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The relationship between viral infection and obesity has been known for several decades but epidemiological data related to obesity is limited to only a few viral pathogens. To identify associations between viral infections and obesity, a high-throughput virome-wide serological profiling tool, VirScan, was used to measure antibody responses to a wide range of viruses. Serum specimens from 457 Qatari adults (lean=184;obese=273) and 231 Qatari children (lean=111;obese=120) were assessed by VirScan. Pediatric specimens were simultaneously tested by conventional serology for several herpesviruses to validate VirScan results. Viral association with obesity was determined by calculation of odds ratio (OR) and p-values from Fisher test, and by multivariate regression analysis to adjust for age and gender, with Bonferroni correction for multiple testing. Comprehensive serological profiling of Qatari adult population with VirScan revealed positive and negative associations (pp-values for multiple comparisons, only herpes simplex virus 1 (HSV-1) and Rhinovirus A were positively (OR=3.3; 95%CI 2.15-4.99; p=2.787E-08) and negatively (OR=0.4; 95%CI 0.26-0.65; p=1.175E-03) associated with obesity. At the peptide level, higher prevalence of antibodies against several peptide epitopes of HSV-1/2 was positively (OR=2.35-3.82; p≤3.981E-05) associated with obesity. No such associations were seen at the species or peptide levels in the pediatric population. By multivariate regression analysis, HSV-1 was independently associated with obesity irrespective of age and gender. These findings are in agreement with limited data on the adipogenic properties of HSV-1 observed in vitro.ImportanceThe state of Qatar has one of the highest rates of obesity and associated morbidities in the world. Although obesity is predominantly caused by the intake of high calorie diet and reduced physical activities, other factors including infections with certain viruses have been reported. Among these viruses, human adenoviruses were widely studied but epidemiological data for other viruses in relation to human obesity are limited. Here, we studied the association of obesity in Qatari adults and children with a wide range of viral pathogens using VirScan, a virome-wide serological profiling tool. Our results indicate significant association HSV-1 with obesity in the adult population only. Furthermore, we have identified a set of HSV peptides as candidate obesogenic factors for future studies.

The etiology of central nervous system (CNS) infections such as meningitis and encephalitis remains unknown in a large proportion of cases partly because the diversity of pathogens that may cause CNS infections greatly outnumber available test methods. We developed a metagenomic next generation sequencing (mNGS)-based approach for broad-range detection of pathogens associated with CNS infections suitable for application in the acute care hospital setting. The analytical sensitivity of mNGS performed on an Illumina MiSeq was assessed using simulated cerebrospinal fluid (CSF) specimens (n = 9). mNGS data were then used as a training dataset to optimize a bioinformatics workflow based on the IDseq pipeline. For clinical validation, residual CSF specimens (n = 74) from patients with suspected CNS infections previously tested by culture and/or PCR, were analyzed by mNGS. In simulated specimens, the NGS reads aligned to pathogen genomes in IDseq were correlated to qPCR CT values for the respective pathogens (R = 0.96; p

Death from sepsis in the neonatal period remains a serious threat for millions. Within 3 days of administration, bacille Calmette-Guérin (BCG) vaccination can reduce mortality from neonatal sepsis in human newborns, but the underlying mechanism for this rapid protection is unknown. We found that BCG was also protective in a mouse model of neonatal polymicrobial sepsis, where it induced granulocyte colony-stimulating factor (G-CSF) within hours of administration. This was necessary and sufficient to drive emergency granulopoiesis (EG), resulting in a marked increase in neutrophils. This increase in neutrophils was directly and quantitatively responsible for protection from sepsis. Rapid induction of EG after BCG administration also occurred in three independent cohorts of human neonates.

