Kenji Izuhara

Ile50Val variant of IL4R alpha upregulates IgE synthesis and associates with atopic asthma.

Atopy is an immune disorder characterized by heightened immunoglobulin E (IgE) production and leads to the clinical disorders of asthma, eczema and rhinitis1. Interleukin 4 (IL4) is a pleiotropic cytokine which plays a crucial role in IgEdependent atopic disorders2; it is central to B cells switching to IgE antibody production and to the maturation of T-helper cells to the Th2 phenotype (type-2 Thelper lymphocyte). Human IL4 operates through the IL4 receptor (IL4R) and thereby Stat6 (signal transducer and activator of transcription 6) activation3. Mice deficient in Stat6 (refs 4,5) or the IL4Rα chain6 lack IgE production and Th2 inflammatory reactions. IL4Rα is therefore a crucial component required for IL4 binding and signal transduction. A cytoplasmic variant of IL4Rα, an Arg576Gln substitution (numbering from the first ATG), has been recently identified and is found in excess in a study of a group of individuals with hyper-IgE syndrome and severe eczema7; functional assays showed impaired binding of the negative regulatory molecule, protein tyrosine phosphatase, SHP-1, and increased expression of CD23 was found on peripheral blood mononuclear cells after being challenged with IL4. Stat6 activation, however, was not upregulated and no information was provided on cellular IgE synthesis. An extracellular variant, Thr49Ile, in IL4Rα of BALB/c mice alters the ligandbinding affinity of IL4Rα (ref. 8). An Ile50Val (numbering for mature peptide) variant of human IL4Rα has also been identified9,10 and it is, to date, the only known extracellular variant of human IL4Rα (ref. 11). To test whether the Ile50Val variant promotes dysregulation of IgE synthesis, we first conducted a genetic association study for serum IgE levels in a Japanese population. There was a significant difference in Ile/Val 50 genotype frequencies between control and atopic subjects (Table 1); Ile50 associated with atopic asthma but not with non-atopic asthma; Ile50 specifically and significantly associated with raised total serum IgE levels and mite-specific IgE. The association with atopy was especially strong in children. The high frequency of Ile50 homozygotes (approximately 60%) in the childhood atopic asthma group described here, and the significant skewing from Hardy-Weinberg equilibrium (P<0.0001), suggest a largely recessive genetic effect for Ile50 on atopy; the previously reported

Atopy and asthma: genetic variants of IL-4 and IL-13 signalling

Abstract Recent genetic and functional studies highlight the importance of IL-4/IL-13 signalling in the development of asthma and atopy. Here, Taro Shirakawa and colleagues discuss genetic variants of IL-4/IL-13 signalling, and whether they promote asthma or atopy among different ethnic groups.

Cloning and Characterization of the Hakata Antigen, a Member of the Ficolin/Opsonin p35 Lectin Family

The Hakata antigen is a novel, thermolabile β2-macroglycoprotein that reacts with sera from patients suffering from systemic lupus erythematosus. In this study we present the structure and the function of the Hakata antigen. We have identified cDNA clones encoding the Hakata antigen and analyzed its function. The cDNA included a possible open reading frame of 897 nucleotides, encoding 299 amino acids. The Hakata antigen consisted of a collagen-like domain in the middle section and a fibrinogen-like domain in the COOH terminus, both of which are homologous to human ficolin-1 and opsonin P35, indicating that these three molecules form a distinct family. The molecular mass of the Hakata antigen expressed in transfected cells was 35 kDa under reduced conditions, and it formed ladder bands under nonreducing conditions compatible with the previous result that the Hakata antigen exists in serum as homopolymers. Purified Hakata antigen sustained lectin activity, showing affinity with GalNAc, GlcNAc, d-fucose as mono/oligosaccharide, and lipopolysaccharides from Salmonella typhimurium andSalmonella minnesota. These results suggest that the Hakata antigen, a new member of the ficolin/opsonin P35 family, plays a role in the serum exerting lectin activity under physiological conditions.

