Los eosinófilos: ¿sólo parasitosis y alergia? / Eosinophils only in allergy and parasitosis?

Se presentan las propiedades biológicas del eosinófilo a la luz de novedosos hallazgos relacionados con su preponderante papel en muchas otras patologías más allá de las clásicas. Su participación como célula inflamatoria vinculada estrechamente con la inmunidad innata o connatural queda demostrada.

Novel aspects of eosinophil functions are exposed. They are closely related to several pathologies that were not taken into account in the past. Their role as an inflammatory cell in innate immunology is reinforced.

Prostaglandin D2 and TH2 Inflammation in the Pathogenesis of Bronchial Asthma

Prostaglandin D2 (PGD2) is a major prostanoid, produced mainly by mast cells, in allergic diseases, including bronchial asthma. PGD2-induced vasodilatation and increased permeability are well-known classical effects that may be involved in allergic inflammation. Recently, novel functions of PGD2 have been identified. To date, D prostanoid receptor (DP) and chemoattractant receptor homologous molecule expressed on TH2 cells (CRTH2) have been shown to be major PGD2-related receptors. These two receptors have pivotal roles mediating allergic diseases by regulating the functions of various cell types, such as TH2 cells, eosinophils, basophils, mast cells, dendritic cells, and epithelial cells. This review will focus on the current understanding of the roles of PGD2 and its metabolites in TH2 inflammation and the pathogenesis of bronchial asthma.

Glycoproteomic analysis of plasma from patients with atopic dermatitis: CD5L and ApoE as potential biomarkers

Atopic dermatitis (AD) is an inflammatory skin disorder that is both uncomfortable and distressing to patients, and its prevalence has been steadily increasing. It is obvious that the identification of efficient markers of AD in plasma would offer the possibility of effective diagnosis, prevention, and treatment strategies. In this study, a proteomic approach was used to analyze plasma glycoproteins from both children with AD and healthy child donors. Several protein spots showing significant quantitative changes in the AD patients were identified. Through sequential studies, it was confirmed that CD5L and ApoE were significantly up-regulated or down-regulated, respectively, in the plasma from AD patients compared with that from healthy donors. In addition, we suggest that the up-regulated CD5L in AD patients causes eosinophilia by inhibiting apoptosis or promoting the proliferation of eosinophils either in combination with or without IL-5. The glycoproteomic data in this study provides clues to understanding the mechanism of atopic alterations in plasma and suggests AD-related proteins can be used as candidate markers for AD.

Inflammatory and Remodeling Events in Asthma with Chronic Exposure to House Dust Mites: A Murine Model

Although animal models with ovalbumin have been used to study chronic asthma, there are difficulties in inducing recurrence as well as in maintaining chronic inflammation in this system. Using a murine model of house dust mite (HDM)-induced bronchial asthma, we examined the airway remodeling process in response to the chronic exposure to HDM. During the seventh and twelfth weeks of study, HDM were inhaled through the nose for three consecutive days and airway responsiveness was measured. Twenty-four hours later, bronchoalveolar lavage and histological examination were performed. The degree of overproduction of mucus, subepithelial fibrosis, and the thickness of the peribronchial smooth muscle in the experimental group was clearly increased compared to the control group. In addition, HDM-exposed mice demonstrated severe airway hyperreactivity to methacholine. In the bronchoalveolar lavage fluid, the number of total cells and eosinophils was increased; during the twelfth week, the number of neutrophils increased in the experimental group. With regard to changes in cytokines, the concentrations of IL-4, IL- 13, and transforming growth factor-beta (TGF-beta) were increased in the experimental group. The data suggest that eosinophils, IL-4, IL-13, and TGF-beta might play an important role in the airway remodeling process and that neutrophils may be involved with increased exposure time.

Mechanisms of eosinophil cytokine release

Human eosinophils have been demonstrated to contain a multitude of cytokines and chemokines that exist pre-formed within these cells. This content of pre-formed cytokines, with diverse potential biologic activities, provides eosinophils with capabilities distinct from most other leukocytes. The localization of pre-formed cytokines within eosinophils is both within specific granules and associated with substantial numbers of morphologically distinct cytoplasmic vesicles. Stimulation for release of specific cytokines, such as IL-4, leads to a regulated signal transduction cascade, which is dependent on the formation of leukotriene C4 within eosinophils where it acts as an intracrine mediator. IL-4 release occurs selectively and is by means of vesicular transport. The capabilities of eosinophils not only to rapidly release pre-formed cytokines but also to differentially regulate which cytokines are released endow eosinophils with distinct abilities in innate and acquired immunity.