BACKGROUND. Multiple therapeutic strategies to restore immune regulation and slow type 1 diabetes (T1D) progression are in development and testing. A major challenge has been defining biomarkers to prospectively identify subjects likely to benefit from immunotherapy and/or measure intervention effects. We previously found that, compared with healthy controls, Tregs from children with new-onset T1D have an altered Treg gene signature (TGS), suggesting that this could be an immunoregulatory biomarker. METHODS. nanoString was used to assess the TGS in sorted Tregs (CD4((+))CD25((hi))CD127((lo))) or peripheral blood mononuclear cells (PBMCs) from individuals with T1D or type 2 diabetes, healthy controls, or T1D recipients of immunotherapy. Biomarker discovery pipelines were developed and applied to various sample group comparisons. RESULTS. Compared with controls, the TGS in isolated Tregs or PBMCs was altered in adult new-onset and cross-sectional T1D cohorts, with sensitivity or specificity of biomarkers increased by including T1D-associated SNPs in algorithms. The TGS was distinct in T1D versus type 2 diabetes, indicating disease-specific alterations. TGS measurement at the time of T1D onset revealed an algorithm that accurately predicted future rapid versus slow C-peptide decline, as determined by longitudinal analysis of placebo arms of START and T1DAL trials. The same algorithm stratified participants in a phase I/II clinical trial of ustekinumab (αIL-12/23p40) for future rapid versus slow C-peptide decline. CONCLUSION. These data suggest that biomarkers based on measuring TGSs could be a new approach to stratify patients and monitor autoimmune activity in T1D. FUNDING. JDRF (1-PNF-2015-113-Q-R, 2-PAR-2015-123-Q-R, 3-SRA-2016-209-Q-R, 3-PDF-2014-217-A-N), the JDRF Canadian Clinical Trials Network, the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (UM1AI109565 and FY15ITN168), and BCCHRI.

IL-17 plays critical roles in host defenses, combating bacterial and fungal infections, as well as the pathogenesis of autoimmune diseases such as experimental autoimmune encephalomyelitis (EAE). The signaling adaptor SAP is essential for normal immune homeostasis and mutations within SH2D1A, the locus encoding this protein, result in serious and sometimes fatal syndromes, including X-linked lymphoproliferative disease and severe cases of common variable immunodeficiency. However, the precise cellular basis of how SAP deficiency contributes to immune dysfunction remains incompletely understood. In this study, we found that CD4 and CD8 T cells lacking SAP had a diminished capacity to differentiate into IL-17–producing Th17 and T cytotoxic (Tc17) cells relative to wild-type lymphocytes. The use of costimulating SLAM Abs was found to augment the differentiation of IL-17–secreting effectors in wild-type but not Sh2d1a−/− splenic T cells under IL-17–polarizing conditions. In addition, SAP’s regulation of IL-17–secreting T cells was shown to be a T cell–intrinsic role, as purified naive Sh2d1a−/− CD4 and CD8 T cells were inherently defective at converting into Th17 and Tc17 cells in vitro and in vivo. Furthermore, Sh2d1a−/− mice were protected from EAE and exhibited greatly decreased numbers of CNS-infiltrating Th17 and Tc17 effector T cells and reduced disease severity. Collectively, these results suggest that SLAM–SAP signaling drives the differentiation and function of Th17 and Tc17 cells in vitro and in vivo and contributes to the pathogenesis of autoimmunity in EAE.

Type 1 diabetes is a T cell-mediated autoimmune disease with a clinically silent prodrome, during which prediction and treatment of disease are theoretically possible. Using retrospective analysis, spontaneous disease in the non-obese diabetic (NOD) mouse has been correlated with islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)-reactive CD8+ T cells in the peripheral blood. In this study, we determined prospectively whether IGRP-reactive T cells in peripheral blood could predict disease occurrence. Since recurrent autoimmunity is an important contributor to transplant failure, we also determined whether failure of islet grafts (syngeneic and allogeneic) could be predicted by the presence of circulating autoreactive T cells.Peripheral blood samples were taken weekly from female NOD mice between the ages of 8 and 30 weeks and from NOD mice transplanted with NODscid islets. Peripheral blood cells and islet grafts were analysed for the presence of IGRP-reactive CD8+ T cells by flow cytometry.Prospective analysis of peripheral blood IGRP-reactive T cells in the prediabetic period predicted disease development with a sensitivity of 100% and a specificity of 60%, resulting in positive and negative predictive values of 85 and 100%, respectively. Significant proportions of IGRP-reactive T cells were found in the grafts, but not in peripheral blood of NOD mice undergoing syngeneic and allogeneic rejection.The occurrence of spontaneous diabetes can be predicted prospectively by measuring peripheral blood autoreactive T cells. Rejection of syngeneic or allogeneic islets is associated with large populations of autoreactive CD8+ T cells within islets, suggesting that immunodominant autoreactive T cells during the prediabetic period are also responsible for autoimmune graft rejection.

