Kazumasa Iwamoto

Coagulation/fibrinolysis and inflammation markers are associated with disease activity in patients with chronic urticaria

To cite this article: Takahagi S, Mihara S, Iwamoto K, Morioke S, Okabe T, Kameyoshi Y, Hide M. Coagulation/fibrinolysis and inflammation markers are associated with disease activity in patients with chronic urticaria. Allergy 2010; 65: 649–656.

Peritoneal injection of fucoidan suppresses the increase of plasma IgE induced by OVA-sensitization

We previously reported that fucoidan, a dietary fiber purified from seaweed, inhibited IgE production by B cells in vitro. In this study, we examined the effect of fucoidan on IgE production in vivo. The OVA-induced increase of plasma IgE was significantly suppressed when fucoidan was intraperitoneally, but not orally, administered prior to the first immunization with OVA. The production of IL-4 and IFN-gamma in response to OVA in spleen cells isolated from OVA-sensitized mice treated with fucoidan in vivo was lower than that from mice treated without fucoidan. Moreover, the flow cytometric analysis and ELISpot assay revealed that the administration of fucoidan suppressed a number of IgE-expressing and IgE-secreting B cells, respectively. These results indicate that fucoidan inhibits the increase of plasma IgE through the suppression of IgE-producing B cell population, and the effect of fucoidan in vivo is crucially dependent on the route and timing of its administration.

Fucoidan suppresses IgE production in peripheral blood mononuclear cells from patients with atopic dermatitis.

We previously reported that fucoidan, a dietary fiber purified from seaweed, inhibited IgE production in B cells from mice spleen in vitro and ovalbumin-sensitized mice in vivo. In this study, we examined the effect of fucoidan on IgE production in human peripheral blood mononuclear cells (PBMC) in vitro. PBMC, obtained from healthy donors or patients with atopic dermatitis (AD) with high levels of serum IgE, were cultured with IL-4 and anti-CD40 antibody in the presence or absence of fucoidan. Fucoidan significantly reduced IgE production in PBMC without affecting cell proliferation and IFN-γ production. Fucoidan also inhibited immunoglobulin germline transcripts of B cells in PBMC, and decreased the number of IgE-secreting cells. The inhibitory effects of fucoidan were similarly observed for both PBMC from patients with AD and those with healthy donors. Our findings indicate that fucoidan suppresses IgE induction by inhibiting immunoglobulin class-switching to IgE in human B cells, even after the onset of AD.

A large heterozygous deletion including the entire C1 inhibitor gene in a sporadic case of hereditary angio-oedema

C1 inhibitor (C1‐INH) deficiency [hereditary or acquired angio‐oedema (HAE or AAE)] is characterized by recurring episodes of subcutaneous or submucosal oedema. Many different mutations in the C1‐INH gene have been identified as a cause of HAE. We investigated the molecular basis of the disease in a Japanese woman with sporadic HAE. Direct sequencing of genomic DNA revealed no point mutation in the C1‐INH gene. Quantitative real‐time PCR showed that the copy number of the C1‐INH gene in the patient was half that of a healthy control. Furthermore, we identified a 650‐kbp deletion on the chromosome, which included the C1‐INH gene. We evaluated the correlation between the patient’s attacks and her coagulation activity. The levels of D‐dimer were high during the angio‐oedema attacks, and often exceeded the normal range even during remission, thus the level of D‐dimer reflected the activity of HAE in this patient.

