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Background: Studies have addressed the immunomodulatory effects of helminths and their protective effects upon asthma. However, anti-Ascaris IgE has been reported to be associated with an increased risk of asthma symptoms. We examined the association between serum levels of anti-Ascaris IgE and bronchial hyper-responsiveness (BHR) in children living in rural Bangladesh. Methods: Serum anti-Ascaris IgE level was measured and the BHR test done in 158 children aged 9 years selected randomly from a general population of 1705 in the Matlab Health and Demographic Surveillance Area of the International Centre for Diarrhoeal Disease Research, Bangladesh. We investigated wheezing symptoms using a questionnaire from the International Study of Asthma and Allergies in Childhood. BHR tests were successfully done on 152 children (108 ‘current wheezers’; 44 ‘never-wheezers’). We examined the association between anti-Ascaris IgE level and wheezing and BHR using multiple logistic regression analyses. Results: Of 108 current-wheezers, 59 were BHR-positive; of 44 never-wheezers, 32 were BHR-negative. Mean anti-Ascaris IgE levels were significantly higher (12.51 UA/ml; 95% confidence interval (CI), 9.21–17.00) in children with current wheezing with BHR-positive than in those of never-wheezers with BHR-negative (3.89; 2.65–5.70; t test, p

Kitamura et al. identify NLRC4 as causing familial cold autoinflammatory syndrome using whole exome sequencing on a family with multiple affected family members. They identify a mutation in the NOD domain and show that the mutant protein increases Nlrc4 oligomerization and is associated with increased IL-1β. Transgenic mice with the same NLRC4 mutation are shown to develop a similar FCAS-like syndrome., Autoinflammatory syndromes cause sterile inflammation in the absence of any signs of autoimmune responses. Familial cold autoinflammatory syndrome (FCAS) is characterized by intermittent episodes of rash, arthralgia, and fever after exposure to cold stimuli. We have identified a missense mutation in the NLRC4 gene in patients with FCAS. NLRC4 has been known as a crucial sensor for several Gram-negative intracellular bacteria. The mutation in NLRC4 in FCAS patients promoted the formation of NLRC4-containing inflammasomes that cleave procaspase-1 and increase production of IL-1β. Transgenic mice that expressed mutant Nlrc4 under the invariant chain promoter developed dermatitis and arthritis. Inflammation within tissues depended on IL-1β–mediated production of IL-17A from neutrophils but not from T cells. Our findings reveal a previously unrecognized link between NLRC4 and a hereditary autoinflammatory disease and highlight the importance of NLRC4 not only in the innate immune response to bacterial infections but also in the genesis of inflammatory diseases.

Introduction Use of inhaled corticosteroid (ICS) is the mainstream maintenance therapy for paediatric asthma. Several forms of ICS are available, but the relative effectiveness among ICS has not been well investigated in published, randomised, controlled trials. The paucity of direct comparisons between ICS may have resulted in insufficient estimation in former systematic reviews/meta-analyses. To supplement the information on the comparative effectiveness of ICS for paediatric asthma, we plan to conduct a network meta-analysis that will enable summary of direct and indirect evidence. Methods and analysis We will retrieve randomised, controlled trials that examined the effectiveness of ICS for paediatric asthma from the PubMed and Cochrane Central Register of Controlled Trials. After one author scans the title and abstract for eligible studies, two authors will independently review study data and assess the quality of the study. Studies of children (≤18 years old) with chronic asthma or recurrent wheezing episodes will be included if they used ICS for ≥4 weeks. We will define a priori core outcomes and supplemental outcomes of paediatric asthma, including exacerbation, healthcare use and pulmonary function. Studies reporting a minimum of one core outcome will be entered into the systematic review. After the systematic review is performed, extracted data of relevant studies will be synthesised in the Bayesian framework using a random-effects model. Ethics and dissemination The results will be disseminated through peer-reviewed publications and conference presentations. Protocol registration number UMIN (000016724) and PROSPERO (CRD42015025889).

Bacterial superantigens have been implicated in the pathogenesis of several human diseases. Among them, toxic shock syndrome (TSS) is a prototypic acute intoxication caused by the pyrogenic exotoxin family of superantigens. In this study, we investigated the pathophysiological mechanism of TSS using the Yersinia pseudotuberculosis-derived mitogen (YPM) and its point mutants. The results indicated that YPM could induce toxic shock in BALB/c mice but not in T cell-deficient SCID mice. We found that Vbeta8(+) T cells activated by YPM migrated from peripheral blood to liver as early as 1 h after injection of YPM and that serum level of IFN-gamma was significantly elevated 4 h after YPM injection. Co-administration of anti-IFN-gamma antibody or anti-YPM monoclonal antibody alleviated the liver injury and protected mice from YPM-induced death. Moreover, anti-YPM antibody also suppressed the early migration of Vbeta8(+) T cells from the peripheral circulation and the elevation of serum IFN-gamma level, indicating a pivotal role of T cells in inducing shock in our mouse model.