Type 1 diabetes results from the autoimmune destruction of insulin-producing pancreatic beta-cells by cytotoxic T-lymphocytes (CTLs). In humans, few beta-cell epitopes have been reported, thereby limiting the study of beta-cell-specific CTLs in type 1 diabetes. To identify additional epitopes, HLA class I peptide affinity algorithms were used to identify a panel of peptides derived from the beta-cell proteins islet amyloid polypeptide (IAPP), islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP), insulin, insulinoma-associated antigen 2 (IA-2), and phogrin that were predicted to bind HLA-A*0201. Peripheral blood mononuclear cells from 24 HLA-A*0201 recent-onset type 1 diabetic patients and 11 nondiabetic control subjects were evaluated for gamma-interferon secretion in response to peptide stimulation in enzyme-linked immunospot assays. We identified peptides IAPP9-17, IGRP215-223, IGRP152-160, islet IA-2(172-180), and IA-2(482-490) as novel HLA-A*0201-restricted T-cell epitopes in type 1 diabetic patients. Interestingly, we observed a strong inverse correlation between the binding affinity of beta-cell peptides to HLA-A*0201 and CTL responses against those peptides in recent-onset type 1 diabetic patients. In addition, we found that self-reactive CTLs with specificity for an insulin peptide are frequently present in healthy individuals. These data suggest that many beta-cell epitopes are recognized by CTLs in recent-onset type 1 diabetic patients. These epitopes may be important in the pathogenesis of type 1 diabetes.

Nocardia Asteroides infection in a non-immunocompromised pediatric patient is extremely rare. We present a case of ethmoid sinusitis and orbital subperiosteal abscess caused by N. asteroides with a 20 year follow up and a review of the literature. N. asteroides was grown from intraoperative cultures for mycobacteria following surgical incision and drainage of the abscess. Postoperatively, the patient received a seven month course of trimethoprim-sulfamethozaxole and had no subsequent sequelae. Nocardia infections are common in immunocompromised patients. We present what we believe to be the first case of pediatric Nocardia sinusitis with 20-year follow up.

Systemic vasculitis is an uncommon manifestation of X-linked lymphoproliferative disease (XLP), a disorder in which there is a selective immune deficiency to Epstein-Barr virus (EBV). The molecular basis for XLP has recently been ascribed to mutations within SLAM-associated protein (SAP), an SH2 domain–containing protein expressed primarily in T cells. The authors describe a patient who died as a result of chronic systemic vasculitis and fulfilled clinical criteria for the diagnosis of XLP. Sequencing of this patient'sSAP gene uncovered a novel point mutation affecting the SH2 domain. The patient presented with virus-associated hemophagocytic syndrome (VAHS) and later had chorioretinitis, bronchiectasis, and hypogammaglobulinemia develop. He further developed mononeuritis and fatal respiratory failure. Evidence of widespread small and medium vessel vasculitis was noted at autopsy with involvement of retinal, cerebral, and coronary arteries as well as the segmental vessels of the kidneys, testes, and pancreas. Immunohistochemical analysis using antibodies to CD20, CD45RO, and CD8 revealed that the vessel wall infiltrates consisted primarily of CD8+ T cells, implying a cytotoxic T-lymphocyte response to antigen. EBV DNA was detected by polymerase chain reaction (PCR) in arterial wall tissue microdissected from infiltrated vessels further suggesting that the CD8+ T cells were targeting EBV antigens within the endothelium. The authors propose that functional inactivation of the SAP protein can impair the immunologic response to EBV, resulting in systemic vasculitis.

X-linked lymphoproliferative disease (XLP) is characterized by a selective immune deficiency to EBV. The molecular basis of XLP has been attributed to mutations of signaling lymphocytic activation molecule-associated protein, an intracellular molecule known to associate with the lymphocyte-activating surface receptors SLAM and 2B4. We have identified a single nucleotide mutation in SLAM-associated protein that affects the NK cell function of males carrying the mutated gene. In contrast to normal controls, both NK and lymphokine-activated killer cell cytotoxicity was significantly reduced in two XLP patients. In addition to decreased baseline cytotoxicity, ligation of 2B4 significantly augmented NK lytic function in normal controls but failed to enhance the cytotoxicity of NK cells from XLP patients. These findings suggest that association of SAP with 2B4 is necessary for optimal NK/lymphokine-activated killer cytotoxicity and imply that alterations in SAP/2B4 signaling contribute to the immune dysfunction observed in XLP.

