Characterization of Ebola convalescent plasma donor immune response and psoralen treated plasma in the United States.

BACKGROUND: In 2014, passive immunization by transfusion of Ebola convalescent plasma (ECP) was considered for treating patients with acute Ebola virus disease (EVD). Early Ebola virus (EBOV) seroconversion confers a survival advantage in natural infection, hence transfusion of ECP plasma with high levels of neutralizing EBOV antibodies is a potential passive immune therapy. Techniques to reduce the risk of other transfusion-transmitted infections (TTIs) are warranted as recent ECP survivors are ineligible as routine blood donors. As part of an ongoing clinical trial to evaluate the safety and effectiveness of ECP, the impact of amotosalen/UVA pathogen reduction technology (PRT) on EBOV antibody characteristics was examined. STUDY DESIGN AND METHODS: Serum and plasma samples were collected from EVD-recovered subjects at multiple timepoints and evaluated by ELISA for antibodies to recombinant EBOV glycoprotein (GP) and irradiated whole EBOV antigen, as well as for EBOV microneutralization, classic plaque reduction neutralization test (PRNT) and EBOV pseudovirion neutralization assay (PsVNA) activity. RESULTS: Six subjects donated 40 individual ECP units. Substantial antibody titers and neutralizing activity results were demonstrated but were generally lower for the ACD plasma samples compared to the serum samples. Anti-EBOV titers by all assays remained essentially unchanged after PRT. CONCLUSION: Treatment of ECP with PRT to reduce the risk of TTI did not significantly reduce EBOV IgG antibody titers or neutralizing activity. Although ECP was used in the treatment of repatriated patients, no PRT units from this study were transfused to EVD patients. This inventory of PRT-treated ECP is currently available for future clinical evaluation.

Influence of aging on germinal centre reaction and antibody response to inactivated influenza virus antigens in mice: sex-based differences.

The study examined sex-specificities in age-related changes in BALB/c mice IgG antibody responses to immunisation with trivalent inactivated split-virus influenza bulk. Aging diminished the total serum IgG antibody responses to H1N1 and H3N2 and B influenza virus antigens in mice of both sexes, but they remained greater in aged females. This sex difference in aged mice correlated with the greater post-immunisation increase in the frequency of spleen germinal centre (GC) B cells and more favourable T follicular regulatory (Tfr)/GC B cell ratio, as Tfr cells are suggested to control antibody production through suppression of glycolysis. The greater post-immunisation GC B cell response in aged females compared with males correlated with the greater proliferation of B cells and CD4+ cells in splenocyte cultures from aged females restimulated with inactivated split-virus influenza from the bulk. To support the greater post-immunisation increase in the frequency GC B cell in aged females was more favourable Tfr/T follicular helper (Tfh) cell ratio. Additionally, compared with aged males, in age-matched females the greater avidity of serum IgG antibodies was found. However, in aged females IgG2a/IgG1 antibody ratio, reflecting spleen Th1/Th2 cytokine balance, was shifted towards IgG1 when compared with age-matched male mice. This shift was ascribed to a more prominent decline in the titres of functionally important IgG2a antibodies in females with aging. The study suggest that biological sex should be considered as a variable in designing strategies to manipulate with immune outcome of immunisation in aged animals, and possibly, at very long distance, humans.

Hypersynchronicity in the default mode-like network in a neurodevelopmental animal model with relevance for schizophrenia.

