Showing papers by "Kenji Matsumoto published in 2012"

Interleukin‐33 in allergy

Abstract: Interleukin-33 (IL-33) is a member of the IL-1 cytokine family, which includes IL-1 and IL-18, and is considered to be important for host defense against nematodes by inducing Th2 cytokine production via the IL-33 receptor IL-33 receptor is a heterodimer of IL-1 receptor-like 1 (IL-1RL1; also called ST2, T1, Der4, and fit-1) and IL-1 receptor accessory protein (IL-1RAcP) On the other hand, excessive and/or inappropriate production of IL-33 is considered to be involved in the development of various disorders, such as allergic and autoimmune diseases Unlike IL-1β and IL-18, IL-33 does not seem to be secreted through the activation of inflammasomes in events such as apoptosis However, IL-33 is localized in the nucleus of cells and is released during tissue injury associated with necrosis This suggests that it acts as an alarmin, like IL-1α and high-mobility group box chromosomal protein-1 (HMGB-1) This review summarizes current knowledge regarding the roles of IL-33 in the functions of various cell types and the pathogenesis of allergy

Epithelial Cell-Derived IL-25, but Not Th17 Cell-Derived IL-17 or IL-17F, Is Crucial for Murine Asthma

Abstract: IL-17A, IL-17F, and IL-25 are ligands for IL-17RA. In the current study, we demonstrated that IL-25-deficient mice-but not IL-17A-, IL-17F-, IL-17A/F-, IL-23p19-, or retinoic acid-related orphan receptor (ROR)-γt-deficient mice-showed significant suppression of 1) the number of eosinophils and the levels of proinflammatory mediators in bronchoalveolar lavage fluids, 2) airway hyperresponsiveness to methacholine, and 3) OVA-specific IgG1 and IgE levels in the serum during OVA-induced Th2-type/eosinophilic airway inflammation. The IL-25 deficiency did not affect lung dendritic cell migration or Ag-specific memory-Th2 cell expansion during Ag sensitization. Adoptive transfer of T cells, mast cells, or bone marrow cells from IL-25-deficient mice revealed that induction of Th2-type/eosinophilic airway inflammation was dependent on activation of lung epithelial cells and eosinophils by IL-25 produced by airway structural cells such as epithelial cells but not by such hematopoietic stem-cell-origin immune cells as T cells and mast cells. Therefore, airway structural cell-derived IL-25-rather than Th17 cell-derived IL-17A and IL-17F-is responsible for induction of local inflammation by promoting activation of lung epithelial cells and eosinophils in the elicitation phase of Th2-type/eosinophilic airway inflammation. It is not required for Ag-specific Th2 cell differentiation in the sensitization phase.

Histamine-releasing factor has a proinflammatory role in mouse models of asthma and allergy

Abstract: IgE-mediated activation of mast cells and basophils underlies allergic diseases such as asthma. Histamine-releasing factor (HRF; also known as translationally controlled tumor protein [TCTP] and fortilin) has been implicated in late-phase allergic reactions (LPRs) and chronic allergic inflammation, but its functions during asthma are not well understood. Here, we identified a subset of IgE and IgG antibodies as HRF-interacting molecules in vitro. HRF was able to dimerize and bind to Igs via interactions of its N-terminal and internal regions with the Fab region of Igs. Therefore, HRF together with HRF-reactive IgE was able to activate mast cells in vitro. In mouse models of asthma and allergy, Ig-interacting HRF peptides that were shown to block HRF/Ig interactions in vitro inhibited IgE/HRF-induced mast cell activation and in vivo cutaneous anaphylaxis and airway inflammation. Intranasally administered HRF recruited inflammatory immune cells to the lung in naive mice in a mast cell– and Fc receptor–dependent manner. These results indicate that HRF has a proinflammatory role in asthma and skin immediate hypersensitivity, leading us to suggest HRF as a potential therapeutic target.

Non–IgE-Mediated Gastrointestinal Food Allergies: Distinct Differences in Clinical Phenotype Between Western Countries and Japan

Abstract: Non-IgE-mediated gastrointestinal food allergies, including food-protein-induced enterocolitis, enteropathy, proctocolitis and allergic eosinophilic gastroenteritis, seem to be increasing in several regions in the world. However, unlike the case of IgE-mediated food allergy, development of diagnostic laboratory tests and our understanding of the immunological mechanisms involved in non-IgE-mediated gastrointestinal food allergies lag. Although the clinical entities in Western countries have been well established, the clinical phenotypes might differ somewhat among the human races and geographical regions. In Japan, non-IgE-mediated gastrointestinal food allergies have increased sharply since the late 1990s, and clinicians have sometimes experienced confusion because of differences in the clinical phenotypes from those seen in Western countries. Aiming to solve this problem, we performed clinical research and determined a useful method for dividing patients into four clusters with distinctive clinical symptoms. We are confident this method will help in diagnosing and treating these patients. We also tried to clarify the differences between these patients in Japan and Western countries.

