Concept: Immune system
Autism spectrum disorder (ASD) is defined by standardized criteria of qualitative impairments in social interaction, qualitative impairments in communication, and restricted and stereotyped patterns of behavior, interests, and activities. A significant number of children diagnosed with ASD suffer a loss of previously-acquired skills, which is suggestive of neurodegeneration or a type of progressive encephalopathy with an etiological pathogenic basis occurring after birth. To date, the etiology of ASD remains under debate, however, many studies suggest toxicity, especially from mercury (Hg), in individuals diagnosed with an ASD. The present study evaluated concerns about the toxic effects of organic-Hg exposure from Thimerosal (49.55% Hg by weight) in childhood vaccines by conducting a two-phased (hypothesis generating/hypothesis testing) study with documented exposure to varying levels of Thimerosal from vaccinations.
It is widely accepted that aging is accompanied by remodelling of the immune system including thymic atrophy and increased frequency of senescent T cells, leading to immune compromise. However, physical activity, which influences immunity but declines dramatically with age, is not considered in this literature. We assessed immune profiles in 125 adults (55-79 years) who had maintained a high level of physical activity (cycling) for much of their adult lives, 75 age-matched older adults and 55 young adults not involved in regular exercise. The frequency of naïve T cells and recent thymic emigrants (RTE) were both higher in cyclists compared with inactive elders, and RTE frequency in cyclists was no different to young adults. Compared with their less active counterparts, the cyclists had significantly higher serum levels of the thymoprotective cytokine IL-7 and lower IL-6, which promotes thymic atrophy. Cyclists also showed additional evidence of reduced immunesenescence, namely lower Th17 polarization and higher B regulatory cell frequency than inactive elders. Physical activity did not protect against all aspects of immunesenescence: CD28-veCD57+vesenescent CD8 T-cell frequency did not differ between cyclists and inactive elders. We conclude that many features of immunesenescence may be driven by reduced physical activity with age.
In the United States, annual vaccination against seasonal influenza is recommended for all persons aged ≥6 months (1). During each influenza season since 2004-05, CDC has estimated the effectiveness of seasonal influenza vaccine to prevent laboratory-confirmed influenza associated with medically attended acute respiratory illness (ARI). This report uses data from 4,562 children and adults enrolled in the U.S. Influenza Vaccine Effectiveness Network (U.S. Flu VE Network) during November 2, 2017-February 3, 2018. During this period, overall adjusted vaccine effectiveness (VE) against influenza A and influenza B virus infection associated with medically attended ARI was 36% (95% confidence interval [CI] = 27%-44%). Most (69%) influenza infections were caused by A(H3N2) viruses. VE was estimated to be 25% (CI = 13% to 36%) against illness caused by influenza A(H3N2) virus, 67% (CI = 54%-76%) against A(H1N1)pdm09 viruses, and 42% (CI = 25%-56%) against influenza B viruses. These early VE estimates underscore the need for ongoing influenza prevention and treatment measures. CDC continues to recommend influenza vaccination because the vaccine can still prevent some infections with currently circulating influenza viruses, which are expected to continue circulating for several weeks. Even with current vaccine effectiveness estimates, vaccination will still prevent influenza illness, including thousands of hospitalizations and deaths. Persons aged ≥6 months who have not yet been vaccinated this season should be vaccinated.
Pathogens and the diseases they cause have been among the most important selective forces experienced by humans during their evolutionary history. Although adaptive alleles generally arise by mutation, introgression can also be a valuable source of beneficial alleles. Archaic humans, who lived in Europe and Western Asia for more than 200,000 years, were probably well adapted to this environment and its local pathogens. It is therefore conceivable that modern humans entering Europe and Western Asia who admixed with them obtained a substantial immune advantage from the introgression of archaic alleles. Here we document a cluster of three Toll-like receptors (TLR6-TLR1-TLR10) in modern humans that carries three distinct archaic haplotypes, indicating repeated introgression from archaic humans. Two of these haplotypes are most similar to the Neandertal genome, and the third haplotype is most similar to the Denisovan genome. The Toll-like receptors are key components of innate immunity and provide an important first line of immune defense against bacteria, fungi, and parasites. The unusually high allele frequencies and unexpected levels of population differentiation indicate that there has been local positive selection on multiple haplotypes at this locus. We show that the introgressed alleles have clear functional effects in modern humans; archaic-like alleles underlie differences in the expression of the TLR genes and are associated with reduced microbial resistance and increased allergic disease in large cohorts. This provides strong evidence for recurrent adaptive introgression at the TLR6-TLR1-TLR10 locus, resulting in differences in disease phenotypes in modern humans.
To date, vaccination is the most cost-effective strategy to combat infectious diseases. Recently, a productivity gap affects the pharmaceutical industry. The productivity gap describes the situation whereby the invested resources within an industry do not match the expected product turn-over. While risk profiles (combining research and development timelines and transition rates) have been published for new chemical entities (NCE), little is documented on vaccine development. The objective is to calculate risk profiles for vaccines targeting human infectious diseases. A database was actively compiled to include all vaccine projects in development from 1998 to 2009 in the pre-clinical development phase, clinical trials phase I, II and III up to Market Registration. The average vaccine, taken from the preclinical phase, requires a development timeline of 10.71 years and has a market entry probability of 6%. Stratification by disease area reveals pandemic influenza vaccine targets as lucrative. Furthermore, vaccines targeting acute infectious diseases and prophylactic vaccines have shown to have a lower risk profile when compared to vaccines targeting chronic infections and therapeutic applications. In conclusion; these statistics apply to vaccines targeting human infectious diseases. Vaccines targeting cancer, allergy and autoimmune diseases require further analysis. Additionally, this paper does not address orphan vaccines targeting unmet medical needs, whether projects are in-licensed or self-originated and firm size and experience. Therefore, it remains to be investigated how these - and other - variables influence the vaccine risk profile. Although we find huge differences between the risk profiles for vaccine and NCE; vaccines outperform NCE when it comes to development timelines.