This FOCIS Centers of Excellence Short Analytical Review is based on the clinical vignette of two boys from the same family with very different outcomes following hematopoietic stem cell transplantation (HSCT) for X-linked severe combined immunodeficiency (SCID). We review the kinetics of immune reconstitution following HSCT in SCID and emphasize the latest information regarding optimizing transplant outcomes for this disorder. The cases illustrate the difficulties and controversies surrounding the optimal strategies for planning SCID transplants. Specifically, we will focus on 3 areas of current debate and investigation: (i) factors involved in donor selection; (ii) the role of pretransplant conditioning; and (iii) benefits of early HSCT for SCID.

NK cells from individuals with X-linked lymphoproliferative (XLP) disease exhibit functional defects when stimulated through the NK receptor, 2B4 (CD244). These defects are likely a consequence of aberrant intracellular signaling initiated by mutations of the adaptor molecule SLAM-associated protein. In this report, we show that NK cells from individuals with XLP but not healthy individuals fail to phosphorylate and thereby inactivate glycogen synthase kinase-3 (GSK-3) following 2B4 stimulation. Lack of GSK-3 phosphorylation prevented the accumulation of the transcriptional coactivator β-catenin in the cytoplasm and its subsequent translocation to the nucleus. Potential signaling pathways leading from 2B4 stimulation to GSK-3 phosphorylation were also investigated. Ligation of 2B4 resulted in the phosphorylation of the guanine nucleotide exchange factor, Vav-1, and subsequent activation of the GTP-binding protein Rac-1 (but not Ras) and the serine-threonine kinase Raf-1 in healthy but not XLP-derived NK cells. In addition, the activity of MEK-2 (but not MEK-1) was up-regulated, and Erk1/2 was phosphorylated in normal NK cells but not those from an individual with XLP suggesting that these proteins relay SLAM-associated protein-dependent signals from 2B4. Finally, inactivation of GSK-3 using a specific inhibitor of GSK-3β increased the cytotoxicity and cytokine secretion of both healthy and XLP NK cells. These data indicate that the signaling of 2B4 in NK cells is mediated by GSK-3 and β-catenin, possibly through a signal transduction pathway that involves Vav-1, Rac-1, Raf-1, MEK-2, and Erk1/2 and that this pathway is aberrant in individuals with XLP.

Background. Neisseria meningitidis continues to be an important cause of invasive bacterial disease among children and young adults worldwide. In Canada, N. meningitidis strains that bear serogroups B and C polysaccharide capsules predominate. We report the first documented case of invasive meningococcal disease in an immunocompetent host caused by an acapsular strain of N. meningitidis containing the capsule null locus (cnl). Methods. Analysis of the isolate was performed with use of serological and molecular methods, including multilocus sequence typing and cnl gene identification. Analysis of 16S ribosomal RNA (rRNA) and porA genes was also performed to confirm the identity of the bacterium. Results. The patient was a healthy, immunocompetent 13-year-old child, and N. meningitidis was recovered from a sample of her cerebrospinal fluid before death. The isolate was nontypeable by both conventional antisera and indirect whole-cell enzyme-linked immuosorbent assay methods using antibodies to serogroups B, C, Y, and W135. The isolate was further identified as a cnl strain, serotype 15 (ST-198). N. meningitidis–specific DNA was identified in the isolate and in the pre- and postmortem specimens by 16S rRNA and porA gene analysis. Conclusions. This is the first reported case of fatal meningococcal disease caused by an acapsular cnl strain of N. meningitidis that was isolated from an immunocompetent host. Routine molecular diagnostic methods targeted at the cnl locus failed to detect this organism, indicating a need to determine the incidence of infection with cnl strains among patients with culture-negative invasive disease.

Autoimmune (type 1) diabetes mellitus results from the destruction of insulin-producing pancreatic beta-cells by T lymphocytes. Beta-cell death that is induced by autoreactive CTL in diabetes involves both Fas/Fas ligand (FasL)- and perforin/granzyme-mediated pathways, although their relative contributions during the progression of the disease remain unknown. We demonstrate here that despite the preferential use of the Fas/FasL pathway for cytolysis of beta-cell targets, transgenic beta-cell-specific CTL were able to kill targets via the perforin pathway when triggered by a higher affinity stimulus. In addition, we show that the killing mechanism used by islet-associated CD8(+) T cells from non-obese diabetic mice changed as the mice aged and correspondingly, with the stage of diabetes. These results provide direct evidence for age-related changes in the cytotoxic pathways used by diabetogenic T cells during the progression of autoimmune diabetes.