BACKGROUND: Immune activation during pregnancy is an important risk factor for schizophrenia. Brain dysconnectivity and NMDA receptor (NMDAR) hypofunction have been postulated to be central to schizophrenia pathophysiology. The aim of this study was to investigate resting-state functional connectivity (resting-state functional MRI-rsfMRI), microstructure (diffusion tension imaging-DTI) and response to NMDAR antagonist (pharmacological fMRI-phMRI) using multimodal MRI in offspring of pregnant dams exposed to immune challenge (maternal immune activation-MIA model), and determine whether these neuroimaging readouts correlate with schizophrenia-related behaviour. METHODS: Pregnant rats were injected with Poly I:C or saline on gestational day 15. The maternal weight response was assessed. Since previous research has shown behavioural deficits can differ between MIA offspring dependent on the maternal response to immune stimulus, offspring were divided into three groups: controls (saline, n = 11), offspring of dams that gained weight (Poly I:C WG, n = 12) and offspring of dams that lost weight post-MIA (Poly I:C WL, n = 16). Male adult offspring were subjected to rsfMRI, DTI, phMRI with NMDAR antagonist, behavioural testing and histological assessment. RESULTS: Poly I:C WL offspring exhibited increased functional connectivity in default mode-like network (DMN). Poly I:C WG offspring showed the most pronounced attenuation in NMDAR antagonist response versus controls. DTI revealed no differences in Poly I:C offspring versus controls. Poly I:C offspring exhibited anxiety. CONCLUSIONS: MIA offspring displayed a differential pathophysiology depending on the maternal response to immune challenge. While Poly I:C WL offspring displayed hypersynchronicity in the DMN, altered NMDAR antagonist response was most pronounced in Poly I:C WG offspring.

Maternal immune activation with staphylococcal enterotoxin A produces unique behavioral changes in C57BL/6 mouse offspring.

Stimulation of the immune system during pregnancy, known as maternal immune activation (MIA), can cause long-lasting neurobiological and behavioral changes in the offspring. This phenomenon has been implicated in the etiology of developmental psychiatric disorders, such as autism and schizophrenia. Much of this evidence is predicated on animal models using bacterial agents such as LPS and/or viral mimics such as Poly I:C, both of which act through toll-like receptors. However, fewer studies have examined the role of direct activation of maternal T-cells during pregnancy using microbial agents. Bacterial superantigens, such as Staphylococcal Enterotoxin A and B (SEA; SEB), are microbial proteins that activate CD4+ T-cells and cause prominent T-cell proliferation and cytokine production. We injected pregnant and non-pregnant adult female C57BL/6 mice with 200 µg/Kg of SEA, SEB, or 0.9% saline, and measured splenic T-cell-derived cytokine concentrations (viz., IL-2, IFN-γ, IL-6, and IL-4) 2 h later; animals injected with SEA were also measured for splenic concentrations of TNF-α and IL-17A. Half of the injected pregnant animals were brought to term, and their offspring were tested on a series of behavioral tasks starting at six weeks of age (postnatal day 42 [P42]). These tasks included social interaction, the elevated plus maze (EPM), an open field and object recognition (OR) task, prepulse inhibition (PPI) of sensorimotor gating, and the Morris water maze (MWM). Results showed that SEA and SEB induced significant concentrations of all measured cytokines, and in particular IFN-γ, although cytokine responses were greater following SEA exposure. In addition, pregnancy induced an inhibitory effect on cytokine production. Behavioral results showed distinct phenotypes among offspring from SEA- or SEB-injected mothers, very likely due to differences in the magnitude of cytokines generated in response to each toxin. Offspring from SEA-injected mothers displayed modest decreases in social behavior, but increased anxiety, locomotion, interest in a novel object, and short-term spatial memory, while offspring of SEB-injected mothers only exhibited increased anxiety and locomotion. There were no deficits in PPI, which was actually pronounced in SEA and SEB offspring. Overall, the novel use of SEA and SEB as prenatal immune challenges elicited distinct behavioral profiles in the offspring that both mirrors and diverges from previous models of maternal immune activation in important ways. We conclude that superantigen-induced T-cell-mediated maternal immune activation is a valid and valuable model for studying and expanding our understanding of the effects of prenatal immune challenge on neurodevelopmental and behavioral alterations in offspring.

Evolution of a maternal immune activation (mIA) model in rats: Early developmental effects.

