Molecular Psychiatry - Maternal immune activation dysregulation of the fetal brain transcriptome and relevance to the pathophysiology of autism spectrum disorder

 Maternal immune activation (MIA) via infection during pregnancy is known to increase risk for autism spectrum disorder (ASD). However, it is unclear how MIA disrupts fetal brain gene expression in ways that may explain this increased risk. Here we examine how MIA dysregulates rat fetal brain gene expression (at a time point analogous to the end of the first trimester of human gestation) in ways relevant to ASD-associated pathophysiology. MIA downregulates expression of ASD-associated genes, with the largest enrichments in genes known to harbor rare highly penetrant mutations. MIA also downregulates expression of many genes also known to be persistently downregulated in the ASD cortex later in life and which are canonically known for roles in affecting prenatally late developmental processes at the synapse. Transcriptional and translational programs that are downstream targets of highly ASD-penetrant FMR1 and CHD8 genes are also heavily affected by MIA. MIA strongly upregulates expression of a large number of genes involved in translation initiation, cell cycle, DNA damage and proteolysis processes that affect multiple key neural developmental functions. Upregulation of translation initiation is common to and preserved in gene network structure with the ASD cortical transcriptome throughout life and has downstream impact on cell cycle processes. The cap-dependent translation initiation gene, EIF4E, is one of the most MIA-dysregulated of all ASD-associated genes and targeted network analyses demonstrate prominent MIA-induced transcriptional dysregulation of mTOR and EIF4E-dependent signaling. This dysregulation of translation initiation via alteration of the Tsc2–mTor–Eif4e axis was further validated across MIA rodent models. MIA may confer increased risk for ASD by dysregulating key aspects of fetal brain gene expression that are highly relevant to pathophysiology affecting ASD.



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Immune alterations in acute bipolar depression. - PubMed - NCBI

OBJECTIVE:

Immunologic abnormalities have been found in bipolar disorder and acute mania.
However, there have been fewer studies of patients with acute bipolar
depression.

METHOD:

Blood samples were obtained from individuals with acute bipolar depression,
acute mania, and controls. These samples were evaluated for antibodies
to human herpesviruses, gliadin, Toxoplasma gondii, and endogenous
retroviruses as well as for C-reactive protein (CRP) and pentraxin-3
using immunoassay methods. Linear regression models were used to compare
the levels of the markers controlling for demographic and clinical
variables. A subset of the bipolar depressed group was evaluated at a
6-month follow-up.

RESULTS:

The sample consisted of 82 individuals with acute bipolar depression, 147
with acute mania, and 280 controls. The levels of CRP and IgG antibodies
to an endogenous retrovirus, Mason-Pfizer monkey virus (MPMV), were
significantly elevated in the bipolar depressed group. Levels of
pentraxin-3 were reduced in both psychiatric groups. An evaluation of 32
individuals 6 months after hospitalization for bipolar depression
showed a significant decrease in the levels of MPMV antibodies, but not a
change in the other markers.

CONCLUSION:

Individuals with acute bipolar depression show immune alterations. Some of the
alterations are similar to those found in acute mania.

Some immune cells defend only one organ

(Medical Xpress)—Scientists have uncovered a new way the immune system may fight cancers and viral infections. The finding could aid efforts to use immune cells to treat illness.

The research, in mice, suggests that some organs have the immunological equivalent of "neighborhood police" – specialized squads of defenders that patrol only one area, a single organ, instead of an entire city, the body.

Scientists at Washington University School of Medicine in St. Louis have shown that the liver, skin and uterus each has dedicated immune cells, which they call tissue-resident natural killer cells. Other organs may have similar arrangements.

Gut Microbes Treat Illness | The Scientist Magazine®

 "An astounding array of microorganisms colonizes the human gut; our large intestines alone are home to 1014 bacteria from more than 1,000 species. Though scientists have long attempted to manipulate these microbial populations to affect health, probiotics have failed to reliably treat disease. However, a new study published today in Nature reports that a blend of specially selected strains of Clostridium bacteria derived from humans can significantly reduce symptoms of certain immune disorders in mice. The treated mice displayed reduced symptoms of colitis and allergy-induced diarrhoea"

Nature Paper Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota

Effects of maternal immune activation on gene expression patterns in the fetal brain.

