Lack of Association between Measles Virus Vaccine and Autism with Enteropathy: A Case-Control Study

Background: The presence of measles virus (MV) RNA in bowel tissue from children with autism spectrum disorders (ASD) and gastrointestinal (GI) disturbances was reported in 1998. Subsequent investigations found no associations between MV exposure and ASD but did not test for the presence of MV RNA in bowel or focus on children with ASD and GI disturbances. Failure to replicate the original study design may contribute to continued public concern with respect to the safety of the measles, mumps, and rubella (MMR) vaccine. Methodology/Principal Findings: The objective of this case-control study was to determine whether children with GI disturbances and autism are more likely than children with GI disturbances alone to have MV RNA and/or inflammation in bowel tissues and if autism and/or GI episode onset relate temporally to receipt of MMR. The sample was an age-matched group of US children undergoing clinically-indicated ileocolonoscopy. Ileal and cecal tissues from 25 children with autism and GI disturbances and 13 children with GI disturbances alone (controls) were evaluated by real-time reverse transcription (RT)-PCR for presence of MV RNA in three laboratories blinded to diagnosis, including one wherein the original findings suggesting a link between MV and ASD were reported. The temporal order of onset of GI episodes and autism relative to timing of MMR administration was examined. We found no differences between case and control groups in the presence of MV RNA in ileum and cecum. Results were consistent across the three laboratory sites. GI symptom and autism onset were unrelated to MMR timing. Eighty-eight percent of ASD cases had behavioral regression. Conclusions/Significance: This study provides strong evidence against association of autism with persistent MV RNA in the GI tract or MMR exposure. Autism with GI disturbances is associated with elevated rates of regression in language or other skills and may represent an endophenotype distinct from other ASD

Pediatric Measles Vaccine Expressing a Dengue Antigen Induces Durable Serotype-specific Neutralizing Antibodies to Dengue Virus

Dengue disease is an increasing global health problem that threatens one-third of the world's population. Despite decades of efforts, no licensed vaccine against dengue is available. With the aim to develop an affordable vaccine that could be used in young populations living in tropical areas, we evaluated a new strategy based on the expression of a minimal dengue antigen by a vector derived from pediatric live-attenuated Schwarz measles vaccine (MV). As a proof-of-concept, we inserted into the MV vector a sequence encoding a minimal combined dengue antigen composed of the envelope domain III (EDIII) fused to the ectodomain of the membrane protein (ectoM) from DV serotype-1. Immunization of mice susceptible to MV resulted in a long-term production of DV1 serotype-specific neutralizing antibodies. The presence of ectoM was critical to the immunogenicity of inserted EDIII. The adjuvant capacity of ectoM correlated with its ability to promote the maturation of dendritic cells and the secretion of proinflammatory and antiviral cytokines and chemokines involved in adaptive immunity. The protective efficacy of this vaccine should be studied in non-human primates. A combined measles–dengue vaccine might provide a one-shot approach to immunize children against both diseases where they co-exist

Effect of Respiratory Syncytial Virus Infection on Plasmacytoid Dendritic Cell Regulation of Allergic Airway Inflammation.

Background: Respiratory syncytial virus (RSV) can infect myeloid dendritic cells (mDCs) and regulate their function in the development of allergy. It has been widely reported that plasmacytoid DCs (pDCs) play a critical role in antiviral innate immunity. In contrast, not much is known about the role of pDCs in the interaction between allergy and viral infection. The purpose of the present study was to investigate the effect of RSV infection on pDC function in the regulation of allergic airway inflammation in a murine model of Dermatophagoides farinae-sensitized allergic asthma. Methods: Splenic pDCs isolated from D. farinae-sensitized donor mice were infected with live RSV ex vivo. Subsequently, these pDCs were inoculated into the airways of D. farinae-sensitized recipient mice. Lung pathology, lung tissue cytokine profiles, the number of regulatory T cells (T(reg)) and mDCs as well as the effects of IL-10 neutralization in the lung tissue of recipient mice were determined. Results: Intranasal inoculation of D. farinae-sensitized pDCs significantly inhibited the development of allergic airway inflammation and both Th1 and Th2 immunity. Live RSV infection of these pDCs prior to inoculation interfered with their inhibitory effects through decreasing T(reg) and IL-10 and increasing mDCs. Conclusions: In asthmatic airways, pDCs mediate tolerance to inhaled allergens through the regulation of T(reg), IL-10 and mDCs. RSV infection of pDCs potentially inhibits their immunotolerogenic effects and thus exacerbates allergic airway inflammation