Novel and recurrent C1 inhibitor gene mutations in nine Japanese patients with hereditary angioedema

C1 inhibitor (C1-INH) deficiency (hereditary or acquired gioedema; HAE [OMIM106100] or AAE) is characterized by curring episodes of subcutaneous or submucosal swellings, pically involving the face, limbs, tongue, bowels or upper airways ]. Laryngeal attack can cause airway obstruction which may be tal. Therefore, prompt diagnosis and treatment are essential. Two assical types of HAE, type 1 and 2, are autosomal dominant sorders due to heterozygous deficiencies of the C1-INH gene ERPING1). Type 1 shows decreased antigenic and functional vels of C1-INH and type 2 shows normal levels of antigenic -INH but low levels of functional C1-INH [2]. DNA screening of the C1-INH gene establishes the genetic termination of the C1-INH deficiency. It is especially useful for e diagnosis of sporadic cases accounting for 20–30% of patients ith HAE as a result of de novo mutations without family history of gioedema [3]. According to the C1-INH mutation database AEdb, http://hae.enzim.hu), more than 250 different mutations ve been reported [4]. The mutations have been found distributed er all exons and splice sites of the C1-INH gene. Gross mutation is sponsible for approximately 15% of the mutations detected in tients with HAE, and the remaining 85% being due to small/point utations. This database has been well established by reports ainly from Europe and North America, while the genetic formation of HAE in Asian races is uncertain. The prevalence HAE type 1 and type 2 has been estimated at 1/50,000 [2]. On the her hand, a nation-wide prevalence survey of HAE in Japan has own only 52 type 1 or type 2 patients with HAE, even though panese population is about 128 million [5], and only 23 utations have been reported in Japan so far [6]. Similarly, only 3 HAE patients have been reported from China, which is the ost populous country in the world [7]. In this study, we investigated the genetic analysis of nine panese patients with HAE in order to increase the genetic formation of HAE in Japan. HAE was diagnosed based on repeated isodes of swelling in the skin and/or mucosa and decreased vels of C1 inhibitor function and C4 in plasma. Genomic DNA was tracted from peripheral blood of the patients by using Genomic A Mini Kit (Invitrogen, Carlsbad, CA). Polymerase chain reaction CR) were carried out using 9 pairs of primers to amplify the 8 ons, referring to previously described information [8]. DNA quencing was performed using an Applied Biosystems 3100ant DNA Analyzer (Applied Biosystems, Warrington, UK). The udy was approved by the Genome Ethics Committee for perimental Research Involving Human Subjects, Hiroshima iversity Hospital, and written informed consent for participan was obtained from the patient and/or their families. se w Subjects of this study consisted of four male and five female tients with an age range from 20 to 69 years. Five patients had milial history of angioedema and the other four patients were oradic cases. Genetic analysis of the C1-INH gene in this study vealed 4 frameshift mutations, 2 nonsense mutations, one issense mutation, one splice site mutation and large deletion. these mutations, 4 mutations: p.Arg40fsX17 (c.119insA), Ala46fsX9 (c.138_207del), p.Asp256fsX22 (c.766delG) and Gln338X (c.1012C > T) were novel (Fig. 1) and 5 mutations: Lys329fsX7 (c.987delG) [6], p.Arg466His (c.1397G > A) [4], p. g492X (c.1480C > T) [4], splicing defect (c.551-2_A > G) [4] and large rearrangement (>650 kbp including entire exons), which as reported separately [8], were recurrent (Table 1). Based on the netic analysis from our study and previous reports about panese patients with HAE, the mutations were widely distributacross the C1-INH gene and the distributions of the mutations by pes in Japan do not seem to be apparently different from those ported in Europe. We have classified four individuals into type 1 HAE and one dividual into type 2 HAE by the level of C1-INH protein. We could t classify four individuals because of lack of the serum test of C1H protein level. According to previous studies, almost 100% in pe 2 HAE showed missense mutations and it almost invariably sults in HAE type II when mutations occur within the C1-INH active site located in exon 8 at arginine 444 [9]. All of four classified individuals showed nonsense or frameshift mutations hich caused premature termination expecting to lead to reduced pression of C1-INH. Actually, the mutation in patient 1, Arg492X, was identified in type 1 HAE. From these observations, e speculated that these 4 unclassified individuals were type 1 E. Only one patient was found with HAE type 2 in this study 1%), which is in accordance with another report in Japan (12.5%) ]. Previously the prevalence of type 2 has been reported around % [2], but a recent study showed the number of type 2 was 6% of tients with HAE identified in several countries of Europe [10]. erefore, there seem to be regional variation in occurrence garding HAE type 2. Among nine patients in this study, two patients received acheostomy due to severe swelling on the respiratory trunk. mamoto et al. [6] also reported that 32% patients with HAE had acheostomy or tracheal intubation in Japan. The risk of severe spiratory symptoms in Japanese patients with HAE was as quent as in western countries. Therefore, proper diagnosis of E is necessary to prevent the patients from asphyxiation. oreover DNA screening of the C1-INH gene is useful in that it veals the segregation of genetic carriers of HAE within affected