Maternal immune activation (mIA) in rodents is rapidly emerging as a key model for neurodevelopmental disorders such as autism spectrum disorder (ASD) and schizophrenia. Here, we optimise a mIA model in rats, aiming to address certain limitations of current work in this field. Specifically, the lack of clear evidence for methodology chosen, identification of successful induction of mIA in the dams and investigation of male offspring only. We focus on gestational and early juvenile changes in offspring following mIA, as detailed information on these critical early developmental time points is sparse. Following strain (Wistar, Lister Hooded, Sprague Dawley) comparison and selection, and polyriboinosinic-polyribocytidylic acid (poly I:C) dose selection (2.5-15 mg/kg single or once daily for 5 days), mIA was induced in pregnant Wistar rats with 10 mg/kg poly I:C i.p. on gestational day (GD) 15. Early morphometric analysis was conducted in male and female offspring at GD21 and postnatal day (PD) 21, eight dams for each treatment at each time point were used, 32 in total. Subsequent microglia analysis was conducted at PD21 in a small group of offspring. Poly I:C at 10 mg/kg i.p. induced a robust, but variable, plasma IL-6 response 3 h post-injection and reduced body weight at 6 h and 24 h post-injection in two separate cohorts of Wistar rats at GD15. Plasma IL-6 was not elevated at PD21 in offspring or dams. Poly I:C-induced mIA did not affect litter numbers, but resulted in PD21 pup, and GD21 placenta growth restriction. Poly I:C significantly increased microglial activation at PD21 in male hippocampi. We have identified 10 mg/kg poly I:C i.p on GD15 as a robust experimental approach for inducing mIA in Wistar rats and used this to identify early neurodevelopmental changes. This work provides a framework to study the developmental trajectory of disease-relevant, sex-specific phenotypic changes in rats.

The impact of mouse strain-specific spatial and temporal immune responses on the progression of neuropathic pain.

The present study was designed to investigate the correlation between the spatial and temporal aspects of immune responses and genetic heterogeneity in the progression of peripheral neuropathic pain. To address this issue, we first screened four inbred mouse strains (C57BL/6J, C3H/He, DBA/2, and A/J mice) to identify high- and low-responder strains to mechanical hypersensitivity induced by partial sciatic nerve ligation (pSNL). Among these strains, the C57BL/6J strain showed the highest vulnerability to pSNL-induced mechanical hypersensitivity, whereas the C3H/HeSlc strain was most resistant. C3H/HeSlc mice exhibited a significant increase in CD206-immunoreactivity (anti-inflammatory macrophages) in the dorsal root ganglia (DRG) at 3 and 7 days, and lower Iba1-immunoreactivity (microglia) in the spinal cord from 3 to 14 days after pSNL than C57BL/6J mice. These phenomena might be associated with a decrease in the production of inflammatory factors (interleukin-1ß, interleukin-6, and CX3CL1) in the DRG and the poor responsiveness of spinal microglia (i.e. microglial production of IL1ß, CCL2, and TNFα) against CX3CL1 in C3H/HeSlc mice. Behavioral experiments using bone marrow (BM) chimeric mice derived by crossing C3H/HeSlc and C57BL/6J strains showed that the strength of mechanical hypersensitivity 3 days following pSNL was inversely correlated with the increase in the ratio of anti-inflammatory/pro-inflammatory DRG macrophages, which was based on the BM-derived hematopoietic cells from donor mice. By contrast, the intensity of Iba1-immunoreactivity (microglia) in the spinal cord was dependent on the phenotypes of recipient mice, but not affected by the phenotypes of BM-derived donor hematopoietic cells. These findings suggest that the strain-specific aspects of DRG macrophages and spinal microglia might be related to the early and late phases of pSNL-induced mechanical hypersensitivity, respectively. This study presents a greater understanding of the differences in neuropathic pain among genetically heterogeneous inbred mouse strains, and provides further insights into the spatial and temporal roles of the immune system in the pathogenesis of neuropathic pain.

Gestational diabetes exacerbates maternal immune activation effects in the developing brain.

