ABSTRACT
PROBLEM: Autism spectrum disorder (ASD)-like phenotypes in murine models are linked to elevated pro-inflammatory cytokine profiles caused by maternal immune activation (MIA), but whether MIA alters the immune response in the offspring remains unclear. METHOD OF STUDY: Polyinosinic:polycytidylic acid (poly:[IC]) was used to induce MIA in immunocompetent and control TLR3-deficient pregnant mice, and cytokine levels were measured in maternal and foetal organs. Furthermore, cytokines and behaviour responses were tested after challenge with lipopolysaccharide in 7-day-old and adult mice. RESULTS: MIA induced on E12 resulted in changes in the cytokine expression profile in maternal and foetal organs and correlated with TNFα and IL-18 dysregulation in immune organs and brains from neonatal mice born to MIA-induced dams. Such changes further correlated with altered behavioural responses in adulthood. CONCLUSION: MIA induced by pathogens during pregnancy can interfere with the development of the foetal immune and nervous systems leading to dysfunctional immune responses and behaviour in offspring.
Subject(s)
Autism Spectrum Disorder/immunology , Immune System Diseases/immunology , Poly I-C/immunology , Pregnancy/immunology , Prenatal Exposure Delayed Effects/immunology , Virus Diseases/immunology , Animals , Autism Spectrum Disorder/psychology , Behavior, Animal , Child of Impaired Parents , Disease Models, Animal , Female , Humans , Immune System Diseases/psychology , Immunity , Immunity, Maternally-Acquired , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Prenatal Exposure Delayed Effects/psychology , Toll-Like Receptor 3/genetics , Transcriptome/immunology , Virus Diseases/psychologyABSTRACT
Adjuvants are used to enhance the immune response against specific antigens for the production of antibodies, with the choice of adjuvant most critical for poorly immunogenic and self-antigens. This study quantitatively and qualitatively evaluated CoVaccine HT™ and Freund's adjuvants for eliciting therapeutic ovine polyclonal antibodies targeting the endogenous alarmin, high mobility group box-1 (HMGB1). Sheep were immunised with HMGB1 protein in CoVaccine HT™ or Freund's adjuvants, with injection site reactions and antibody titres periodically assessed. The binding affinity of antibodies for HMGB1 and their neutralisation activity was determined in-vitro, with in vivo activity confirmed using a murine model of endotoxemia. Results indicated that CoVaccine HT™ elicited significantly higher antibody tires with stronger affinity and more functional potency than antibodies induced with Freund's adjuvants. These studies provide evidence that CoVaccine HT™ is superior to Freund's adjuvants for the production of antibodies to antigens with low immunogenicity and supports the use of this alternative adjuvant for clinical and experimental use antibodies.
Subject(s)
Adjuvants, Immunologic , Antibodies, Neutralizing/biosynthesis , Freund's Adjuvant/immunology , HMGB1 Protein/immunology , Adjuvants, Immunologic/administration & dosage , Animals , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/immunology , Antibody Affinity , Disease Models, Animal , Endotoxemia/blood , Endotoxemia/chemically induced , Endotoxemia/immunology , Freund's Adjuvant/administration & dosage , HMGB1 Protein/administration & dosage , HMGB1 Protein/metabolism , Immunization , Lipopolysaccharides , Mice, Inbred C57BL , Sheep, Domestic , Time FactorsABSTRACT
BACKGROUND: Influenza infection can result in severe disease with debilitating complications. Young children have the highest rate of influenza hospitalisations with various factors influencing influenza susceptibility and severity. OBJECTIVES: This study aimed to determine the disease burden and assess risk factors for severe hospitalised influenza in South Australian children under 5 years of age. METHODS: Influenza admissions to the tertiary paediatric hospital in South Australia from 2008 to 2012 were identified. Data from laboratory-confirmed influenza cases were collected, including infecting influenza strain, co-infections, prematurity, pre-existing medical comorbidities and other potential risk factors. Predictors of high-level care were assessed using logistic regression. RESULTS: A total of 267 children with laboratory-confirmed influenza were hospitalised. Of these, 147 admissions (53%) occurred in children without underlying medical risk factors. Eighteen children (7%) required high-level care, of which 11 (61%) had no underlying medical risk factors. No deaths were reported. The majority of children were unimmunised against influenza. Co-infections were identified in 40% of children (n = 107). Influenza B was associated with a requirement for higher care (OR 3.7, CI 1.3-10.9, P = .02) as was a history of food allergies (OR 9.7, CI 1.5-61.4, P = .02) and iron deficiency anaemia (OR 4.8, CI 1.4-16.1, P = .01). CONCLUSIONS: Influenza can be a severe illness, even in children without underlying medical conditions. The identification of Influenza B strain, history of food allergies and iron deficiency anaemia as predictors of severity in hospitalised cases warrants further investigation and may have important implications for preventative strategies to reduce the burden of childhood influenza.