Staphylococcus aureus from atopic dermatitis skin alters cytokine production triggered by monocyte-derived Langerhans cell

BACKGROUND Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases. The skin of patients with AD presents as a disbalance of the microbiome with a strong colonization by Staphylococcus aureus, which positively correlates with the severity of the disease. However, the effect of colonized S. aureus on the skin immune system has not been fully elucidated. OBJECTIVE The aim of this study is to explore whether S. aureus isolated from AD skin is able to skew T cell responses via Langerhans cells (LC) as compared to a standard strain of S. aureus and S. epidermidis. METHODS We prepared monocyte-derived LC (MoLC) from healthy controls and patients with AD, and stimulated MoLC with a standard strain of S. aureus NCTC8325, S. aureus TF3378 isolated from AD skin, or S. epidermidis. Stimulated MoLC were co-cultured with autologous CD4pos T cells and then T cell responses were analyzed by T cell polarization assays, cytokine analysis and real-time PCR. RESULTS MoLC stimulated by S. aureus TF3378 induced significantly high and rapid proliferation of T cells as compared to those by S. aureus NCTC8325 and S. epidermidis. Cytokine productions from T cells cultured with S. aureus TF3378-stimulated MoLC showed significantly high amounts of IL-2 and less IFN-γ production with imbalanced Th1/Th2 (decreased TBX21/GATA3 ratio) mRNA expression. The T cell proliferation with increased IL-2 production via S. aureus TF3378-stimulated MoLC was diminished by treatment of proteinase K. CONCLUSION S. aureus TF3378 on AD skin can skew T cell responses via LC toward imbalanced Th1/Th2 skin immunity.

Tissue factor expression on the surface of monocytes from a patient with hereditary angioedema.

Hereditary angioedema (HAE) presents as severe angioedema, which is mostly due to the C1 inhibitor (C1‐INH) gene mutations. Environmental factors, minor trauma and oral contraceptives have been reported to induce angioedema attack, but the trigger may often be uncertain. Activated factor XII controlled by C1‐INH facilitates bradykinin generation and also regulates coagulation cascade, but the relationship between edema formation and coagulation is still unclear. We have described a 35‐year‐old female patient with HAE, presenting with frequent angioedema attacks in the absence of an apparent triggering factor. She showed higher levels of FDP and D‐dimer during angioedema than those in remission. In addition, tissue factor (TF), an initiator of the extrinsic coagulation cascade, was expressed on the surface of monocytes. It was significantly higher than that of monocytes from healthy controls and tends to further increase during attacks. The expression of TF on monocytes may play a role in the induction of angioedema attacks in HAE by activating the coagulation pathway in association with reduced functions of C1‐INH.

Hereditary angioedema as the cause of death from asphyxia: postmortem computed tomography study.

