Increased Numbers Of Eosinophils Research Articles

Rapamycin Controls Lymphoproliferation and Reverses T-Cell Responses in a Patient with a Novel STIM1 Loss-of-Function Deletion

PurposeDeficiency of stromal interaction molecule 1 (STIM1) results in combined immunodeficiency accompanied by extra-immunological findings like enamel defects and myopathy. We here studied a patient with a STIM1 loss-of-function mutation who presented with severe lymphoproliferation. We sought to explore the efficacy of the mTOR inhibitor rapamycin in controlling disease manifestations and reversing aberrant T-cell subsets and functions, which has never been used previously in this disorder.MethodsClinical findings of the patient were collected over time. We performed immunological evaluations before and after initiation of rapamycin treatment, including detailed lymphocyte subset analyses, alterations in frequencies of circulating T follicular helper (cTFH) and regulatory T (Treg) cells and their subtypes as well as T cell activation and proliferation capacities.ResultsA novel homozygous exon 2 deletion in STIM1 was detected in a 3-year-old girl with severe lymphoproliferation, recurrent infections, myopathy, iris hypoplasia, and enamel hypoplasia. Lymphoproliferation was associated with severe T-cell infiltrates. The deletion resulted in a complete loss of protein expression, associated with a lack of store-operated calcium entry response, defective T-cell activation, proliferation, and cytokine production. Interestingly, patient blood contained fewer cTFH and increased circulating follicular regulatory (cTFR) cells. Abnormal skewing towards TH2-like responses in certain T-cell subpopulations like cTFH, non-cTFH memory T-helper, and Treg cells was associated with increased eosinophil numbers and serum IgE levels. Treatment with rapamycin controlled lymphoproliferation, improved T-cell activation and proliferation capacities, reversed T-cell responses, and repressed high IgE levels and eosinophilia.ConclusionsThis study enhances our understanding of STIM1 deficiency by uncovering additional abnormal T-cell responses, and reveals for the first time the potential therapeutic utility of rapamycin for this disorder.

The neurotropic schistosome vs experimental autoimmune encephalomyelitis: are there any winners?

The incidences of multiple sclerosis have risen worldwide, yet neither the trigger nor efficient treatment is known. Some research is dedicated to looking for treatment by parasites, mainly by helminths. However, little is known about the effect of helminths that infect the nervous system. Therefore, we chose the neurotropic avian schistosome Trichobilharzia regenti, which strongly promotes M2 polarization and tissue repair in the central nervous system, and we tested its effect on the course of experimental autoimmune encephalomyelitis (EAE) in mice. Surprisingly, the symptoms of EAE tended to worsen after the infection with T. regenti. The infection did not stimulate tissue repair, as indicated by the similar level of demyelination. Eosinophils heavily infiltrated the infected tissue, and the microglia number increased as well. Furthermore, splenocytes from T. regenti-infected EAE mice produced more interferon (IFN)-γ than splenocytes from EAE mice after stimulation with myelin oligodendrocyte glycoprotein. Our research indicates that the combination of increased eosinophil numbers and production of IFN-γ tends to worsen the EAE symptoms. Moreover, the data highlight the importance of considering the direct effect of the parasite on the tissue, as the migrating parasite may further tissue damage and make tissue repair even more difficult.

The A118G single-nucleotide polymorphism in OPRM1 is a risk factor for asthma severity