Infant acute lymphoblastic leukemia (ALL) with MLL gene rearrangements is characterized by early pre-B phenotype (CD10 − /CD19 + ) and poor treatment outcome. The t(4;11), creating MLL-AF4 chimeric transcripts, is the predominant 11q23 chromosome translocation in infant ALL and is associated with extremely poor prognosis as compared with other 11q23 translocations. We analyzed an infant early preB ALL with ins(5;11)(q31;q13q23) and identified the AF5q31 gene on chromosome 5q31 as a fusion partner of the MLL gene. The AF5q31 gene, which encoded a protein of 1,163 aa, was located in the vicinity of the cytokine cluster region of chromosome 5q31 and contained at least 16 exons. The AF5q31 gene was expressed in fetal heart, lung, and brain at relatively high levels and fetal liver at a low level, but the expression in these tissues decreased in adults. The AF5q31 protein was homologous to AF4-related proteins, including AF4, LAF4, and FMR2. The AF5q31 and AF4 proteins had three homologous regions, including the transactivation domain of AF4, and the breakpoint of AF5q31 was located within the region homologous to the transactivation domain of AF4. Furthermore, the clinical features of this patient with the MLL-AF5q31 fusion transcript, characterized by the early pre-B phenotype (CD10 − /CD19 + ) and poor outcome, were similar to those of patients having MLL-AF4 chimeric transcripts. These findings suggest that AF5q31 and AF4 might define a new family particularly involved in the pathogenesis of 11q23-associated-ALL.

The function of the kinase Btk in neutrophil activation is largely unexplored. Here we found that Btk-deficient neutrophils had more production of reactive oxygen species (ROS) after engagement of Toll-like receptors (TLRs) or receptors for tumor-necrosis factor (TNF), which was associated with more apoptosis and was reversed by transduction of recombinant Btk. Btk-deficient neutrophils in the resting state showed hyperphosphorylation and activation of phosphatidylinositol-3-OH kinase (PI(3)K) and protein tyrosine kinases (PTKs) and were in a 'primed' state with plasma membrane-associated GTPase Rac2. In the absence of Btk, the adaptor Mal was associated with PI(3)K and PTKs at the plasma membrane, whereas in control resting neutrophils, Btk interacted with and confined Mal in the cytoplasm. Our data identify Btk as a critical gatekeeper of neutrophil responses.

The molecular mechanisms involving in B-cell survival/proliferation are poorly understood. Here we investigated the molecules affecting the survival of human naive and memory B cells. Without stimulation, naive B cells survived longer than memory B cells. Moreover, the viability of memory B cells decreased more rapidly than that of naive B cells following with Staphylococcus aureus Cowan strain (SAC), anti-immunoglobulin (Ig), or anti-CD40 stimulation, but displayed the same levels of survival following CpG DNA stimulation. We analyzed the transcriptional differences between B-cell subsets by gene expression profiling, and identified 15 genes significantly correlated to survival/proliferation. Among them, IL-21 receptor (IL-21R) and T-cell leukemia 1 (TCL1) proto-oncogene were highly expressed in naive B cells. IL-21 induced the proliferation of both naive and memory B cells. Marked phosphorylation of Akt was found in naive B cells compared with memory B cells. This study suggests that naive and memory B cells are regulated by several distinct molecules, and the IL-21R and TCL1/Akt pathways might play crucial roles in naive B cells for their maintenance.

Among the various systemic manifestations in Y. pseudotuberculosis infection, renal complication such as acute renal failure, and an erythematous skin rash were more strongly related to the elevation of anti-YPM titer. Acute renal failure might be caused by the T cells that was stimulated and matured under the Th1 type inflammatory cytokine milieu produced by YPM during the acute phase of the disease. Patients with erythematous skin rash had an elevated level of serum IL-12p40 during the acute phase. The in vitro experiments indicated that YPM could contribute to the pathogenesis of skin rash through the enhanced production of IL-12 and the expansion of the skin-homing receptor CLA+ T cells in patients.

YPM had an acute toxic effect on BALB/c mice, which was dependent on the presence of T cells and correlated with the elevation of serum IFN-gamma. One monoclonal antibody (YSA8E3) rescued BALB/c mice from development of toxic shock after YPM injection.