Hereditary angioedema (HAE) is an autosomal dominant disorder. Type I and type II HAE result from a deficiency of the C1-esterase inhibitor (C1-INH) due to a deletion or mutation(s) of C1INH. It may cause episodic and transient swellings of deep cutaneous and or mucosal tissues. Symptoms usually last for a few days and may resolve spontaneously. However, airway edema may cause asphyxia and lead to death if not properly treated. 1,2 Although the asphyxia is generally due to laryngeal edema,3 “upper airway obstruction ” is more characteristic than “ laryngeal edema” to depict symptoms of HAE. Here, we report a case of HAE which led to the patient’s death and revealed fatal pharyngeal edema on postmortem CT. A 23-year-old man visited Niigata City General Hospital because of severe facial edema. He had had three similar episodes since he was 19-years-old. At this time, he did not complain of breathlessness. Laboratory examination showed reduced levels of CH50, 12 U ml (normal 30-40 U ml) and C4, 4 mg dl (normal 13-34 mg dl). Serum C1INH concentration was also decreased to 6 mg dl (normal 10-25 mg dl) and its enzymatic activity was <25% (normal 80-125%). On the other hand, the level of his serum C1q was normal, 10.1 mg dl (normal 8.8-15.3 mg dl). Upon the administration of 1000 units of C1INH concentrate ( BerinertTM ) , all symptoms remarkably improved within one day. His mother, until her menopause, had had a history of recurrent ileus and episodes of swelling of extremities and face. Her serum C1-INH protein concentration and its enzymatic activity ware low (9 mg dl, and <25%). According to these clinical and laboratory observations, we diagnosed him as Type I HAE. We prophylactically administered danazol (400 mg day), but could not completely prevent recurrent occurrences of edema. When he was 24-years-old, he also experienced an episode of severe abdominal pain, and was diagnosed as ileus, based on significant bowel swelling revealed by CT scans. On one occasion at the age of 25-years, he noticed swelling of his face, and several hours later, he felt dyspnea. When emergency crews arrived at his house by ambulance, his face and throat were extremely edematous and his pulse was weak. He then died, although he was conducted to our hospital and received cardiopulmonary resuscitation. His family declined the traditional autopsy, but granted postmortem imaging, which was performed 67 minutes later after his arrival at our hospital. Examinations were performed with a 6-row detector multislice CT scanner (SOMATOM Emotion 6, Siemens, Munich, Germany). Images were obtained using the spiral mode from the neck to the diaphragm for the routine body studies. The neck CT showed a diffuse increased density in the fat layer, which represents tissue edema. Severe mucosal thickness was presented in the oropharynx (Fig. 1a) and the hypopharynx (Fig. 1b). The airway in the oropharynx and the hypopharynx had almost disappeared. Although submucosal density was also increased in the larynx, the edema was milder than that observed in the pharynx and the glottis remained opened (Fig. 1c). We therefore concluded that the cause of his death was Allergology International. 2014;63:493-494

Neuromedin U directly induces degranulation of skin mast cells, presumably via MRGPRX2

Sung-Yoon Kang Woo-Jung Song Min-Hye Kim Sae-Hoon Kim Sang-Heon Cho Yoon-Seok Chang Min-Suk Yang Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Korea Department of Allergy and Clinical Immunology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea Department of Internal Medicine, Ewha Womans University School of Medicine, Seoul, Korea Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea Seoul National University Medical Research Center, Seoul National University College of Medicine, Seoul, Korea Department of Internal Medicine, SMG-SNU Boramae Medical Center, Seoul, Korea

Contact urticaria syndrome with IgE antibody against a cefotiam‐unique structure, evoked by nonapparent exposure to cefotiam

A 26‐year‐old woman presented with recurrent attacks of widespread urticaria and systemic symptoms. The patient was a nurse, and the attacks occurred only in her workplace, without an apparent trigger. A patch test to cefotiam (CTM) induced an immediate skin reaction. ELISA detected the patients serum IgE antibody binding to CTM conjugated with human serum albumin (CTM‐HSA), and her basophils released histamine in response to CTM‐HSA in a histamine release assay (HRA). Both reactions in ELISA and HRA were inhibited by pretreatment of the patient’s serum or basophils with cefotiam. No crossreactivity in skin tests or in vitro assays was observed against other antibiotics, even those containing a beta‐lactam ring and/or side chains similar to CTM. Certain antibiotics including CTM may cause extremely sensitive and specific contact urticaria syndrome, which is mediated by IgE and evoked even without apparent skin contact with the culprit drug and in the absence of any history of an allergic reaction against other antibiotics with similar structures.