BackgroundAlthough population studies have implicated emotional burden in asthma severity, the underlying genetic risk factors are not completely understood. We aimed to evaluate the genetic influence of a functional single-nucleotide polymorphism (SNP) in the stress-related μ-opioid receptor gene (OPRM1; A118G SNP, rs1799971) on asthma severity. MethodsWe initially assessed disease severity in asthmatic outpatients carrying A118G. Using an ovalbumin-induced experimental asthma rodent model harboring the functionally equivalent SNP, we investigated the mechanism by which this SNP influences the allergic immune response. ResultsAmong 292 outpatients, 168 underwent airway hyperresponsiveness (AHR) to methacholine testing. Compared with patients carrying the AA and AG genotypes, those carrying the GG genotype exhibited enhanced AHR. The stress levels were presumed to be moderate among patients and were comparable among genotypes. Compared with Oprm1 AA mice, GG mice demonstrated aggravated asthma-related features and increased pulmonary interleukin-4+CD4+ effector and effector memory T cells under everyday life stress conditions. Intraperitoneal naloxone methiodide injection reduced effector CD4+ T cell elevation associated with increased eosinophil numbers in bronchoalveolar lavage fluid of GG mice to the levels in AA mice, suggesting that elevated Th2 cell generation in the bronchial lymph node (BLN) of GG mice induces enhanced eosinophilic inflammation. ConclusionsWithout forced stress exposure, patients with asthma carrying the OPRM1 GG genotype exhibit enhanced AHR, attributable to enhanced Th2 cell differentiation in the regional lymph node. Further research is necessary to elucidate the role of the OPRM1 A118G genotype in the Th2 cell differentiation pathway in the BLN.

Eosinophils Suppress the Migration of T Cells Into the Brain of Plasmodium berghei-Infected Ifnar1-/- Mice and Protect Them From Experimental Cerebral Malaria.

Cerebral malaria is a potentially lethal disease, which is caused by excessive inflammatory responses to Plasmodium parasites. Here we use a newly developed transgenic Plasmodium berghei ANKA (PbAAma1OVA) parasite that can be used to study parasite-specific T cell responses. Our present study demonstrates that Ifnar1-/- mice, which lack type I interferon receptor-dependent signaling, are protected from experimental cerebral malaria (ECM) when infected with this novel parasite. Although CD8+ T cell responses generated in the spleen are essential for the development of ECM, we measured comparable parasite-specific cytotoxic T cell responses in ECM-protected Ifnar1-/- mice and wild type mice suffering from ECM. Importantly, CD8+ T cells were increased in the spleens of ECM-protected Ifnar1-/- mice and the blood-brain-barrier remained intact. This was associated with elevated splenic levels of CCL5, a T cell and eosinophil chemotactic chemokine, which was mainly produced by eosinophils, and an increase in eosinophil numbers. Depletion of eosinophils enhanced CD8+ T cell infiltration into the brain and increased ECM induction in PbAAma1OVA-infected Ifnar1-/- mice. However, eosinophil-depletion did not reduce the CD8+ T cell population in the spleen or reduce splenic CCL5 concentrations. Our study demonstrates that eosinophils impact CD8+ T cell migration and proliferation during PbAAma1OVA-infection in Ifnar1-/- mice and thereby are contributing to the protection from ECM.

IL-33 sensitizes mast cells to respond to a second alarmin, ATP, but not PAMPs.

Abstract Barrier defenses must respond rapidly to pathogen infection but avoid responses to innocuous antigens or microbes. Aberrant recognition can lead to hypersensitivity and/or chronic inflammatory conditions. Barrier tissues actively release alarmins such as IL-33 in response to cell stress helping to identify pathogenic stimuli. Additional alarmin molecules such as ATP, uric acid crystals, and HMBG protein have also been identified but it remains unclear how the innate immune system integrates these multiple signals. We have used mast cells to address how IL-33 and ATP signals interact. While best known for their role in IgE-mediated allergic responses, mast cells readily produce inflammatory cytokines in response to either IL-33 or ATP. Measuring secreted IL-6, TNF alpha and IL-13 we found that bone marrow-derived and peritoneal mast cells had a 3–6-fold increased response to ATP when sensitized by pretreatment with IL-33. This synergistic effect was observed at relatively low ATP concentrations (<300μM) and required <1hr exposure to IL-33. Stimulating with PAMPs (LPS, LTA, poly I:C, ß-glucan) failed to show any enhancement with IL-33 pretreatment. Inhibitor studies indicated that the P2X3 receptor and the NFAT transcription factor mediated the ATP response. To test IL-33 and ATP synergy in vivo, we assessed eosinophil mobilization to the peritoneal cavity in mice. Consistent with the in vitro studies, co-administration of IL-33 and ATP increased eosinophil numbers compared to either alarmin alone. These results support the hypothesis that alarmins collaborate to surpass a threshold level of barrier stress necessary to initiate an inflammatory immune response.