Neoplasms occur naturally in invertebrates but are not known to develop in tapeworms. We observed nests of monomorphic, undifferentiated cells in samples from lymph-node and lung biopsies in a man infected with the human immunodeficiency virus (HIV). The morphologic features and invasive behavior of the cells were characteristic of cancer, but their small size suggested a nonhuman origin. A polymerase-chain-reaction (PCR) assay targeting eukaryotes identified Hymenolepis nana DNA. Although the cells were unrecognizable as tapeworm tissue, immunohistochemical staining and probe hybridization labeled the cells in situ. Comparative deep sequencing identified H. nana structural genomic variants that are compatible with mutations described in cancer. Invasion of human tissue by abnormal, proliferating, genetically altered tapeworm cells is a novel disease mechanism that links infection and cancer.
Public trust in immunization is an increasingly important global health issue. Losses in confidence in vaccines and immunization programmes can lead to vaccine reluctance and refusal, risking disease outbreaks and challenging immunization goals in high- and low-income settings. National and international immunization stakeholders have called for better monitoring of vaccine confidence to identify emerging concerns before they evolve into vaccine confidence crises.
Zika virus (ZIKV) is an emerging flavivirus that causes congenital abnormalities and Guillain-Barré syndrome. ZIKV infection also results in severe eye disease characterized by optic neuritis, chorioretinal atrophy, and blindness in newborns and conjunctivitis and uveitis in adults. We evaluated ZIKV infection of the eye by using recently developed mouse models of pathogenesis. ZIKV-inoculated mice developed conjunctivitis, panuveitis, and infection of the cornea, iris, optic nerve, and ganglion and bipolar cells in the retina. This phenotype was independent of the entry receptors Axl or Mertk, given that Axl(-/-), Mertk(-/-), and Axl(-/-)Mertk(-/-) double knockout mice sustained levels of infection similar to those of control animals. We also detected abundant viral RNA in tears, suggesting that virus might be secreted from lacrimal glands or shed from the cornea. This model provides a foundation for studying ZIKV-induced ocular disease, defining mechanisms of viral persistence, and developing therapeutic approaches for viral infections of the eye.
Systems analysis of sex differences reveals an immunosuppressive role for testosterone in the response to influenza vaccination
- Proceedings of the National Academy of Sciences of the United States of America
- Published over 6 years ago
Females have generally more robust immune responses than males for reasons that are not well-understood. Here we used a systems analysis to investigate these differences by analyzing the neutralizing antibody response to a trivalent inactivated seasonal influenza vaccine (TIV) and a large number of immune system components, including serum cytokines and chemokines, blood cell subset frequencies, genome-wide gene expression, and cellular responses to diverse in vitro stimuli, in 53 females and 34 males of different ages. We found elevated antibody responses to TIV and expression of inflammatory cytokines in the serum of females compared with males regardless of age. This inflammatory profile correlated with the levels of phosphorylated STAT3 proteins in monocytes but not with the serological response to the vaccine. In contrast, using a machine learning approach, we identified a cluster of genes involved in lipid biosynthesis and previously shown to be up-regulated by testosterone that correlated with poor virus-neutralizing activity in men. Moreover, men with elevated serum testosterone levels and associated gene signatures exhibited the lowest antibody responses to TIV. These results demonstrate a strong association between androgens and genes involved in lipid metabolism, suggesting that these could be important drivers of the differences in immune responses between males and females.
Background Child-parent screening for familial hypercholesterolemia has been proposed to identify persons at high risk for inherited premature cardiovascular disease. We assessed the efficacy and feasibility of such screening in primary care practice. Methods We obtained capillary blood samples to measure cholesterol levels and to test for familial hypercholesterolemia mutations in 10,095 children 1 to 2 years of age during routine immunization visits. Children were considered to have positive screening results for familial hypercholesterolemia if their cholesterol level was elevated and they had either a familial hypercholesterolemia mutation or a repeat elevated cholesterol level 3 months later. A parent of each child with a positive screening result for familial hypercholesterolemia was considered to have a positive screening result for familial hypercholesterolemia if he or she had the same mutation as the child or, if no mutations were identified, had the higher cholesterol level of the two parents. Results The use of a prespecified cholesterol cutoff value of 1.53 multiples of the median (MoM, corresponding to a percentile of 99.2) identified 28 children who had positive screening results for familial hypercholesterolemia (0.3% of the 10,095 children; 95% confidence interval [CI], 0.2 to 0.4), including 20 with a familial hypercholesterolemia mutation and 8 with a repeat cholesterol level of at least 1.53 MoM. A total of 17 children who had a cholesterol level of less than 1.53 MoM also had a familial hypercholesterolemia mutation. The overall mutation prevalence was 1 in 273 children (37 in 10,095; 95% CI, 1 in 198 to 1 in 388). The use of an initial cholesterol cutoff value of 1.35 MoM (95th percentile) plus a mutation, or two cholesterol values of at least 1.50 MoM (99th percentile), identified 40 children who had positive screening results for familial hypercholesterolemia (0.4% of the 10,095 children, including 32 children who had a familial hypercholesterolemia mutation and 8 who did not have the mutation) and 40 parents who had positive screening results for familial hypercholesterolemia. Conclusions Child-parent screening was feasible in primary care practices at routine child immunization visits. For every 1000 children screened, 8 persons (4 children and 4 parents) were identified as having positive screening results for familial hypercholesterolemia and were consequently at high risk for cardiovascular disease. (Funded by the Medical Research Council.).