Hakata Antigen, a New Member of the Ficolin/Opsonin p35 Family, Is a Novel Human Lectin Secreted into Bronchus/Alveolus and Bile

Hakata antigen was first reported as a serum protein that reacted with an autoantibody from patients with systemic lupus erythematosus. Recently, it has been found that Hakata antigen is a new member of the ficolin/opsonin p35 family, which is a distinct lectin family, on the basis of homology of structures and the common characteristic of possessing lectin activity. In this study we analyzed the tissue distribution of Hakata antigen. Hakata antigen mRNA and protein were generated in the lung and liver. In the lung, Hakata antigen was produced by both ciliated bronchial epithelial cells and Type II alveolar epithelial cells and was secreted into the bronchus and alveolus. In the liver, Hakata antigen was produced by bile duct epithelial cells and hepatocytes and was also secreted into the bile duct. These results demonstrate that Hakata antigen is a unique lectin protein that exists not only in serum but also in bronchus/alveolus and bile, and indicate that Hakata antigen plays a role in bronchus/alveolus and bile under physiological conditions.

Interleukin-13 and interleukin-13 receptor in Hodgkin's disease: possible autocrine mechanism and involvement in fibrosis.

Aims: Hodgkins disease (HD) is characterized by the presence of Hodgkin and Reed–Sternberg (H–RS) cells against a hyperplastic background of reactive cells such as lymphocytes, histiocytes, plasma cells, eosinophils, neutrophils, and stromal cells. There is ample evidence to suggest that proliferation and survival of HD‐derived cells is due to cytokine signalling. Recently, high expression of interleukin (IL)‐13 was described in HD‐derived cell lines. Here we investigated the possible involvement of IL‐13 in the pathophysiology, especially autocrine pathways of H–RS cells.

Childhood Atopic Asthma: Positive Association with a Polymorphism of IL-4 Receptor α Gene but Not with That of IL-4 Promoter or Fc ε Receptor I β Gene

We examined the relative contributions of three representative candidate genes for atopy (Fc ε receptor I β, IL-4, and IL-4 receptor α) to the development of atopic asthma. Four polymorphisms of the three candidate genes including Ile50Val and Gln551Arg of IL-4 receptor α, -590C/T of IL-4 promoter and Glu237Gly of Fc ε receptor I β were studied in 100 patients with atopic asthma and 100 nonatopic controls in the northern Kyushu area in Japan. Among the four polymorphisms of the three candidate genes, the Ile50 allele of the IL-4 receptor α chain gene demonstrated an association with atopic asthma subjects (p = 0.044), especially in patients with onset at 2 years of age or earlier (p = 0.034) and in patients with moderate to severe atopic asthma (p = 0.031). Gln551Arg of IL-4 receptor α, -590C/T of IL-4 promoter and Glu237Gly of Fc ε receptor I β showed no association with atopic asthma. A slight linkage disequilibrium between Ile50Val and Gln551Arg polymorphisms of the IL-4 receptor α chain gene was observed in both patients and nonatopic controls. The identification of additional atopy genes in areas with a certain genetic background is essential for genetic diagnosis and to establish new therapeutic modalities for atopic asthma.