Gastrointestinal Helminth Infection Improves Insulin Sensitivity, Decreases Systemic Inflammation, and Alters the Composition of Gut Microbiota in Distinct Mouse Models of Type 2 Diabetes.

Type 2 diabetes (T2D) is a major health problem and is considered one of the top 10 diseases leading to death globally. T2D has been widely associated with systemic and local inflammatory responses and with alterations in the gut microbiota. Microorganisms, including parasitic worms and gut microbes have exquisitely co-evolved with their hosts to establish an immunological interaction that is essential for the formation and maintenance of a balanced immune system, including suppression of excessive inflammation. Herein we show that both prophylactic and therapeutic infection of mice with the parasitic hookworm-like nematode, Nippostrongylus brasiliensis, significantly reduced fasting blood glucose, oral glucose tolerance and body weight gain in two different diet-induced mouse models of T2D. Helminth infection was associated with elevated type 2 immune responses including increased eosinophil numbers in the mesenteric lymph nodes, liver and adipose tissues, as well as increased expression of IL-4 and alternatively activated macrophage marker genes in adipose tissue, liver and gut. N. brasiliensis infection was also associated with significant compositional changes in the gut microbiota at both the phylum and order levels. Our findings show that N. brasiliensis infection drives changes in local and systemic immune cell populations, and that these changes are associated with a reduction in systemic and local inflammation and compositional changes in the gut microbiota which cumulatively might be responsible for the improved insulin sensitivity observed in infected mice. Our findings indicate that carefully controlled therapeutic hookworm infection in humans could be a novel approach for treating metabolic syndrome and thereby preventing T2D.

Systemic administration of IL-33 induces a population of circulating KLRG1hi type 2 innate lymphoid cells and inhibits type 1 innate immunity against multiple myeloma.

Type 2 innate lymphoid cells (ILC2s) are important producers of type 2 cytokines whose role in hematological cancers remains unclear. ILC2s are a heterogeneous population encompassing distinct subsets with different tissue localization and cytokine responsiveness. In this study, we investigated the role of bone marrow (BM) ILC2s and interleukin (IL)-33-stimulated ILC2s in multiple myeloma, a plasma cell malignancy that develops in the BM. We found that myeloma growth was associated with phenotypic and functional alterations of BM ILC2s, characterized by an increased expression of maturation markers and reduced cytokine response to IL-2/IL-33. We identified a population of KLRG1hi ILC2s that preferentially accumulated in the liver and spleen of Il2rg-/- Rag2-/- mice reconstituted with BM ILC2s. A similar population of KLRG1hi ILC2s was observed in the blood, liver and spleen of IL-33-treated wild-type mice. The presence of KLRG1hi ILC2s in ILC2-reconstituted Il2rg-/- Rag2-/- mice or in IL-33-treated wild-type mice was associated with increased eosinophil numbers but had no effect on myeloma progression. Interestingly, while decreased myeloma growth was observed following treatment of Rag-deficient mice with the type 1 cytokines IL-12 and IL-18, this protection was reversed when mice received a combined treatment of IL-33 together with IL-12 and IL-18. In summary, our data indicate that IL-33 treatment induces a population of circulating inflammatory KLRG1hi ILC2s and inhibits type 1 immunity against multiple myeloma. These results argue against therapeutic administration of IL-33 to myeloma patients.

Zinc-depletion associates with tissue eosinophilia and collagen depletion in chronic rhinosinusitis.

Zinc plays an important role in many biological processes. Reduced zinc levels have been found in chronic rhinosinusitis (CRS) patients, however, its role in the pathophysiology of this disease remains unknown. This study examined zinc levels in the serum, mucus and tissue from CRS patients in relation to collagen content and eosinophil infiltration. The effect of zinc depletion on inflammatory cytokine production and collagen synthesis was assessed in vitro. Zinc levels were determined in serum, mucus and tissue from controls, CRS with (CRSwNP) and without nasal polyps (CRSsNP) patients. Tissue zinc levels, collagen and inflammatory cell infiltration was examined using zinquin assays, immunofluorescence and histology on Tissue Micro Arrays. Cytokine expression and collagen synthesis was evaluated in zinc depleted primary human nasal epithelial cells (HNECs) and primary fibroblasts. CRSwNP patients showed reduced tissue zinc levels in correlation with a reduction in collagen content, and increased eosinophil numbers. Zinc depletion of HNECs and fibroblasts induced the production of pro-inflammatory cytokines and MUC5AC and reduced collagen secretion. These results suggest mucosal zinc depletion associates with tissue eosinophilia and collagen depletion in CRSwNP and induces pro-inflammatory cytokine expression and reduction of collagen synthesis in vitro.