A Mouse Model for Osseous Heteroplasia

GNAS/Gnas encodes Gsa that is mainly biallelically expressed but shows imprinted expression in some tissues. In Albright Hereditary Osteodystrophy (AHO) heterozygous loss of function mutations of GNAS can result in ectopic ossification that tends to be superficial and attributable to haploinsufficiency of biallelically expressed Gsa. Oed-Sml is a point missense mutation in exon 6 of the orthologous mouse locus Gnas. We report here both the late onset ossification and occurrence of benign cutaneous fibroepithelial polyps in Oed-Sml. These phenotypes are seen on both maternal and paternal inheritance of the mutant allele and are therefore due to an effect on biallelically expressed Gsa. The ossification is confined to subcutaneous tissues and so resembles the ossification observed with AHO. Our mouse model is the first with both subcutaneous ossification and fibroepithelial polyps related to Gsa deficiency. It is also the first mouse model described with a clinically relevant phenotype associated with a point mutation in Gsa and may be useful in investigations of the mechanisms of heterotopic bone formation. Together with earlier results, our findings indicate that Gsa signalling pathways play a vital role in repressing ectopic bone formation

Differentiation and immune function of human dendritic cells following infection by respiratory syncytial virus

RSV causes annual epidemics of bronchiolitis in winter months resulting in the hospitalization of many infants and the elderly. Dendritic cells (DCs) play a pivotal role in coordinating immune responses to infection and some viruses skew, or subvert, the immune functions of DCs. RSV infection of DCs could alter their function and this could explain why protection after natural RSV infection is incomplete and of short duration. In this study, this interaction between DCs and RSV was investigated using a human primary culture model. DCs were generated from purified healthy adult volunteer peripheral blood monocytes. Effects of RSV upon DC phenotype with RSV primed DCs was measured using flow cytometry. Changes to viability and proliferation of cocultured DCs and T-cells were determined using microscopy with fluorescent dyes (Hoechst 33342 and propidium iodide). DC maturation was not prevented by the RSV challenge. RSV infected a fraction of DCs (10–30%) but the virus replicated slowly in these cells with only small reduction to cell viability. DCs challenged with RSV stimulated T-cell proliferation less well than lipopolysaccharide. This is the first study to demonstrate RSV infection of human monocyte derived DCs and suggests that the virus does not significantly interfere with the function of these cells and potentially may promote cellular rather than humoral responses

Changes in human dendritic cell number and function in severe obesity may contribute to increased susceptibility to viral infection

Dendritic cells (DCs) are key immune sentinels linking the innate and adaptive immune systems. DCs recognise danger signals and initiate T-cell tolerance, memory and polarisation. They are critical cells in responding to a viral illness. Obese individuals have been shown to have an impaired response to vaccinations against virally mediated conditions and to have an increased susceptibility to multi-organ failure in response to viral illness. We investigated if DCs are altered in an obese cohort (mean body mass index 51.7±7.3 kg m(-2)), ultimately resulting in differential T-cell responses. Circulating DCs were found to be significantly decreased in the obese compared with the lean cohort (0.82% vs 2.53%). Following Toll-like receptor stimulation, compared with lean controls, DCs generated from the obese cohort upregulated significantly less CD83 (40% vs 17% mean fluorescence intensity), a molecule implicated in the elicitation of T-cell responses, particularly viral responses. Obese DCs produced twofold more of the immunosuppressive cytokine interleukin (IL)-10 than lean controls, and in turn stimulated fourfold more IL-4-production from allogenic naive T cells. We conclude that obesity negatively impacts the ability of DCs to mature and elicit appropriate T-cell responses to a general stimulus. This may contribute to the increased susceptibility to viral infection observed in severe obesity

Effects of repeated respiratory syncytial virus infections on pulmonary dendritic cells in a murine model of allergic asthma.

BACKGROUND: Primary and secondary respiratory syncytial virus (RSV) infection differentially regulates preexisting allergic airway inflammation. OBJECTIVES: The present study was designed to determine the effects of primary and secondary low-grade RSV infections on pulmonary dendritic cell (DC) functions. METHODS: Eight groups of BALB/c mice were used: one group each for control primary and secondary sensitization, primary and secondary sensitization to Dermatophagoides farinae (Derf) allergen, primary and secondary infection with RSV, and primary and secondary sensitization to Derf plus infection with RSV. CD11c+ pulmonary DCs were isolated from these mice and then transferred to naive mice followed by intranasal Derf challenge. Furthermore, either anti-IL-12 monoclonal antibody (alphaIL-12 mAb) or anti-IL-10 (alphaIL-10) mAb were injected into donor mice after Derf challenge and during RSV infection to determine the involvement of IL-12 and IL-10. RESULTS: Primary RSV infection failed to induce polarization in DCs since it failed to induce IL-10 and IL-12 production in Derf-sensitized donor lung. In contrast, secondary RSV infection significantly enhanced IL-12 production from Derf-sensitized donor lung, thereby enhancing both Th1 and Th2 responses. During RSV infection, alphaIL-12 but not alphaIL-10 mAb treatment blocked these immunological effects. CONCLUSION: Via IL-12, DCs may play a critical role in shifting the immune response in this experimental model of repeated respiratory viral infection in allergic asthma