Expression of Pendrin Periostin in Allergic Rhinitis Chronic Rhinosinusitis

BACKGROUND Pendrin and periostin are newly identified mediators of the inflammatory process. The expression of these proteins in human sinonasal tissue and their roles in allergic rhinitis and chronic rhinosinusitis remain to be elucidated. This study investigated the expression of pendrin and periostin in sinonasal tissue of patients with allergic rhinitis, chronic rhinosinusitis, and aspirin-induced asthma. Prospective control study conducted at Yamagata University, Japan. METHODS Surgical samples were investigated by means of real-time reverse transcription-polymerase chain reaction to evaluate the expression of pendrin and periostin mRNA. The presence and location of pendrin and periostin were determined by immunohistochemistry and Western blotting. RESULTS Pendrin and periostin production was significantly higher in patients with nasal disorders than in controls. Further significant increases in periostin expression were noted in patients with chronic rhinosinusitis with nasal polyps and in those with aspirin-induced asthma. Immunohistochemistry revealed positive staining for pendrin in epithelial cells and submucosal glands and for periostin in the basement membrane in all three disorders, and additionally for periostin in nasal polyp tissue in chronic rhinosinusitis and aspirin-induced asthma. CONCLUSIONS Production of pendrin and periostin is upregulated in allergic rhinitis, chronic rhinosinusitis with nasal polyps, and aspirin-induced asthma. These findings suggest that pendrin can induce mucus production and that periostin can induce tissue fibrosis and remodeling in the nasal mucosa. Therefore, these mediators may be therapeutic target candidates for allergic rhinitis, chronic rhinosinusitis with nasal polyps, and aspirin-induced asthma.

Multidimensional endotyping in patients with severe asthma reveals inflammatory heterogeneity in matrix metalloproteinases and chitinase 3-like protein 1.

Background Disease heterogeneity in patients with severe asthma and its relationship to inflammatory mechanisms remain poorly understood. Objective We aimed to identify and replicate clinicopathologic endotypes based on analysis of blood and sputum parameters in asthmatic patients. Methods One hundred ninety-four asthmatic patients and 21 control subjects recruited from 2 separate centers underwent detailed clinical assessment, sputum induction, and phlebotomy. One hundred three clinical, physiologic, and inflammatory parameters were analyzed by using topological data analysis and Bayesian network analysis. Results Severe asthma was associated with anxiety and depression, obesity, sinonasal symptoms, decreased quality of life, and inflammatory changes, including increased sputum chitinase 3–like protein 1 (YKL-40) and matrix metalloproteinase (MMP) 1, 3, 8, and 12 levels. Topological data analysis identified 6 clinicopathobiologic clusters replicated in both geographic cohorts: young, mild paucigranulocytic; older, sinonasal disease; obese, high MMP levels; steroid resistant TH2 mediated, eosinophilic; mixed granulocytic with severe obstruction; and neutrophilic, low periostin levels, severe obstruction. Sputum IL-5 levels were increased in patients with severe particularly eosinophilic forms, whereas IL-13 was suppressed and IL-17 levels did not differ between clusters. Bayesian network analysis separated clinical features from intricately connected inflammatory pathways. YKL-40 levels strongly correlated with neutrophilic asthma and levels of myeloperoxidase, IL-8, IL-6, and IL-6 soluble receptor. MMP1, MMP3, MMP8, and MMP12 levels were associated with severe asthma and were correlated positively with sputum IL-5 levels but negatively with IL-13 levels. Conclusion In 2 distinct cohorts we have identified and replicated 6 clinicopathobiologic clusters based on blood and induced sputum measures. Our data underline a disconnect between clinical features and underlying inflammation, suggest IL-5 production is relatively steroid insensitive, and highlight the expression of YKL-40 in patients with neutrophilic inflammation and the expression of MMPs in patients with severe asthma.

The squamous cell carcinoma antigens as relevant biomarkers of atopic dermatitis.

Background Although it is thought that both Th1‐ and Th2‐type inflammations are involved in the pathogenesis of atopic dermatitis (AD), it is controversial which immune response is more involved in regulating the clinical severity of AD. We recently found that the squamous cell carcinoma antigens 1 (SCCA1) and SCCA2 are novel biomarkers of bronchial asthma, downstream of IL‐4 and IL‐13.

Periostin levels correlate with disease severity and chronicity in patients with atopic dermatitis

Recent findings indicate that periostin, an extracellular matrix protein induced by T helper 2 cytokines, plays a critical role in the pathogenesis of atopic dermatitis (AD).