Single and Synergistic Effects of Type 2 Cytokines on Eosinophils and Asthma Hallmarks.

The type 2 cytokines IL-5, IL-13, and IL-4 play an important role in the induction and progression of asthma. According to the Global Initiative for Asthma guidelines, blood eosinophil numbers are one marker that helps to guide treatment decisions in patients suffering from severe forms of asthma. Effects of type 2 cytokines were analyzed, alone or in combination, on eosinophils in blood and other compartments and on the development of asthma symptoms. C57BL/6 mice received a single intranasal application of equimolar amounts of IL-5, IL-13, and IL-4, alone or in combination. Numbers, activation state, and migratory behavior of eosinophils in bone marrow (BM), blood, lung, and bronchoalveolar lavage as well as airway hyperresponsiveness and goblet cell metaplasia were evaluated. Only IL-13 was associated with airway eosinophilia, development of airway hyperresponsiveness, and goblet cell metaplasia, without any synergistic effects. IL-5 increased the number of eosinophils in BM and lung tissue but failed to affect structural changes. IL-4 had similar, but weaker, effects to IL-13. Cytokine combinations synergistically affected eosinophils but failed to enhance IL-13-driven effects on lung function or goblet cell metaplasia. IL-5 and IL-13 markedly increased eosinophil numbers locally in lung and airways and distally in blood and BM, whereas IL-5 and IL-4 only increased eosinophils in lung and BM. IL-13 together with IL-4 failed to demonstrate any synergistic effect. These insights into single and combined effects of type 2 cytokines on disease-driving mechanisms could improve understanding of the impact and effectiveness of new therapies in asthma.

A case of pediatric drug-induced hypersensitivity syndrome

A 10-year and 9-month-old female patient presented with skin rashes all over the body, fever and superficial lymphadenectasis for 18 days after an intravenous drip of fosfomycin. Skin examination showed generalized swollen erythema all over the body, whose surfaces were covered with a large number of sticky furfuraceous grey-white scales. Laboratory examination revealed markedly increased levels of alanine aminotransferase and aspartate aminotransferase, as well as an increased number of eosinophils. Histopatho-logical examination of skin lesions showed infiltration of scattered lymphocytes in the superficial dermis, as well as around skin appendages. Immunohistochemical study demonstrated that the infiltrating lymphocytes mainly included T lymphocytes, and no atypical cells were observed. The patient was diagnosed with drug-induced hypersensitivity syndrome. After the treatment with intravenous glucocorticoids, immunoglobulin and oral cyclosporine, favorable therapeutic effects were achieved. Key words: Drug hypersensitivity; Drug eruptions; Fosfomycin; Skin manifestations; Treatment outcome