Maternal inflammation and diabetes increase the risk for psychiatric disorders in offspring. We hypothesized that these co-occurring risk factors may potentiate each other. To test this, we maternally exposed developing mice in utero to gestational diabetes mellitus (GDM) and/or maternal immune activation (MIA). Fetal mouse brains were exposed to either vehicle, GDM, MIA or GDM+MIA. At gestational day (GD) 12.5, GDM produced a hyperglycemic, hyperleptinemic maternal state, whereas MIA produced significant increases in proinflammatory cytokines and chemokines. Each condition alone resulted in an altered, inflammatory and neurodevelopmental transcriptome profile. In addition, GDM+MIA heightened the maternal inflammatory state and gave rise to a new, specific transcriptional response. This exacerbated response was associated with pathways implicated in psychiatric disorders, including dopamine neuron differentiation and innate immune response. Based on these data, we hypothesize that children born to GDM mothers and exposed to midgestation infections have an increased vulnerability to psychiatric disorder later in life, and this should be tested in follow-up epidemiological studies.

Activated immune response in an inherited leukodystrophy disease caused by the loss of oligodendrocyte gap junctions.

Oligodendrocyte:oligodendrocyte (O:O) gap junction (GJ) coupling is a widespread and essential feature of the CNS, and is mediated by connexin47 (Cx47) and Cx32. Loss of function mutations affecting Cx47 results in a severe leukodystrophy, Pelizeus-Merzbacher-like disease (also known as Hypomyelinating Leukodystrophy 2), which can be reproduced in mice lacking both Cx47 and Cx32. Here we report the gene expression profile of the cerebellum--an affected brain region--in mice lacking both Cx47 and Cx32. Of the 43,174 mRNA probes examined, we find decreased expression of 23 probes (corresponding to 23 genes) and increased expression of 545 probes (corresponding to 348 genes). Many of the genes with reduced expression map to oligodendrocytes, and two of them (Fa2h and Ugt8a) are involved in the synthesis of myelin lipids. Many of the genes with increased expression map to lymphocytes and microglia, and involved in leukotrienes/prostaglandins synthesis and chemokines/cytokines interactions and signaling pathways. In accord, immunostaining showed T- and B-cells in the cerebella of mutant mice as well as activated microglia and astrocytes. Thus, in addition to the loss of GJ coupling, there is a prominent immune response in mice lacking both Cx47 and Cx32.

Effects of partial substitution of fish meal by soybean meal with or without heat-killed Lactobacillus plantarum (LP20) on growth performance, digestibility, and immune response of amberjack, Seriola dumerili juveniles.

A 56-day feeding trial was conducted to evaluate the effects of supplemented diets with heat-killed Lactobacillus plantarum (HK-LP) with graded levels of soybean meal (SBM) on growth, digestibility, blood parameters, and immune response of Seriola dumerili (initial weight, 25.05 ± 0.1 g). Seven isonitrogenous and isolipidic practical diets were formulated to contain 0%, 15%, 30%, and 45% SBM, and each SBM level was supplemented with HK-LP at 0.0 and 0.1%. Fish fed diet which contains 30% SBM with HK-LP grew significantly faster than the other groups with notable feed intake and protein retention. Further, protein gain, whole body protein content, protease activity, protein, and lipid digestibility were significantly increased for all fish groups except for fish fed diet which contains 45% SBM with or without HK-LP. Interestingly, lysozyme activity was significantly enhanced in fish fed diets that contain 15% and 30% SBM with HK-LP. Hematocrit, peroxidase, and bactericidal activities revealed a significant increase in 30% SBM with HK-LP group. In addition, fish fed diets which contain 0% and 30% SBM with HK-LP showed higher tolerance against low-salinity stress compared with other groups. In conclusion, the addition of HK-LP to amberjack diets appeared to improve SBM utilization, immune response, and stress resistance.

Inmunosenescencia: efectos de la edad sobre el sistema inmune / Immunosenescence: effects of aging process on immune system

El proceso de envejecimiento provoca cambios en el sistema inmune que afectan su funcionamiento y desarrollo. Estos cambios pueden manifestarse desde la linfopoyesis hasta la respuesta que orquesta el sistema inmune frente a determinada enfermedad o agente infeccioso. Ambas ramas de la inmunidad, innata y adaptativa, se afectan en este proceso, lo que genera un impacto negativo en la respuesta inmune de los ancianos y los predispone a padecer enfermedades infecciosas, cáncer, autoinmunidad y a desarrollar respuestas pobres tras la administración de vacunas...