Eosinófilos: su rol en la patología dermatológica severa: segunda parte / Eosinofilos: the role in severe dermatologic pathology: second part

El eosinófilo es un granulocito pequeño derivado de la médula ósea, tiene un núcleo bilobulado característico y gránulos citoplasmáticos responsables de muchas de sus funciones pro inflamatorias; estas células interactúan con otras por la expresión de múltiples receptores en su superficie, lo que la convierte en una célula efectora de la respuesta inmune con importante tropismo hacia los tejidos. La producción y acumulación de eosinófilos implica la proliferación y diferenciación de células hermatopoyéticas, la interacción con las células endoteliales, la quimiotaxis, activación celular y el balance entre la sobrevida y apoptosis del eosinófilo. La eosinófilia persistente en sangre periférica puede ocurrir en un gran número de enfermedades y en algunas el eosinófilo es la principal célula efecto. La eosinofilia ocurre en una variedad de enfermedades severas en las que destacan las enfermedades alérgicas, infecciones parasitarias y neoplasias. Las enfermedades cutáneas en las que existe una infiltración tisular por eosinófilos constituye un grupo aparentemente heterogéneo, que se ha denominado dermatosis eosinofílica. Existe un grupo de desórdenes donde no se conoce el origen de la eosinofilia que se ha denominado "síndrome hipereosinofílico", en el cual la piel tambien es un órgano blanco de estas células. Es importante conocer la función efectora del eosinófilo en las reacciones inflamatorias cutáneas y de otros órganos, su papel modulador y las circunstancias donde predominan sus efectos citotóxicos generadores de enfermedad.

Degranulation of human eosinophils induced by Paragonimus westermani-secreted protease

Eosinophil degranulation is considered to be a key effector function for the killing of helminthic worms and tissue inflammation at worm-infected lesion sites. However, relatively little data are available with regard to eosinophil response after stimulation with worm-secreted products which contain a large quantity of cysteine proteases. In this study, we attempted to determine whether the degranulation of human eosinophils could be induced by the direct stimulation of the excretory-secretory products (ESP) of Paragonimus westermani, which causes pulmonary paragonimiasis in human beings. Incubation of eosinophils for 3 hr with Paragonimus-secreted products resulted in marked degranulation, as evidenced by the release of eosinophil-derived neurotoxin (EDN) in the culture supernatants. Moreover, superoxide anion was produced by eosinophils after stimulation of the ESP. The ESP-induced EDN release was found to be significantly inhibited when the ESP was pretreated with protease inhibitor cocktail or the cysteine protease inhibitor, E-64. These findings suggest that human eosinophils become degranulated in response to P. westermani-secreted proteases, which may contribute to in vivo tissue inflammation around the worms.

Eosinophil Inflammation of Nasal Polyp Tissue: Relationships with Matrix Metalloproteinases, Tissue Inhibitor of Metalloproteinase-1, and Transforming Growth Factor-beta1

Eosinophil and mast cell infiltrations are consistent findings in nasal polyp tissue. Previous studies have shown that matrix metalloproteinases (MMPs) may be involved in eosinophil infiltration in airway mucosa of asthmatic patients, and that transforming growth factor-beta1 (TGF-beta1) induces extracellular matrix deposition in nasal polyp tissue. The aim of this study was to evaluate the role of MMPs and tissue-inhibitor of metalloproteinase-1 (TIMP-1) in association with TGF-beta1, eosinophils and mast cell activation in nasal polyp tissue. Nasal polyp tissues from 20 patients who underwent polypectomies were collected and prepared into tissue homogenate. Eosinophil cationic protein (ECP) and tryptase levels were measured by CAP system (Pharmacia, Sweden). MMP-2, MMP-9, TIMP-1 and TGF-beta1 levels were measured by enzyme-liked immunosorbent assay. MMP-2 was the predominant form of MMPs, followed by MMP-9 and TIMP-1. There were significant correlations between ECP, and MMP-9, MMP-2, TGF-beta1 and tryptase, but not with TIMP-1. Significant correlations were noted between tryptase, and MMP-2, MMP-9, and TGF-beta1, but not with TIMP-1. Close correlations were noted between TGF-beta1, and MMP-9 and MMP-2, but not with TIMP-1. MMP-2, MMP-9, and TGF-beta1 may contribute to eosinophil and mast cell migrations into nasal polyp tissue.