IFN-γ inhibits acute allergic airway inflammation in mice

Objective To investigate the inhibitory effect of IFN-γ on acute allergic airway inflammation induced by IL-33 in mice. Methods Twenty-four female C57BL/6 mice (6-8 weeks) were randomly divided into four groups: IL-33 model group, IFN-γ treatment group, IL-33+ IFN-γ treatment group and PBS control group. A mouse model of acute allergic airway inflammation was induced by IL-33. Samples of bronchial alveolar lavage fluid (BALF) and lung tissues were collected. Group 2 innate lymphoid cells (ILC2s) and eosinophils were analyzed by flow cytometry. Levels of IL-5 and IL-13 in the supernatants of lung homogenate and BALF were measured by ELISA. Expression of IL-5, IL-13 and ST2 at mRNA level was detected by real-time PCR. Pathological changes in lung tissues were observed following hematoxylin and eosin (HE) and periodic acid-Schiff (PAS) staining. Results Compared with the PBS control group, no infiltration with inflammatory cells, goblet cell hyperplasia or mucus secretion was observed in the IFN-γ group; the numbers of ILC2s and eosinophils were not affected by IFN-γ; the levels of IL-5 and IL-13 in the supernatants of BALF and lung homogenate, and the expression of IL-5, IL-13 and ST2 at mRNA level in lung tissues were not significantly changed by IFN-γ (P>0.05). Compared with the PBS control group, massive infiltration with inflammatory cells, excessive mucus secretion, increased numbers of ILC2s and eosinophils, up-regulated levels of IL-5 and IL-13 in the supernatants of BALF and lung homogenate, and enhanced expression of IL-5, IL-13 and ST2 at mRNA level in lung tissues were detected in the IL-33 model group (P<0.05). Compared with the IL-33 model group, the combined treatment with IL-33 and IFN-γ significantly alleviated inflammatory cell infiltration, inhibited mucus secretion, reduced the numbers of ILC2s and eosinophils, down-regulated the levels of IL-5 and IL-13 in the supernatants of BALF and lung homogenate, and suppressed the expression of IL-5, IL-13 and ST2 at mRNA in lung tissues (P<0.05). Conclusion IFN-γ can inhibit the proliferation of eosinophils and ILC2s induced by IL-33, and reduce the secretion of IL-5 and IL-13, which indicates that IFN-γ has an inhibitory effect on acute allergic airway inflammation induced by IL-33 in mice. Key words: IFN-γ; Group 2 innate lymphoid cell; IL-33; Acute airway inflammation

The effects of intrauterine infusion of peanut oil on endometrial health, salivary cortisol and interovulatory period in mares

Intrauterine infusion of peanut oil at Day 10 post-ovulation has been reported to prolong dioestrus in mares. However, the effects of peanut oil treatment on the endometrium and whether the technique is painful have not been assessed. The objectives of this study were, (i) to determine the effect of intrauterine infusion of peanut oil on endometrial health, (ii) to determine whether use of intrauterine peanut oil is painful and (iii) to confirm that peanut oil causes prolonged dioestrus. Six mares aged 3–12 years old were used in a cross-over design with each mare administered both 1 ml of intrauterine peanut oil and a sham treatment on different oestrous cycles. The effect of intrauterine infusion of 1 ml peanut oil or sham treatment were measured using interovulatory period, uterine fluid accumulation as determined by transrectal ultrasonography, serum progesterone levels, endometrial Kenney biopsy scores and histological features, endometrial eosinophil numbers and salivary cortisol measurements. The individual mare response to intrauterine infusion of peanut oil was variable. Peanut oil infusion did not statistically prolong the luteal phase, nor elevate salivary cortisol levels but did cause superficial erosion of the endometrial surface epithelium in all mares and significantly increased eosinophil numbers in the endometrium (P = 0.0068). The Kenney grade for biopsies from 2/6 mares worsened transiently following infusion. In conclusion, intra-uterine peanut oil does not statistically increase the duration of the luteal phase but results in an inflammatory response and increase in endometrial eosinophil numbers suggesting treatment may be associated with a hypersensitivity-type reaction. Those contemplating using peanut oil to suppress oestrus should also be aware of the legislative and regulatory implications.