We are exploring the mechanisms underlying how maternal infection increases the risk for schizophrenia and autism in the offspring. Several mouse models of maternal immune activation (MIA) were used to examine the immediate effects of MIA induced by influenza virus, poly(I:C) and interleukin IL-6 on the fetal brain transcriptome. Our results indicate that all three MIA treatments lead to strong and common gene expression changes in the embryonic brain. Most notably, there is an acute and transient upregulation of the α, β and γ crystallin gene family. Furthermore, levels of crystallin gene expression are correlated with the severity of MIA as assessed by placental weight. The overall gene expression changes suggest that the response to MIA is a neuroprotective attempt by the developing brain to counteract environmental stress, but at a cost of disrupting typical neuronal differentiation and axonal growth. We propose that this cascade of events might parallel the mechanisms by which environmental insults contribute to the risk of neurodevelopmental disorders such as schizophrenia and autism.

Increased level of serum cytokines, chemokines and adipokines in patients with schizophrenia is associated with disease and metabolic syndrome.

At present there are strong indications of a shared vulnerability factor for schizophrenia (SZ), diabetes and the metabolic syndrome (metS). In this study we focus on an aberrantly activated monocyte/macrophage system as the shared factor. We measured in SZ patients (n=144), the serum levels of monocyte/macrophage cytokines/chemokines/adipokines CCL2, CCL4, IL-1β, TNF-α, IL-6, PTX3, leptin, adiponectin, PAI-1, OPG and ICAM-1 and compared these levels to healthy controls (HC) (n=138). Using multivariate analysis, we studied the effect of the presence of the disease SZ, the components of the metS including BMI, the levels of lipids (HDL cholesterol and triglycerides (TG)), diabetes (hyperglycemia) and the use of antipsychotic medication, on the serum levels of these immune compounds. We found all measured immune compounds with the exception of PAI-1 and OPG to be elevated in the SZ patient population. Multivariate analysis showed that elevations were linked to gender (ICAM-1, leptin, TNF-α and adiponectin), an increased BMI (leptin, adiponectin), hyperglycemia/diabetes (CCL4, and OPG), reduced HDL-cholesterol or increased levels of TG (adiponectin and PTX3) or the metS (CCL2, leptin and adiponectin). IL-1β and IL-6 were the only immune compounds raised in the serum of patients not affected by any of the included factors. Although many of the immune compounds were found linked to (components of) the metS, the most dominant linkage was found with the disease schizophrenia, confirming earlier reports on increased monocyte/macrophage activation as a key component for understanding the pathogenesis of schizophrenia.

How cells distinguish between disease-causing and innocuous invaders

In a paper published in this week's early online issue of the journal Cell Host & Microbe, the researchers discovered that intestinal cells in the roundworm C. elegans, which are similar in structure to those in humans, internalize bacterial toxins that inactivate several host processes. This then triggers an immune response, which results in the body mounting an immediate attack against the disease-causing microbes.

Gastrointestinal inflammation and associated immune activation in schizophrenia.

Immune factors are implicated in normal brain development and in brain disorde pathogenesis. Pathogen infection and food antigen penetration across gastrointestinal barriers are means by which environmental factors might affect immune-related neurodevelopment. Here, we test if gastrointestinal inflammation is associated with schizophrenia and therefore, might contribute to bloodstream entry of potentially neurotropic milk and gluten exorphins and/or immune
activation by food antigens. IgG antibodies to Saccharomyces cerevisiae (ASCA, a marker of intestinal inflammation), bovine milk casein, wheat-derived gluten, and 6 infectious agents were assayed. Cohort 1 included 193 with non-recent onset schizophrenia, 67 with recent onset schizophrenia and 207 non-psychiatric controls. Cohort 2 included 103 with first episode schizophrenia, 40 of whom were antipsychotic-naïve. ASCA markers were significantly elevated and correlated with food antigen antibodies in recent onset and non-recent onset schizophrenia
compared to controls (p≤0.00001-0.004) and in unmedicated individuals with first episode schizophrenia compared to those receiving antipsychotics (p≤0.05-0.01). Elevated ASCA levels were especially evident in non-recent onset females (p≤0.009), recent onset males (p≤0.01) and in antipsychotic-naïve males (p≤0.03). Anti-food antigen antibodies were correlated to antibodies against Toxoplasma gondii, an intestinally-infectious pathogen, particularly in males with recent
onset schizophrenia (p≤0.002). In conclusion, gastrointestinal inflammation is a relevant pathology in schizophrenia, appears to occur in the absence of but may be modified by antipsychotics, and may link food antigen sensitivity and microbial infection as sources of immune activation in mental illness.