The aging process produces functional and developmental changes in the immune system. Those changes may appear from lymphopoiesis up to the final response of the immune system facing a certain disease. Both branches of immunity, innate and adaptive, are affected by the aging process; hence these changes can have a negative impact on the immune response of elderly patients and increase their susceptibility to infectious diseases, cancer and decreased vaccine efficacy...

Body height, immunity, facial and vocal attractiveness in young men.

Health, facial and vocal attributes and body height of men may affect a diverse range of social outcomes such as attractiveness to potential mates and competition for resources. Despite evidence that each parameter plays a role in mate choice, the relative role of each and inter-relationships between them, is still poorly understood. In this study, we tested relationships both between these parameters and with testosterone and immune function. We report positive relationships between testosterone with facial masculinity and attractiveness, and we found that facial masculinity predicted facial attractiveness and antibody response to a vaccine. Moreover, the relationship between antibody response to a hepatitis B vaccine and body height was found to be non-linear, with a positive relationship up to a height of 188 cm, but an inverse relationship in taller men. We found that vocal attractiveness was dependent upon vocal masculinity. The relationship between vocal attractiveness and body height was also non-linear, with a positive relationship of up to 178 cm, which then decreased in taller men. We did not find a significant relationship between body height and the fundamental frequency of vowel sounds provided by young men, while body height negatively correlated with the frequency of second formant. However, formant frequency was not associated with the strength of immune response. Our results demonstrate the potential of vaccination research to reveal costly traits that govern evolution of mate choice in humans and the importance of trade-offs among these traits.

Immune quiescence: a model of protection against HIV infection.

Aberrant immune activation is a strong correlate of HIV disease progression, but little is known about how immune activation alters susceptibility to HIV infection. Susceptibility to HIV infection varies between individuals, but the immunological determinants of HIV transmission are not well understood. Here, we present evidence from studies of HIV transmission in the context of clinical trials and HIV-exposed seronegative (HESN) cohorts that implicates elevated immune activation as a risk factor for acquiring HIV. We propose a model of protection from infection based on a phenotype of low baseline immune activation referred to as immune quiescence. Immune quiescence is evidenced by reduced expression of T cell activation markers, low levels of generalized gene transcription and low levels of proinflammatory cytokine and chemokine production in the periphery and genital mucosa of HESN. Since HIV preferentially replicates in activated CD4+ T cells, immune quiescence may protect against infection by limiting HIV target cell availability. Although the determinants of immune quiescence are unclear, several potential factors have been identified that may be involved in driving this phenotype. HESN were shown to have elevated proportions of regulatory T cells (Tregs), which are known to suppress T cell activation. Likewise, proteins involved in controlling inflammation in the genital tract have been found to be elevated in HESN. Furthermore, expression of interferon regulatory factor 1 (IRF-1) is reduced in HESN as a consequence of genetic polymorphisms and differential epigenetic regulation. Since IRF-1 is an important regulator of immune responses, it may play a role in maintaining immune quiescence. Based on this model, we propose a novel avenue for HIV prevention targeted based on reducing host mucosal immune activation.

[Resolving factors of inflammation - a bridge between innate immunity and adaptive immunity].

Acute inflammation, a physiologic response to protect cells from microbial infection and other stimuli, is automatically terminated by endogenous anti-inflammatory and pro-resolving mediators to restore homeostatic conditions. However, if timely resolution of inflammation is failed, inflammation persists and can progress to a chronic inflammation such as rheumatoid arthritis, interstitial pneumonitis. To prevent chronic inflammation, understanding the process that resolves inflammation is essential. Resolution of inflammation is an active coordinated process regulated by distinct anti-inflammatory and pro-resolving endogenous lipid mediators, such as lipoxins/ALX, chemerin/chemR23. In resolution of inflammation these resolving factors contribute a bridge between innate and adaptive immunity.