Ultrasonic features of pediatric eosinophilic gastroenteritis of children

Objective To summarize the manifestation of pediatric eosinophilic gastroenteritis by ultrasound and discuss the diagnostic value of ultrasonography in pediatric eosinophilic gastroenteritis. Methods The ultrasonic appearances of 31 cases of pediatric eosinophilic gastroenteritis confirmed by clinics and pathology were reviewed and analyzed. Results Nineteen of 31 cases were observed in association with eosinophilic infiltration of other organs which were diagnosed as idiopathic hypereosinophilic syndrome. Eosinophilic cystitis was the most common among the complications(89.4%, 17/19). Twelve of 31 cases were diagnosed as eosinophilic gastroenteritis without complications. The endoscopic appearances of eosinophilic gastroenteritis were nonspecific which include erythematous, hyperemia edema, and partiality erosion changes. Endoscopy demonstrates increased numbers of eosinophils in the propria of stomach and the duodenum. Ultrasound features of the gastroenteritis appeared diffuse or the parts of gastrointestinal tract. The most common sites of eosinophilic gastroenteritis were the stomach and duodenum.Involvement of muscle layer and serosal layer showed wall thickening of cyclic annular and uniformity. Ultrasound might show nodular or irregular thickening of the folds in the gastric antrum when the submucosa were thickening. The mucosal layer involvement was not easy to be found by ultrasound. The echo of serous layer and submucosa associated with the disease stage. The thickening of surrounding omentum and mesenteric tissue, echo enhancement and nonspecific hyperplastic mesenteric lymph nodes infiltrated with eosinophils might be present.Eosinophilic ascites could often be detected. Conclusions Ultrasound has obvious advantages in the diagnosis of pediatric eosinophilic gastroenteritis, and the ultrasonic changes of pediatric eosinophilic gastroenteritis are characterized. Ultrasonography can provide the possible diagnosis when combined with inflammatory of other organs, especially cystitis inflammatory changes. Key words: Ultrasonography; Pediatric; Eosinophilic gastroenteritis

The soluble guanylyl cyclase activator BAY 60-2770 inhibits murine allergic airways inflammation and human eosinophil chemotaxis

ObjectivesActivators of soluble guanylyl cyclase (sGC) act preferentially in conditions of enzyme oxidation or haem group removal. This study was designed to investigate the effects of the sGC activator BAY 60-2770 in murine airways inflammation and human eosinophil chemotaxis. MethodsC57Bl/6 mice treated or not with BAY 60-2770 (1 mg/kg/day, 14 days) were intranasally challenged with ovalbumin (OVA). At 48 h, bronchoalveolar lavage fluid (BALF) was performed, and circulating blood, bone marrow and lungs were obtained. Human eosinophils purified from peripheral blood were used to evaluate the cell chemotaxis. ResultsOVA-challenge promoted marked increases in eosinophil number in BAL, lung tissue, circulating blood and bone marrow, all of which were significantly reduced by BAY 60-2770. The IL-4 and IL-5 levels in BALF were significantly reduced by BAY 60-2770. Increased protein expression of iNOS, along with decreases of expression of sGC (α1 and β1 subunits) and cGMP levels were detected in lung tissue of OVA-challenged mice. BAY 60-2770 fully restored to baseline the iNOS and sGC subunit expressions, and cGMP levels. In human isolated eosinophils, BAY 60-2770 (1–5 μM) had no effects on the cGMP levels and eotaxin-induced chemotaxis; however, prior incubation with ODQ (10 μM) markedly elevated the BAY 60-2770-induced cyclic GMP production, further inhibiting the eosinophil chemotaxis. ConclusionsBAY 60-2770 reduces airway eosinophilic inflammation and rescue the sGC levels. In human eosinophils under oxidized conditions, BAY 60-2770 elevates the cGMP levels causing cell chemotaxis inhibition. BAY 60-2770 may reveal a novel therapeutic target for asthma treatment.

Echocardiography-guided percutaneous per-ventricular laser ablation of ventricular septum: in vivo study in a canine model.

Surgical myectomy and ethanol ablation are established intervention strategies for left ventricular outflow obstruction in hypertrophic cardiomyopathy. Safety and efficacy limitations of these interventions call for a minimally invasive, potentially safer, and more efficacious strategy. In this study, we aimed to evaluate the feasibility of echocardiography-guided percutaneous per-ventricular laser ablation of a ventricular septum in a canine model. Six domestic dogs were chosen for the study. A 21G needle was inserted into the right ventricle with its tip reaching the targeted basal to mid-septum, after which laser ablation was performed as follows: 1-W laser for 3 min (180 J) at the basal segment and 5 min (300 J) at middle segment of the septum, respectively. Echocardiography, blood chemistry tests, and pathology examination were performed to assess the results of laser ablation. No death or major complications, i.e., tamponade, pericardial effusion, or ventricular fibrillation, occurred. The laser-ablated areas were well demarcated in the results of the pathological examination. The diameters of the ablated regions were 4.42 ± 0.57 and 5.28 ± 0.83 mm for 3 and 5 min ablation, respectively. Pre-ablation and post-ablation, cardiac enzymes were found to increase significantly while no significant differences were found among M-mode, 2D (LVEF), pulsed-wave (PW) Doppler, and tissue Doppler imaging (TDI) measurements. Contrast echocardiography confirmed the perfusion defects in the ablated regions. Microscopically, the ablated myocardium showed coagulative changes and a sparse distribution of disappearing nuclei and an increase in eosinophil number were observed. Our study suggests that percutaneous and per-ventricular laser ablation of the septum is feasible, potentially safe and efficacious, and warrants further investigation and validation.