Atopic dermatitis positive to Japanese cedar pollen showed the recurrence or worsening of the symptoms during the pollen season. In 22 cases, 6 children (mean, 11.4 y) and 16 adults (29.5 y) who showed positive to Japanese cedar pollen by RAST, CAST analysis were done by Cry j 1 0.01 approximately 10 micro g/ml and they showed the significant higher simulation indices compared to controls (P0.01). Randomized analysis of the hyposensitized patients (10 cases) and non-hyposensitized (12 cases) showed significant lower stimulation indices in hyposensitized patients (P0.01). In six cases stimulation indices were compared after one year of hyposensitization therapy. Four cases to whom hyposensitization were newly introduced showed the significant decreases of stimulation indices: 19.83+/-4.97 (mean+/-SEM) to 6.84+/-6.36 (65.0%) by Cry j 1 0.01 microg/ml, 19.73+/-5.65 to 6.85+/-1.78 (65.3%) by 0.1, 17.88+/-5.11 to 6.36+/-1.53 (64.4%) by 1, and 20.03+/-5.29 to 6.11+/-1.39 (69.5%) by 10, and they showed the significant decreases (P0.05). By anti-IgE it decreased significantly from 35.08+/-3.42 to 7.00+/-1.77 (79.7%) (P0.01). In two cases who got hyposensitization therapy for 2 years and 1 1/2 years each, there were no significant decreases of stimulation indices. The symptoms improved significantly and there were little or no recurrence of the symptoms. Symptom scores (RajkaLangeland) showed significant decreases. Thus, hyposensitization by cedar pollen in atopic dermatitis is a promising treatment.

Background Infection is a serious complication after liver transplantation. Immunization is one means of controlling infections. The objective of this study was to investigate the efficacy and safety of simultaneous administration of several vaccines before transplantation and the efficacy and safety of administration under immunosuppressive conditions after transplantation. Methods Fifty-eight patients who underwent living-related liver transplantation between April 1994 and March 2000 were included in this study. Simultaneous administration of a maximum of six vaccines was performed in a short period of time before transplantation. We also readministered vaccines to 15 patients with waning antibody titers after transplantation from June 1999. We investigated whether patients could seroconvert for measles, rubella, mumps, and varicella after immunization and how long antibody titers could be retained by measuring them several times throughout the period before and after transplantation. We also examined side effects caused by immunization. Results The rates of seroconversion against measles, rubella, mumps, and varicella after the pretransplantation vaccination were 82%, 100%, 90%, and 95%, respectively. The rates of reseroconversion against measles, rubella, mumps, and varicella after the posttransplantation revaccination were 85%, 100%, 100%, and 71%, respectively. Although antibody titers against these viruses generally waned with time, no patient exhibited any serious illness or side effects. Conclusion Although 12 of 58 patients (21%) had an infection, pretransplantation immunization was effective to prevent serious illness, especially for the 6 months after transplantation. Posttransplantation live-vaccine administration under immunosuppressive conditions is effective and safe.

We identified unusually large von Willebrand factor (vWF) multimers caused by deficient activity of vWF-cleaving protease in 2 patients with Upshaw-Schulman syndrome. The autoantibodies that inhibited the protease activity were not detected in the plasma of either patient. Periodic fresh-frozen plasma transfusion was effective for management of the hemolysis and thrombocytopenia. We detected enriched enzyme activity in a particular plasma fraction, although molecular cloning of this specific protease is needed to determine a more detailed pathogenesis and to develop new therapeutic approaches.

We report a case of a 31-year-old woman with common variable immunodeficiency (CVID) complicated with intractable diarrhea and the functional disorder of renal tubules. The patient became hypogammaglobulinemic after she suffered from measles at 6 years of age. She also suffered from lupus-like syndrome at 7 years of age. The complete remission was obtained by glucocorticosteroid treatment. An intravenous immunoglobulin replacement therapy was introduced at 11 years of age, since then her general condition was stable for more than 20 years. When she was 29 years old, she suffered from generalized malaise, anorexia with body weight loss, and numbness of face. The intractable diarrhea as protein loosing syndrome, and the severe abnormality of electrolyte balance with metabolic acidosis as the functional disorder of renal tubules were found. Her condition was not improved by the electrolytes or alkali replacement therapy. She was admitted for further evaluation and treatment. The intractable diarrhea and the functional disorder of renal tubules were dramatically improved after absolute restriction of food intake under hyperalimentation. When she began to take food, the symptom and sign became worse again. The interstitial nephritis and nonspecific inflammation of intestine were found by the tissue biopsy. The most characteristic finding was the infiltration of lymphocytes (predominantly CD 8 + T lymphocytes) in both intestinal mucosa and renal interstitium. The introduction of glucocorticosteroids improved her general condition and biochemical findings. This CVID case is complicated with intractable diarrhea and the functional disorder of renal tubules which is associated with the infiltration of CD 8 + lymphocytes in intestine and kidney. We consider that such case is very rare and valuable to report.