Gut Microbes Keep Rare Immune Cells in Line

 The idea that exposure to microbes can be good for us—by tuning up our immune systems and preventing overreactions like asthma and autoimmune diseases—is catching. Now, a new study of this provocative notion, known as the hygiene hypothesis, suggests that microbes furnish some of their benefits in an unexpected way. Researchers have found that the typical intestinal bacteria in mice rein in a rare type of immune cell, curtailing asthma and colitis in the rodents. Scientists following the long-running discussion over the hygiene hypothesis give the new work, reported online in Science this week

Immune Role in Brain Disorder? RETT syndrome The Scientist

Nature abstract

Rett syndrome is an X-linked autism spectrum disorder. The disease is characterized in most cases by mutation of the MECP2 gene, which encodes a methyl-CpG-binding protein^{1, 2, 3, 4, 5}. Although MECP2 is expressed in many tissues, the disease is generally attributed to a primary neuronal dysfunction⁶. However, as shown recently, glia, specifically astrocytes, also contribute to Rett pathophysiology. Here we examine the role of another form of glia, microglia, in a murine model of Rett syndrome. Transplantation of wild-type bone marrow into irradiation-conditioned Mecp2-null hosts resulted in engraftment of brain parenchyma by bone-marrow-derived myeloid cells of microglial phenotype, and arrest of disease development. However, when cranial irradiation was blocked by lead shield, and microglial engraftment was prevented, disease was not arrested. Similarly, targeted expression of MECP2 in myeloid cells, driven by Lysm^cre on an Mecp2-null background, markedly attenuated disease symptoms. Thus, through multiple approaches, wild-type Mecp2-expressing microglia within the context of an Mecp2-null male mouse arrested numerous facets of disease pathology: lifespan was increased, breathing patterns were normalized, apnoeas were reduced, body weight was increased to near that of wild type, and locomotor activity was improved. Mecp2^+/− females also showed significant improvements as a result of wild-type microglial engraftment. These benefits mediated by wild-type microglia, however, were diminished when phagocytic activity was inhibited pharmacologically by using annexin V to block phosphatydilserine residues on apoptotic targets, thus preventing recognition and engulfment by tissue-resident phagocytes. These results suggest the importance of microglial phagocytic activity in Rett syndrome. Our data implicate microglia as major players in the pathophysiology of this devastating disorder, and suggest that bone marrow transplantation might offer a feasible therapeutic approach for it.

Scientists identify unexpected player in intestinal immunity

Goblet cells may be a potential target for therapies against inflammatory bowel disease, celiac disease and food allergies. Above, a sugar antigen ingested by a mouse fills a goblet cell (red) in the intestine, which delivers the antigen to a dendritic cell (green). Dendritic cells use the antigens to educate the immune system to recognize food antigens as harmless rather than as infectious agents.

Pregnancy and pregnancy-associated hormones alter immune responses and disease pathogenesis.