Elevated Plasma Level of Interferon-λ1 in Chronic Spontaneous Urticaria: Upregulated Expression in CD8(+) and Epithelial Cells and Induction of Inflammatory Cell Accumulation.

Interferon- (IFN-) λ1 is regarded as a potent bio-active molecule in innate immunity. However, little is known about its role in chronic spontaneous urticaria (CSU). We therefore investigated expression of IFN-λ1 in CSU, its cellular location, and its influence on inflammatory cell accumulation by using flow cytometry analysis, skin tissue dispersion, immunohistochemical stain, and a mouse peritoneal inflammation model. The results showed that level of IFN-λ1 was 2.0-fold higher in plasma of the patients with CSU than the level in healthy control (HC) subjects. Among leukocytes examined, only CD8+ T cells expressed more IFN-λ1 in CSU blood. Double labeling immunohistochemical staining revealed that IFN-λ1+ inflammatory cells such as mast cells, eosinophils, B cells, neutrophils, and macrophages were mainly located in dermis, whereas epidermis tissue highly expressed IFN-λ1. IFN-λ1 induced a dose-dependent increase in number of eosinophils, lymphocytes, mast cells, macrophages, and neutrophils in the peritoneum of mice at 6 h following injection, which was inhibited by pretreatment of the animals with anti-intercellular adhesion molecule- (ICAM-) 1 and/or anti-L-selectin antibodies. In conclusion, IFN-λ1 is likely to play a role in the pathogenesis of CSU. Blocking IFN-λ1 production may help to reduce the accumulation of inflammatory cells in the involved CSU skin.

Depletion of Neutrophils Exacerbates the Early Inflammatory Immune Response in Lungs of Mice Infected with Paracoccidioides brasiliensis.

Neutrophils predominate during the acute phase of the Paracoccidioides brasiliensis infection. Herein, we determined the role of the neutrophil during the early stages of experimental pulmonary paracoccidioidomycosis using a monoclonal antibody (mAb) specific for neutrophils. Male BALB/c mice were inoculated intranasally with 1.5 × 106 or 2 × 106 P. brasiliensis yeast cells. The mAb was administered 24 h before infection, followed by doses every 48 h until mice were sacrificed. Survival time was evaluated and mice were sacrificed at 48 h and 96 h after inoculation to assess cellularity, fungal load, cytokine/chemokine levels, and histopathological analysis. Neutrophils from mAb-treated mice were efficiently depleted (99.04%). Eighty percent of the mice treated with the mAb and infected with 1.5 × 106 yeast cells died during the first two weeks after infection. When mice were treated and infected with 2 × 106 yeast cells, 100% of them succumbed by the first week after infection. During the acute inflammatory response significant increases in numbers of eosinophils, fungal load and levels of proinflammatory cytokines/chemokines were observed in the mAb-treated mice. We also confirmed that neutrophils are an important source of IFN-γ and IL-17. These results indicate that neutrophils are essential for protection as well as being important for regulating the early inflammatory immune response in experimental pulmonary paracoccidioidomycosis.

Eosinophil count at intensive care unit admission was not predictor of hospital mortality: results of a case control study.

