic and luminal epithelial mucin was observed in all cases. In three of the cases a prominent eosinophilic cellular infiltrate was intimately identified within the neoplastic proliferation. One other case was noteworthy for the presence of ciliated epithelium. In all of the cases the uninvolved thyroid tissue showed the presence of lymphocytic thyroiditis. Rare foci of squamous metaplasia were observed in two of the cases. A microscopic focus of thyroid papillary carcinoma was observed adjacent to the mucoepidermoid carcinoma in one case. Immunohistochemical evaluation of the mucoepidermoid carcinoma showed the following antigenic profile: cytokeratin (five of five), CAM 5.2 (four of four), thyroglobulin (five of six), calcitonin (none of six), chromogranin (none of six), polyclonal carcinoembryonic antigen (four of four), and monoclonal carcinoembryonic antigen (none of five). Surgical excision was the treatment of choice. All of the patients reported are alive without disease (recurrence or metastasis) over periods ranging from 1 to 15 years. Based on our findings, we believe that these tumors are of low-grade malignant potential and originate from thyroid follicular epithelial cells rather than from solid cell nests of the ultimobranchial body.

Effect of tumor necrosis factor receptor binding protein on cell infiltration induced by lipopolysaccharide and sephadex beads in guinea pig lung

In the present study, the effect of a tumor necrosis factor receptor binding protein (TNFbp) on the cell infiltration induced by lipopolysaccharide (LPS) and Sephadex beads in guinea pig lung was examined. The intratracheal injection of LPS (2.5 micrograms) induced a six-fold increase in total cell number recovered in bronchoalveolar lavage (BAL) fluid at 24 hr. This increase in bronchopulmonary inflammation was mainly due to a neutrophil and macrophage infiltration, representing 60% and 35% of the total cells, respectively. The intravenous or intratracheal injection of Sephadex beads to guinea pigs induced a three-fold increase in total cell number recovered in BAL at 24 h and was characterized by a prominent eosinophil, macrophage, and neutrophil infiltration representing 36%, 42%, and 16% of the total cells, respectively. In addition, bronchial tissues isolated from Sephadex-treated guinea pigs showed an increased in vitro reactivity to both histamine and acetylcholine. TNFbp (1-50 micrograms) induced a dose-dependent inhibition of cell infiltration induced by LPS. In contrast TNFbp neither attenuated the bronchopulmonary cell infiltration observed 24 h following intravenous or intratracheal administration of Sephadex beads nor inhibited the increase in bronchial reactivity. These results show that TNF plays an important role in cell infiltration induced by LPS, but not that induced by Sephadex, in the guinea pig lung.

Trichinella spiralis: Genetic Basis and Kinetics of the Anti-encysted Muscle Larval Response in Miniature Swine

Primary-infected swine lymphocyte antigen (SLA) inbred miniature swine, NIH minipigs, of the SLA a/a haplotype ( aa) display markedly reduced Trichinella spiralis-encysted muscle larval (ML) burdens 6 weeks after homologous challenge and are therefore referred to as responders against encysted T. spiralis ML. To investigate the kinetics and genetics of the anti-encysted ML response, and in an attempt to ascertain the mechanisms underlying this phenomenon, NIH minipigs of multiple SLA haplotypes, designated either as ax ( aa, ac, ad, af, ag, dh and hh) or non- ax ( cc, cd, and dd), received a primary inoculation of 300 T. spiralis ML followed by a challenge inoculation of 10,000 ML 6 or 17 weeks later. Pigs were examined at necropsy and at Weeks 1, 2, 3.5, and 6 after challenge. Statistical cluster analyses, based on final ML burdens, performed on 129 pigs in 13 trials, revealed that 47% of primary-plus-challenged ax pigs exhibited responder phenotype as early as 1–2 weeks after T. spiralis challenge whereas this response was manifested in only 8% of non-ax pigs. No correlation was observed between responder phenotype and T. spiralis-specific blastogenesis, cell expression of class I or class II SLA molecules, lymphoid cell subsets, adult worm numbers, or fecundity. Although some ax responder pigs exhibited a localized inflammatory response with a prominent eosinophilic infiltrate surrounding degenerating encysted ML, no correlation was observed between responder phenotype and either peripheral blood eosinophilia or the ability of eosinophil-enriched cell populations from responder pigs to adhere to or destroy encysted ML in vitro.