Mecanismos de defensa del hospedero en estomatitis subprotÚsica inducida por Cßndida / Host defense mechanisms in Candida-induced denture stomatitis

La estomatitis subprotÚsica (E.S.P.) es una entidad que se localiza principalmente en la mucosa del paladar que se encuentra por debajo de la superficie de ajuste de las prótesis removibles parciales y totales. Esta patologÝa es mßs común en hombres que en mujeres y se observa mßs frecuentemente en sujetos con edades comprendidas entre 25 a 90 años. Diversos estudios han revelado que la E.S.P. estß asociada con la deteccion de especies de Cßndida y otros microorganismos, mientras que otros factores tales como trauma, ciertas enfermedades sistÚmicas y alteraciones del sistema inmune pueden estar involucrados, por lo que el hospedero responde mediante ciertos mecanismos ante la presencia de esta enfermedad. De allÝ que se han propuesto dos lÝneas de defensa ante la presencia de E.S.P. inducida por Cßndida; la primera de Ústas incluye entre otros: 1) factores fÝsicos, donde se destaca el papel que juegan las membranas mucosas bucales como barreras anatómicas; 2) compuestos salivales como la lisozima, lactoferrina e histatinas que inhiben el crecimiento de Cßndida y la interferencia de la microbiota bucal, la cual limita el sobrecrecimiento de este hongo, en tanto que la segunda destaca bßsicamente los mecanismos de inmunidad celular y humoral a nivel de los tejidos, haciendo Únfasis en la capacidad por parte de los polimorfonucleares y de los leucocitos eosinófilos de fagocitar a Cßndida, asÝ como el rol que juegan los anticuerpos como mecanismos de defensa contra esta enfermedad

Estudo revisional sobre a morfologia e as funçöes dos leucócitos / Revisional study of morphology and functions of leococytes

Revisäo bibliográfica da morfologia e propriedades químicas da Série Branca e suas principais funçöes, incluindo a fagocitose e ingestäo de partículas pelos neutrófilos, bem como suas funçöes secretórias. Descreve-se um estudo sobre o sistema fagocitário mononuclear e os linfócitos T e B, constatando-se a importância da análise da Série Branca para o profissional médico, seja para fim diagnóstico, terapêutico, ou de acompanhamento de uma patologia.

Síndrome de Wells ou celulite eosinofílica / Well's syndrome or eosinophilic cellulitis

Os autores relatam o caso de menino de nove anos que apresentava um quadro recorrente, com lesöes pruriginosas localizadas nos membros inferiores, iniciadas como pequenas placas eritematosas e evoluindo para lesöes com bordas infiltradas e resoluçäo central semelhantes ao granuloma anular. A única anormalidade nos exames laboratoriais foi eosinofilia. A histopatologia mostrou infiltrado inflamatório com predominância de eosinófilos, presença de focos de degeneraçäo eosinofílica do colágeno (flame figures), circundados por histiócitos e gigantócitos dispostos em paliçada. A patogênese ainda é desconhecida, parecendo tratar-se de reaçäo de hipersensibilidade desencandeada por diversos estímulos. A revisäo bibliográfica reuniu 19 casos em menores de 15 anos