Anti-inflammatory effects of high-dose IgG on TNF-α-activated human coronary artery endothelial cells.

Abstract: High-dose infusion of IgG (IVIG) is used to treat autoimmune and inflammatory diseases, including Kawasaki disease (KD). Although the immunomodulatory effects of IVIG on blood cells such as macrophages have been well studied, its effects on tissue cells remain unclear. Here, we show that high-dose IgG specifically and completely inhibited TNF-α-induced, but not IL-1β-induced, secretion of proinflammatory cytokines such as G-CSF and IL-6 by cultured human coronary artery endothelial cells (HCAECs). High-dose IgG did not inhibit TNF-α-mediated early signaling events of the NF-κB and MAPK pathways but it potently inhibited gene expression of G-CSF and IL-6 12 h after TNF-α-stimulation. Interestingly, suppression of the G-CSF and IL-6 gene expression correlated closely with functional inhibition of a transcription factor, C/EBPδ, whose binding sites in the promoters of G-CSF and IL-6 have been shown to be critical for their transcriptional activation. Furthermore, the inhibitory effect of intact IgG on HCAECs was exerted mainly via its F(ab’)2 fragment, and not its Fc fragment. These findings suggest that the clinical effects of IVIG on KD patients are at least in part due to its direct anti-inflammatory effects on the coronary endothelium, which is a major lesion site in the pathogenesis of KD.

The role of Staphylococcal enterotoxin in atopic keratoconjunctivitis and corneal ulceration

Abstract: Background Patients with atopic eczema frequently experience colonization with Staphylococcus aureus that is directly correlated with the eczema severity. We hypothesized that S. aureus-secreted enterotoxins (SE) are involved in the pathophysiology of atopic keratoconjunctivitis (AKC). Methods A total of 45 subjects (18 with AKC, nine vernal keratoconjunctivitis (VKC), eight seasonal allergic conjunctivitis (SAC), and ten healthy volunteers) were enrolled. Slit lamp examinations, including fluorescein staining, were performed. Scraped samples were collected from the upper tarsal conjunctiva, lower conjunctival sacs, and the skin around the eyelid margins. Superantigen (SAg) genes were detected using polymerase chain reaction (PCR). Results Among 45 cases, S. aureus was detected significantly more in AKC patients than VKC patients (P = 0.026), SAC patients (P = 0.0003), and healthy volunteers (P = 0.0001). SAg genes were detected in 11 patients. SEB (2/11), SEG (8/11), and SEI (8/11) were detected, but no other SE. There was a significant difference in SE detection between AKC and SAC patients (P = 0.03). In severe types of ocular allergic disease such as AKC and VKC (N = 27), SE was detected in six of ten patients with corneal ulcers and two of 17 patients without corneal ulcers. SE was detected in significantly more patients with corneal ulcers (P = 0.025). Conclusions In patients with AKC,S. aureus and SE were detected more frequently compared with other patients and healthy volunteers, especially in association with corneal ulceration suggesting a role of SE. So far, it is unknown whether SE leads to tissue damage of the cornea by initiating an immune response or has direct toxic effects.

Omalizumab inhibits acceleration of FcεRI-mediated responsiveness of immature human mast cells by immunoglobulin E

Abstract: Background A large body of evidence has demonstrated that treatment with omalizumab is clinically effective for the management of moderate to severe allergic asthma, emphasizing the importance of IgE in the pathogenesis of allergic asthma. We hypothesized that IgE accelerates FceRI-mediated responsiveness of "immature" human mast cells (MCs) and that omalizumab downregulates the acceleration. Objectives To examine when MC progenitors acquired the ability to degranulate following FceRI aggregation, whether IgE accelerates the responsiveness of immature MCs following FceRI aggregation, and whether omalizumab regulates such an acceleration. Methods Gene expression was examined using a microarray and quantitative reverse transcription polymerase chain reaction. Protein expression was investigated using FACS. Histamine release was examined using an EIA. Results The time-course analysis of the mRNA expression of MC-related genes, including FceRI, in Kit + sorted cells during the differentiation and histamine experiments revealed that the expression level of FceRI in 5 week (w)-cultured MCs was not sufficient to induce degranulation following FceRI aggregation but that 5 w-cultured MCs were fully responsive to calcium ionophore. By addition of IgE in culture medium FceRI expression level and FceRI-mediated histamine release of 5 w-cultured MCs were significantly increased compared with those without addition of IgE, whereas the expression level of tryptase and number of MCs was not affected. Omalizumab significantly inhibited IgE-dependent enhancement of FceRI expression level and FceRI-mediated histamine release. Conclusions High levels of IgE in the microenvironment in vivo may upregulate the responsiveness of immature MCs to allergens. Omalizumab may inhibit the IgE-mediated responsiveness of not only mature MCs, but also immature MCs.