During pregnancy, it is evolutionary advantageous for inflammatory immune
responses that might lead to fetal rejection to be reduced and anti-inflammatory 
responses that promote transfer of maternal antibodies to the fetus to be
increased. Hormones modulate the immunological shift that occurs during
pregnancy. Estrogens, including estradiol and estriol, progesterone, and
glucocorticoids increase over the course of pregnancy and affect transcriptional 
signaling of inflammatory immune responses at the maternal-fetal interface and
systemically. During pregnancy, the reduced activity of natural killer cells,
inflammatory macrophages, and helper T cell type 1 (Th1) cells and production of 
inflammatory cytokines, combined with the higher activity of regulatory T cells
and production of anti-inflammatory cytokines, affects disease pathogenesis. The 
severity of diseases caused by inflammatory responses (e.g., multiple sclerosis) 
is reduced and the severity of diseases that are mitigated by inflammatory
responses (e.g., influenza and malaria) is increased during pregnancy. For some
infectious diseases, elevated inflammatory responses that are necessary to
control and clear a pathogen have a negative consequence on the outcome of
pregnancy. The bidirectional interactions between hormones and the immune system 
contribute to both the outcome of pregnancy and female susceptibility to disease.

Why The Immune System Specifically Attacks Beta Cells In Type 1 Diabetes

A new JDRF-funded study shows that many of the genes known to play a role in type 1 diabetes (T1D) are expressed in pancreatic beta cells, suggesting that the cell responsible for producing insulin may be playing a part in its own destruction to lead to T1D. Published in the March issue of PLoS Genetics, researchers in Belgium suggest this interpretation after producing an extensive catalogue of more than 15,000 genes expressed in human islets, forming the most extensive characterization of human islets reported to date.

Related articles

• Type 1 Diabetes Reversed With Stem Cells From Cord Blood (medicalnewstoday.com)

Why we don't become immune to colds

A team of researchers at the MedUni Vienna has discovered why we never become immune to colds, and why we are able to keep catching them: the MedUni Vienna study, published in The FASEB Journal in the USA by Katarzyna Niespodziana from the Institute of Pathophysiology and Allergy Research, shows that the human immune response to the rhinovirus is misdirected.

Prenatal immune activation interacts with genetic Nurr1 deficiency in the development of attentional impairments.

Prenatal exposure to infection has been linked to increased risk of neurodevelopmental brain disorders, and recent evidence implicates altered dopaminergic development in this association. However, since the relative risk size of prenatal infection appears relatively small with respect to long-term neuropsychiatric outcomes, it is likely that this prenatal insult interacts with other factors in shaping the risk of postnatal brain dysfunctions.

METHOD

In the present study, we show that the neuropathological consequences of prenatal viral-like immune activation are exacerbated in offspring with genetic predisposition to dopaminergic abnormalities induced by mutations in Nurr1, a transcription factor highly essential for normal dopaminergic development.

RESULT

We combined a mouse model of heterozygous genetic deletion of Nurr1 with a model of prenatal immune challenge by the viral mimetic poly(I:C) (polyriboinosinic polyribocytidilic acid). In our gene-environment interaction model, we demonstrate that the combination of the genetic and environmental factors not only exerts additive effects on locomotor hyperactivity and sensorimotor gating deficits, but further produces synergistic effects in the development of impaired attentional shifting and sustained attention. We further demonstrate that the combination of the two factors is necessary to trigger maldevelopment of prefrontal cortical and ventral striatal dopamine systems.

CONCLUSION

Our findings provide evidence for specific gene-environment interactions in the emergence of enduring attentional impairments and neuronal abnormalities pertinent to dopamine-associated brain disorders such as schizophrenia and attention deficit/hyperactivity disorder, and further emphasize a critical role of abnormal dopaminergic development in these etiopathological processes.

PLoS ONE: Marked Reduction of AKT1 Expression and Deregulation of AKT1-Associated Pathways in Peripheral Blood Mononuclear Cells of Schizophrenia Patients

A case-control study, investigating whole-genome Peripheral Blood Mononuclear Cells gene expression in male, recent onset (<5 years) schizophrenia patients (N = 41) as compared to controls (N = 29). Genes, differentially expressed between patients and controls were identified using ANOVA with Benjamini-Hochberg correction (false discovery rate (FDR) = 0.05). Functional aspects of the deregulated set of genes were investigated with the Ingenuity Pathway Analysis (IPA) Software Tool. We found significantly decreased PBMC expression of AKT1 (p<0.001, t = −4.25) in the patients. AKT1 expression was decreased in antipsychotic-free or -naive patients (N = 11), in florid psychotic (N = 20) and in remitted (N = 21) patients. A total of 1224 genes were differentially expressed between patients and controls (FDR = 0.05). Functional analysis of the entire deregulated gene set indicated deregulated canonical pathways involved in a large number of cellular processes: immune system, cell adhesion and neuronal guidance, neurotrophins and (neural) growth factors, oxidative stress and glucose metabolism, and apoptosis and cell-cycle regulation. Many of these processes are associated with AKT1.