Efficacy, safety, and immunology of an inactivated alum-adjuvant enterovirus 71 vaccine in children in China: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: A vaccine for enterovirus 71 (EV71) is needed to address the high burden of disease associated with infection. We assessed the efficacy, safety, immunogenicity, antibody persistence, and immunological correlates of an inactivated alum-adjuvant EV71 vaccine. METHODS: We did a randomised, double-blind, placebo-controlled, phase 3 trial. Healthy children aged 6-35 months from four centres in China were randomly assigned (1:1) to receive vaccine or alum-adjuvant placebo at day 0 and 28, according to a randomisation list (block size 30) generated by an independent statistician. Investigators and participants and their guardians were masked to the assignment. Primary endpoints were EV71-associated hand, foot, and mouth disease (HFMD) and EV71-associated disease during the surveillance period from day 56 to month 14, analysed in the per-protocol population. This study is registered with ClinicalTrials.gov, number NCT01508247. FINDINGS: 10,245 participants were enrolled and assigned: 5120 to vaccine versus 5125 to placebo. 4907 (with three cases of EV71-associated HFMD and eight cases of EV71-associated disease) versus 4939 (with 30 cases of EV71-associated HFMD and 41 cases of EV71-associated disease) were included in the primary efficacy analysis. Vaccine efficacy was 90·0% (95% CI 67·1-96·9) against EV71-associated HFMD (p=0·0001) and 80·4% (95% CI 58·2-90·8) against EV71-associated disease (p<0·0001). Serious adverse events were reported by 62 of 5117 (1·2%) participants in the vaccine group versus 75 of 5123 (1·5%) in the placebo group (p=0·27). Adverse events occurred in 3644 (71·2%) versus 3603 (70·3%; p=0·33). INTERPRETATION: EV71 vaccine provides high efficacy, satisfactory safety, and sustained immunogenicity. FUNDING: China's 12-5 National Major Infectious Disease Program, Beijing Vigoo Biological.

IgE-mediated immune responses and airway detection of Aspergillus and Candida in adult cystic fibrosis.

BACKGROUND: The recovery of Aspergillus and Candida from the respiratory secretions of patients with cystic fibrosis (CF) is common. Their relationship to the development of allergic sensitization and effect on lung function has not been established. Improved techniques to detect these organisms are needed to increase knowledge of these effects. METHODS: A 2-year prospective observational cohort study was performed. Fifty-five adult patients with CF had sputum monitored for Aspergillus by culture and real-time polymerase chain reaction and Candida by CHROMagar and carbon assimilation profile (API/ID 32C). Skin prick tests and ImmunoCAP IgEs to a panel of common and fungal allergens were performed. Lung function and pulmonary exacerbation rates were monitored over 2 years. RESULTS: Sixty-nine percent of patient sputum samples showed chronic colonization with Candida and 60% showed colonization with Aspergillus. There was no association between the recovery of either organism and the presence of specific IgE responses. There was no difference in lung function decline for patients with Aspergillus or Candida colonization compared with those without (FEV1 percent predicted, P = .41 and P = .90, respectively; FVC % predicted, P = .87 and P = .37, respectively). However, there was a significantly greater decline in FEV1 and increase in IV antibiotic days for those sensitized to Aspergillus (FEV1 decline, P = .03; IV antibiotics days, P = .03). CONCLUSIONS: Allergic sensitization is not associated with recovery of Candida or Aspergillus from the sputum of patients with CF. Aspergillus but not Candida sensitization is associated with greater lung function decline and pulmonary exacerbations.

Gestational immune activation and Tsc2 haploinsufficiency cooperate to disrupt fetal survival and may perturb social behavior in adult mice.

Approximately 40-50% of individuals affected by tuberous sclerosis (TSC) develop autism spectrum disorders (ASDs). One possible explanation for this partial penetrance is an interaction between TSC gene mutations and other risk factors such as gestational immune activation. In this study, we report the interactive effects of these two ASD risk factors in a mouse model of TSC. Combined, but not single, exposure had adverse effects on intrauterine survival. Additionally, provisional results suggest that these factors synergize to disrupt social approach behavior in adult mice. Moreover, studies in human populations are consistent with an interaction between high seasonal flu activity in late gestation and TSC mutations in ASD. Taken together, our studies raise the possibility of a gene × environment interaction between heterozygous TSC gene mutations and gestational immune activation in the pathogenesis of TSC-related ASD.