Expression of eosinophil chemotactic factors in stomach cancer

We have occasionally experienced eosinophilic abscess of the liver in patients with gastric carcinoma, suggesting that some eosinophil mobilizing (chemotactic and proliferative) factors might be produced by carcinoma cells. The aim of this study was to determine whether or not gastric carcinoma expresses the well-known eosinophil chemotactic factors (ECFs) and whether or not the expression is related to the histologic subtypes. Seventeen consecutive surgically removed tumor-bearing stomachs were collected: 7 signet ring cell type, 7 poorly differentiated tubular adenocarcinoma, and 3 moderately differentiated tubular adenocarcinoma. Hematoxylin-eosin stained sections were re-evaluated for eosinophil and mast cell infiltration. The expression of IL-2, IL-5 and granulocyte-macrophage colony stimulating factor (GM-CSF) were examined by immunocytochemical stain. There was no available frozen tissue for IL-2 and IL-5 in one case. Gastric carcinoma expressed IL-2 in all 16 cases, IL-5 in 12 of 16 cases and GM-CSF in 10 of 17 cases. Of particular interest, 7 of 10 GM-CSF-expressing carcinomas were signet ring cell type. Even in the remaining 3 cases, most GM-CSF-positive cells were signet ring cells scattered within tubular adenocarcinoma. No correlation of ECF expression between either eosinophil/mast cell infiltration or peripheral blood eosinophilia was identified. In conclusion, most gastric carcinomas express the well-known ECFs and the expression of GM-CSF is specific for signet ring carcinoma cells.

Eosinophil-active chemokines: assessment of in vivo activity

The selective recruitment of eosinophils in tissue is a striking feature of allergic diseases. Recently, a family of chemoattractant molecules, namely chemokines, has been described which potently activates eosinophil function in vitro. We have developed a murine model of eosinophil recruitment to compare the relative potency and efficacy of chemokines in vivo. Of the chemokines tested, only eotaxin and MIP-1alpha induced significant accumulation of eosinophils in vivo, but eotaxin was more effective than MIP-1alpha. Chemokines, especially eotaxin acting via the CCR-3 receptor, may have a fundamental role in determining selective eosinophil recruitment in vivo.

The role of interleukin-5 (IL-5) in vivo: studies with IL-5 deficient mice

Eosinophil recruitment is a characteristic feature of a number of pathological conditions and was the topic of the recent International Symposium on allergic inflammation, asthma, parasitic and infectious diseases (Rio de Janeiro, June 3-5, 1996). Since interleukin-5 (IL-5) is believed to regulate the gowth, differentiation and activation of eosinophils (Conffman et al. 1989, Sanderson 1992), the role of eosinophils and IL-5 are closely linked. Although IL-5 specifically regulates eosinophilia in vivo and this is its most well established activity, it is becoming clear that IL-5 also has other biological effects. The recent derivation of an IL-5 deficient mouse (Kopf et al. 1996), provides a model for exploring not only the role of IL-5 and eosinophils but also other novel activities of IL-5. Of note is that although the IL-5 deficient mice cannot elicit a pronounced eosinophilia in response of inflammatory stimulation following aeroallergen challenge or parasite infection they still produce basal levels of eosinophils that appear to be morphologically and functionally normal. However, the basal levels of eosinophils appear insufficient for normal host defense as IL-5 deficiency has been shown to compromise defence against several helminth infections. In addition, IL-5 deficient mice appear to have functional deficiencies in B-1 B lymphocytes and in IgA production.

The debate over the effector function of eosinophils in helminth infection: new evidence from studies on the regulation of vaccine immunity by IL-12

The production of Th1-type cytokines is associated with strong cell-mediated immunity while Th2-type cytokines are typically involved in the generation of humoral immune responses. In mice vaccinated a single time (1x) with attenuated cercariae of Schistosoma mansoni, the immunity induced is highly dependent on CD4+ T cells and IFN-gamma. In contrast, mice vaccinated multiple times (3x) have decreased IFN-gamma expression, develop a more dominant Th2-type cytokine response as well as protective antibodies which can passively transfer immunity to naive recipients. Previously, we demonstrated the ability of IL-12, a potent IFN-gamma-inducing cytokine to enhance (1x) schistosome cell-mediated immunity when administered during the period of immunization. More recently, we asked what effects IL-12 would have on the development humoral-based immunity. While multiply-immunized/saline-treated mice demonstrated a 70-80 per cent reduction in parasite burden, 3x/IL-12-vaccinated animals displayed an even more striking >90 per cent reduction in challenge infection, which many mice in the later group demonstrating complete protection. Analysis of pulmonary cytokine mRNA responses demonstrated that control challenged mice elicited a dominant Th2-type response, 3x/saline-vaccinated produced a mixed Th1/Th2-type cytokine response, while 3x/saline-vaccinated produced a mixed Th1/Th2-type cytokine response, while 3x/IL-12 immunized animals displayed a dominant Th1-type response. The IL-12-treated group also showed a marked reduction in total serum IgE and tissue eosinophilia while SWAP-specific IgG2a and IgG2b Abs elevated. Interestingly, animals vaccinated with IL-12 also showed a highly significant increase in total Ig titers specific for IrV-5, a known protective antigen. More importantly, 3x/IL-12 serum alone, when transferred to naive mice reduced worm burdens by over 60 per cent while 3x/saline serum transferred significantly less protection. Nevertheless, animals vaccinated in the presence of IL-12 also develop macrophages with enhanced nitric oxide dependent killing activity against the parasites. Together, these observations suggest that IL-12, initially described as an adjuvant for cell-mediated immunity, may also be used as an adjuvant for promoting both humoral and cell-mediated protective responses.