Age- and disease-related innate immunity of human leukocytes ex vivo.

Two mechanisms of innate immunity, i.e. resistance to viral infection and the production of cytokines by leukocytes, were compared in blood isolated from four groups of donors: healthy young (19-35 years old), healthy elderly (over 60), elderly Alzheimer's disease (AD) patients, and elderly patients with alimentary tract cancer (CA). Peripheral blood leukocytes (PBLs) were isolated by gradient centrifugation in Gradisol G. The degree of resistance was calculated from the kinetics of vesicular stomatitis virus (VSV) replication in the PBLs. Cytokine (TNFα, IFNα, IFNγ, IL-12, and IL-10) levels were determined by ELISA. The antiviral resistance of the PBLs varied, but a difference was observed only between the young and elderly groups and not between the healthy elderly controls and those with AD or cancer. Differences observed in all the groups concerned the ability and intensity of cytokine production. The most impressive results were obtained for spontaneous TNF and IFNα release. While TNF was released spontaneously by the PBLs of the elderly CA patients and the young healthy group, it was usually undetected in the AD and only sometimes in the healthy elderly group. Leukocytes isolated from the elderly groups responded to VSV infection with more intense IFNα and IFNγ production than the younger group.

When body clock runs down, immune system takes time off

It's been said that timing is everything, and that may be particularly true when it comes to the ability to fight off disease. New research published by Cell Press in the February issue of the journal Immunity shows that the success of host immune defense depends in part on an organism's "body clock." The study may lead to therapeutic strategies designed to optimize the immune response and to protect patients at the time when they are most vulnerable.

Brain IL-6 elevation causes neuronal circuitry imbalances and mediates autism-like behaviors.

Abnormal immune responses have been reported to be associated with autism. A number of studies showed that cytokines were increased in the blood, brain, and cerebrospinal fluid of autistic subjects. Elevated IL-6 in autistic brain has been a consistent finding. However, the mechanisms by which IL-6 may be involved in the pathogenesis of autism are not well understood. Here we show that mice with elevated IL-6 in the brain display many autistic features, including impaired cognitive abilities, deficits in learning, abnormal anxiety traits and habituations, as well as decreased social interactions. IL-6 elevation caused alterations in excitatory and inhibitory synaptic formations and disrupted the balance of excitatory/inhibitory synaptic transmissions. IL-6 elevation also resulted in an abnormal change in the shape, length and distributing pattern of dendritic spines. These findings suggest that IL-6 elevation in the brain could mediate autistic-like behaviors, possibly though the imbalances of neural circuitry and impairments of synaptic plasticity.

Natural killer cell activation enhances immune pathology and promotes chronic infection by limiting CD8+ T-cell immunity

Infections with HIV, hepatitis B virus, and hepatitis C virus can turn into chronic infections, which currently affect more than 500 million patients worldwide. It is generally thought that virus-mediated T-cell exhaustion limits T-cell function, thus promoting chronic disease. Here we demonstrate that natural killer (NK) cells have a negative impact on the development of T-cell immunity by using the murine lymphocytic choriomeningitis virus. NK cell-deficient (Nfil3^−/−, E4BP4^−/−) mice exhibited a higher virus-specific T-cell response. In addition, NK cell depletion caused enhanced T-cell immunity in WT mice, which led to rapid virus control and prevented chronic infection in lymphocytic choriomeningitis virus clone 13- and reduced viral load in DOCILE-infected animals. Further experiments showed that NKG2D triggered regulatory NK cell functions, which were mediated by perforin, and limited T-cell responses. Therefore, we identified an important role of regulatory NK cells in limiting T-cell immunity during virus infection.