Context.—Meningococcal infection has a high public profile because of its dramatic presentation, high fatality rate, and propensity to occur in outbreaks and clusters of cases. Use of a diagnostic polymerase chain reaction (PCR) assay could enhance laboratory confirmation of cases and guide the public health response in North America.Objective.—To assess the performance of a PCR assay for the diagnosis of meningococcal disease after its implementation in a North American setting and to evaluate sensitivity and specificity of the assay for the detection of prevalent bacterial isolates.Design.—Laboratory evaluation of the sensitivity and specificity of a PCR assay for Neisseria meningitidis and observational study of a series of cases comparing molecular diagnosis against the criterion standard of conventional laboratory diagnostic tests.Setting.—A Canadian province with a population of 4 million people.Patients.—Children and adults presenting with suspected meningococcal disease in British Columbia.Main Outcome Measures.—The sensitivity and specificity of the PCR assay when compared against standard laboratory methods.Results.—The PCR assay correctly identified all of 38 Canadian isolates of Neisseria meningitidis and correctly assigned the serogroup to each isolate. None of 57 other gram-positive or gram-negative bacteria or yeasts were detected by the PCR assay. In a clinical evaluation, for diagnosis of meningococcal disease, the PCR assay had a sensitivity and specificity of 91% and 76%, respectively, against conventional methods of diagnosis. Use of the PCR assay increased the laboratory confirmation of clinically suspected cases by 36%. During an outbreak, the PCR assay allowed serogroup determination in 3 of 7 cases, aiding in the public health decision to launch an immunization campaign.Conclusions.—The PCR assay is more sensitive than conventional methods for the diagnosis of meningococcal disease, and enhanced surveillance may help direct the public health response to the changing epidemiology of disease in North America.

Background & Aims Type 1 diabetes is caused by an aberrant response against pancreatic β cells. Intestinal K cells are glucose-responsive endocrine cells that might be engineered to secrete insulin. We generated diabetes-prone non-obese diabetic (NOD) mice that express insulin, via a transgene, in K cells. We assessed the effects on immunogenicity and diabetes development. Methods Diabetes incidence and glucose homeostasis were assessed in NOD mice that expressed mouse preproinsulin II from a transgene in K cells and nontransgenic NOD mice (controls); pancreas and duodenum tissues were collected and analyzed by histology. We evaluated T cell responses to insulin, levels of circulating autoantibodies against insulin, and the percentage of circulating antigen-specific T cells. Inflammation of mesenteric and pancreatic lymph node cells was also evaluated. Results The transgenic mice tended to have lower blood levels of glucose than control mice, associated with increased plasma levels of immunoreactive insulin and proinsulin. Fewer transgenic mice developed diabetes than controls. In analyses of pancreas and intestine tissues from the transgenic mice, insulin-producing K cells were not affected by the immune response and the mice had reduced destruction of endogenous β cells. Fewer transgenic mice were positive for insulin autoantibodies compared with controls. Cells isolated from mesenteric lymph nodes of the transgenic mice had significantly lower rates of proliferation and T cells from transgenic mice tended to secrete lower levels of inflammatory cytokines than from controls. At 15 weeks, transgenic mice had fewer peripheral CD8 + T cells specific for NRP-V7 than control mice. Conclusions NOD mice with intestinal K cells engineered to express insulin have reduced blood levels of glucose, are less likely to develop diabetes, and have reduced immunity against pancreatic β cells compared with control NOD mice. This approach might be developed to treat patients with type 1 diabetes.

Epstein-Barr virus (EBV) infection results in rapid loss of CD1d expression from the surface of infected B cells, thus enabling the virus to evade immune recognition by natural killer T (NKT) cells. Using pharmacologic means to boost CD1d expression, potent NKT cell effector functions can be elicited toward EBV-infected B cells, suggesting the promise of novel strategies to target EBV-associated diseases such as some B-cell malignancies.

An assessment was made of the utilization and impact of a diagnostic polymerase chain reaction (PCR) assay for the diagnosis of herpes simplex viruses (HSV) 1 and 2 in cerebrospinal fluid of children who attended a Canadian pediatric referral centre. One hundred and three assays were performed on specimens from 103 patients during the period August 1997 to September 1998. Patient ages ranged from newborn to 16 years. Indications for HSV PCR included seizures with or without fever (56.3%), aseptic meningitis (16.5%), and encephalopathy with or without fever (10.7%). Only 2 of 103 (1.9%) assays were positive, including one each for HSV1 and HSV2. Control specimens that were seeded with virus indicated inhibition for 24.3, 8.8, and 6.8% of assays for HSV1, HSV2, and both HSV1 and HSV2, respectively. The mean turn-around time for HSV PCR was 2.5 days, and 90.3% were completed in less than 5 days. Acyclovir was administered to 78.6% of the patients overall; the results of the HSV PCR impacted on the treatment courses for 36 individuals. Nevertheless, 16.5% of patients continued to receive extended courses of antiviral therapy despite negative HSV PCR assays. Although it is desirable to decrease the frequency of PCR inhibitions and to further decrease the interval to assay completion, HSV PCR does have a significant impact on antiviral use in this setting.Key words: herpes simplex, polymerase chain reaction, central nervous system.