Participation of interleukin-5, interleukin-8 and leukotriene B4 in eosinophil accumulation in two different experimental models

There are several experimental models descibing in vivo eosinophil (EO) migration, including injection of a large volume of saline (SAL) or Sephadex beads (SEP). The aim of this study was to investigate the mechanisms involved in the EO migration in these two models. Two consecutive injections of SAL given 48 hr apart, induced a selective recruitment of EO into peritoneal cavity of rats, which peaked 48 hr after the last injection. SEP, when injected, promoted EO accumulation in rats. The phenomenom was dose-related and peaked 48 hr after injection. To investigate the mediators involved in this process we showed that BW A4C, MK 886 and dexamethasone (DXA) inhibited the EO migration induced by SAL and SEP. To investigate the source of the EO chemotactic factor we showed that mast cells, macrophages (MO), but not lymphocytes, incubated in vitro in presence of SAL released a factor which induced EO migration. With SEP, only mast cells release a factor that induced EO migration, which was inhibited by BW A4C, MK 886 and DXA. Furthermore, the chemotactic activity of SAL-stimulated mast cells was inhibited by antisera against IL-5 and IL-8 (interleukin). SAL-stimulated MO were only inhibited by anti-IL-8 antibodies as well as SEP-stimulated mast cells. These results suggest that the EO migration induced by SAL may be dependent on resident mast cells and MO mediated by LTB4, IL-5 and IL-8. SEP-induced EO migration was dependent on mast cells and may be mediated by LTB4 and IL-8. Furthermore, IL-5 and IL-8 induced EO migration, which was also dependent on resident cells and mediated by LTB4. In conclusion, EO migration induced by SAL is dependent on mast cells and MO, whereas that induced by SEP is dependent on mast cells alone. Stimulated mast cells release LTB4, IL-5 and IL-8 while MO release LTB4 and IL-8. The IL-5 and and IL-8 release by the SAL or SEP-stimulated resident cells may act in an autocrine fashion, thus potentiating LTB4 release.

Role of eosinophilic airway inflammation in models of asthma

Eosinophils play a central role in the establishment and outcome of bronchial inflammation in asthma. Animal models of allergy are useful to answer questions related to mechanisms of allergic inflammation. We have used models of sensitized and boosted guinea pigs to investigate the nature of bronchial inflammation in allergic conditions. These animals develop marked bronchial infiltration composed mainly of CD4+ T-lymphocytes and eosinophils. Further provocation with antigen leads to degranulation of eosinophils and ulceration of the bronchial mucosa. Eosinophils are the first cells to increase in number in the mucosa after antigen challenge and depend on the expression of alpha4 integrin to adhere to the vascular endothelium and transmigrate to the mucosa. Blockage of alpha4 integrin expression with specific antibody prevent not only the transmigration of eosinophils but also the development of bronchial hyperresponsiveness (BHR) to agonists in sensitized and challenged animals, clearly suggesting a role for this cell type in this altered functional site. Moreover, introduction of antibody against Major Basic Protein into the airways also prevents the development of BHR in similar model. BHR can also be suppressed by the use of FK506, an immunosuppressor that reduces in almost 100 per cent the infiltration of eosinophils into the bronchi of allergic animals. These data support the concept that eosinophil is the most important pro-inflammatory factor in bronchial inflammation associated with allergy.