BackgroundPredicting mortality in the intensive care unit (ICU) is one of the biggest challenges in critical care medicine. Several studies have linked the presence of eosinopenia with adverse outcomes in different populations.MethodsWe performed a case control study to determine whether the eosinophil count at ICU admission was a predictor of hospital mortality. We included data from patients 18 years or older admitted to the medical or surgical ICU in a university hospital in northern of Mexico. Medical records of 86 non-survivors (cases) and 99 discharged alive patients (controls) were randomly reviewed; clinical records of patients with an ICU stay of less than 24 h and those whose information was incomplete were excluded.ResultsMedian of eosinophil count at ICU admission was 0.013 (interquartile range (IQR) 0.00 to 0.57) K/μL. There was no significant statistical difference in eosinophils at admission between survivors and non-survivors (0.014 [IQR 0.00 to 0.36] vs. 0.010 [IQR 0.00 to 0.57] K/μL, P = 0.35). In the multivariate analysis, APACHE II score at ICU admission and discharge were the only mortality predictors. Survivors had a significantly greater increase in eosinophil count during the first 7 days of ICU stay (0.104 [IQR −0.64 to 0.41] vs. 0.005 [IQR −1.79 to 0.43] K/μL, P = 0.004).ConclusionsIn our study, eosinophil count at ICU admission was not associated with increased hospital mortality. The larger increase in number of eosinophils observed during the first week of ICU stay in surviving patients deserves to be investigated further.

Early life exposure to bisphenol A investigated in mouse models of airway allergy, food allergy and oral tolerance

The impact of early life exposure to bisphenol A (BPA) through drinking water was investigated in mouse models of respiratory allergy, food allergy and oral tolerance. Balb/c mice were exposed to BPA (0, 10 or 100 μg/ml), and the offspring were intranasally exposed to the allergen ovalbumin (OVA). C3H/HeJ offspring were sensitized with the food allergen lupin by intragastric gavage, after exposure to BPA (0, 1, 10 or 100 μg/ml). In separate offspring, oral tolerance was induced by gavage of 5 mg lupin one week before entering the protocol for the food allergy induction. In the airway allergy model, BPA (100 μg/ml) caused increased eosinophil numbers in bronchoalveolar lavage fluid (BALF) and a trend of increased OVA-specific IgE levels. In the food allergy and tolerance models, BPA did not alter the clinical anaphylaxis or antibody responses, but induced alterations in splenocyte cytokines and decreased mouse mast cell protease (MMCP)-1 serum levels. In conclusion, early life exposure to BPA through drinking water modestly augmented allergic responses in a mouse model of airway allergy only at high doses, and not in mouse models for food allergy and tolerance. Thus, our data do not support that BPA promotes allergy development at exposure levels relevant for humans.

Roles of 5-lipoxygenase and cysteinyl-leukotriene type 1 receptors in the hematological response to allergen challenge and its prevention by diethylcarbamazine in a murine model of asthma.

Diethylcarbamazine (DEC), which blocks leukotriene production, abolishes the challenge-induced increase in eosinopoiesis in bone-marrow from ovalbumin- (OVA-) sensitized mice, suggesting that 5-lipoxygenase (5-LO) products contribute to the hematological responses in experimental asthma models. We explored the relationship between 5-LO, central and peripheral eosinophilia, and effectiveness of DEC, using PAS or BALB/c mice and 5-LO-deficient mutants. We quantified eosinophil numbers in freshly harvested or cultured bone-marrow, peritoneal lavage fluid, and spleen, with or without administration of leukotriene generation inhibitors (DEC and MK886) and cisteinyl-leukotriene type I receptor antagonist (montelukast). The increase in eosinophil numbers in bone-marrow, observed in sensitized/challenged wild-type mice, was abolished by MK886 and DEC pretreatment. In ALOX mutants, by contrast, there was no increase in bone-marrow eosinophil counts, nor in eosinophil production in culture, in response to sensitization/challenge. In sensitized/challenged ALOX mice, challenge-induced migration of eosinophils to the peritoneal cavity was significantly reduced relative to the wild-type PAS controls. DEC was ineffective in ALOX mice, as expected from a mechanism of action dependent on 5-LO. In BALB/c mice, challenge significantly increased spleen eosinophil numbers and DEC treatment prevented this increase. Overall, 5-LO appears as indispensable to the systemic hematological response to allergen challenge, as well as to the effectiveness of DEC.