For unknown reasons, autoimmune diseases such as type 1 diabetes develop after prolonged periods of inflammation of mononuclear cells in target tissues. Here we show that progression of pancreatic islet inflammation to overt diabetes in nonobese diabetic (NOD) mice is driven by the 'avidity maturation' of a prevailing, pancreatic beta-cell-specific T-lymphocyte population carrying the CD8 antigen. This T-lymphocyte population recognizes two related peptides (NRP and NRP-A7) in the context of H-2Kd class I molecules of the major histocompatibility complex (MHC). As pre-diabetic NOD mice age, their islet-associated CD8+ T lymphocytes contain increasing numbers of NRP-A7-reactive cells, and these cells bind NRP-A7/H-2Kd tetramers with increased specificity, increased avidity and longer half-lives. Repeated treatment of pre-diabetic NOD mice with soluble NRP-A7 peptide blunts the avidity maturation of the NRP-A7-reactive CD8+ T-cell population by selectively deleting those clonotypes expressing T-cell receptors with the highest affinity and lowest dissociation rates for peptide-MHC binding. This inhibits the local production of T cells that are cytotoxic to beta cells, and halts the progression from severe insulitis to diabetes. We conclude that avidity maturation of pathogenic T-cell populations may be the key event in the progression of benign inflammation to overt disease in autoimmunity.

Rationale . Human herpesvirus 6 (HHV-6) has been demonstrated to be the causative agent in roseola infantum. It has been suggested that HHV-6 may have neurotropic properties and be involved in the pathogenesis of febrile seizures in infants. We describe a case-control study to examine the hypothesis that acute HHV-6 infection occurs more commonly in children with febrile seizures than in controls. Methods . Patients presenting with a first or second febrile seizure between 6 months and 2 years of age were entered in the study. Control patients did not have a seizure but had similar inclusion and exclusion criteria. Specimens were obtained for HHV-6 viral serology and polymerase chain reaction in the acute stage and approximately 2 weeks later. A diagnosis of HHV-6 infection was based on HHV-6-specific IgM and IgG serology and HHV-6 polymerase chain reaction of peripheral blood mononuclear cells and saliva. Results . Eighty-six patients (45 with febrile seizures; 41 controls) were enrolled. The HHV-6 infection status could be determined in only 68 patients (35 with febrile seizures; 33 controls). Acute HHV-6 infection was identified in 15 of 35 febrile seizure patients and in 15 of 33 controls. Evidence of past HHV-6 infection was demonstrated in 13 febrile seizure patients and in 8 controls. Conclusions . The incidence of primary HHV-6 infection is similar in patients with febrile seizures and age-matched controls. HHV-6 does not seem to be a major factor in the pathogenesis of first and second febrile seizures.

s / Can J Diabetes 36 (2012) S24eS76 S76 injection into the pancreatic duct of C57Bl/6 mice, resulting in beta beta cell specific expression throughout the pancreas. When XIAPexpressing mouse islets were isolated from C57 Bl/6 donors and transplanted into streptozotocin-diabetic, MHC-mismatched (Balb/ c) mice, all recipients were protected from allograft rejection and return of hyperglycemia for more than 125 days. Histological analysis of the islet graft confirmed numerous insulin-positive cells within XIAP-expressing islets and a progressive lost of immune infiltration cells. Diminished alloantibodies and non-proliferation of splenocytes after exposure to alloantigens suggested that tolerance was induced in the recipients. These findings indicate that dsAAV8-mediated expression of XIAP in islets may induce tolerance to islet allograft recipients, thereby preventing recurrence of diabetes. Manipulation of islets for long-term expression of XIAP may be a novel therapeutic strategy for diabetes.

Summary Objectives We assessed the safety of ustekinumab (a monoclonal antibody used in psoriasis to target the IL-12 and IL-23 pathways) in a small cohort of recent-onset (, Graphical Abstract