Publications by authors named "Judy Van de Water"

131 Publications

Malaria-induced bacteremia as a consequence of multiple parasite survival strategies.

Curr Res Microb Sci 2021 Dec 8;2:100036. Epub 2021 May 8.

Department of Biological Sciences, University of Idaho, Moscow, ID, USA.

Globally, malaria continues to be an enormous public health burden, with concomitant parasite-induced damage to the gastrointestinal (GI) barrier resulting in bacteremia-associated morbidity and mortality in both adults and children. Infected red blood cells sequester in and can occlude the GI microvasculature, ultimately leading to disruption of the tight and adherens junctions that would normally serve as a physical barrier to translocating enteric bacteria. Mast cell (MC) activation and translocation to the GI during malaria intensifies damage to the physical barrier and weakens the immunological barrier through the release of enzymes and factors that alter the host response to escaped enteric bacteria. In this context, activated MCs release Th2 cytokines, promoting a balanced Th1/Th2 response that increases local and systemic allergic inflammation while protecting the host from overwhelming Th1-mediated immunopathology. Beyond the mammalian host, recent studies in both the lab and field have revealed an association between a Th2-skewed host response and success of parasite transmission to mosquitoes, biology that is evocative of parasite manipulation of the mammalian host. Collectively, these observations suggest that malaria-induced bacteremia may be, in part, an unintended consequence of a Th2-shifted host response that promotes parasite survival and transmission. Future directions of this work include defining the factors and mechanisms that precede the development of bacteremia, which will enable the development of biomarkers to simplify diagnostics, the identification of therapeutic targets to improve patient outcomes and better understanding of the consequences of clinical interventions to transmission blocking strategies.
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http://dx.doi.org/10.1016/j.crmicr.2021.100036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8610325PMC
December 2021

Neonatal chemokine markers predict subsequent diagnosis of autism spectrum disorder and delayed development.

Brain Behav Immun 2021 Nov 19. Epub 2021 Nov 19.

Department of Internal Medicine, Division of Rheumatology, Allergy, and Clinical Immunology, University of California, Davis, California, USA; MIND Institute, University of California, Davis, California, USA. Electronic address:

Immune dysregulation has been found to be related to a diagnosis of autism spectrum disorder (ASD). However, investigations in very early childhood examining immunological abnormalities such as altered neonatal cytokine/chemokine profiles in association with an aberrant developmental trajectory, are sparse. We assessed neonatal blood spots from 398 children, including 171 with ASD, which were subdivided according to severity (121 severe, 50 mild/moderate) and cognitive/adaptive levels (144 low-functioning, 27 typical to high-functioning). The remainder were 69 children with developmental delay (DD), and 158 with typical development (TD), who served as controls in the Childhood Autism Risks from Genetics and the Environment (CHARGE) study. Exploratory analysis suggested that, in comparisons with TD and DD, CTACK (CCL27) and MPIF-1 (CCL23), respectively, were independently associated with ASD. Higher neonatal levels of CTACK were associated with decreased odds of ASD compared to TD (odds ratio [OR]= 0.40, 95% confidence interval [Cl] 0.21, 0.77), whereas higher levels of MPIF-1 were associated with increased odds of ASD (OR= 2.38, 95% Cl 1.42, 3.98) compared to DD but not to TD. MPIF-1 was positively associated with better scores in several developmental domains. Dysregulation of chemokine levels in early life can impede normal immune and neurobehavioral development, which can lead to diagnosis of ASD or DD. This study collectively suggests that certain peripheral chemokines at birth are associated with ASD progression during childhood and that children with ASD and DD have distinct neonatal chemokine profiles that can differentiate their diagnoses.
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http://dx.doi.org/10.1016/j.bbi.2021.11.009DOI Listing
November 2021

Maternal immune activation during pregnancy alters postnatal brain growth and cognitive development in nonhuman primate offspring.

J Neurosci 2021 Oct 1. Epub 2021 Oct 1.

Department of Psychiatry and Behavioral Sciences, University of California, Davis

Human epidemiologic studies implicate exposure to infection during gestation in the etiology of neurodevelopmental disorders. Animal models of maternal immune activation (MIA) have identified the maternal immune response as the critical link between maternal infection and aberrant offspring brain and behavior development. Here we evaluate neurodevelopment of male rhesus monkeys () born to MIA-treated dams (=14) injected with a modified form of the viral mimic, Polyinosinic:polycytidylic acid (Poly IC) at the end of the first trimester. Control dams received saline injections at the same gestational time points (=10) or were untreated (=4). MIA-treated dams exhibited a strong immune response as indexed by transient increases in sickness behavior, temperature, and inflammatory cytokines. Although offspring born to control or MIA-treated dams did not differ on measures of physical growth and early developmental milestones, the MIA-treated animals exhibited subtle changes in cognitive development and deviated from species-typical brain growth trajectories. Longitudinal magnetic resonance imaging revealed significant gray matter volume reductions in the prefrontal and frontal cortices of MIA-treated offspring at 6 months that persisted through the final time point at 45 months along with smaller frontal white matter volumes in MIA-treated animals at 36 and 45 months. These findings provide the first evidence of early postnatal changes in brain development in MIA-exposed nonhuman primates (NHPs) and establish a translationally relevant model system to explore the neurodevelopmental trajectory of risk associated with prenatal immune challenge from birth through late adolescence.Women exposed to infection during pregnancy have an increased risk of giving birth to a child who will later be diagnosed with a neurodevelopmental disorder. Preclinical MIA models have demonstrated that the effects of maternal infection on fetal brain development are mediated by maternal immune response. Since the majority of MIA models are carried out in rodents, the NHP provides a unique system to evaluate the MIA hypothesis in a species closely related to humans. Here we report the first longitudinal study conducted in a NHP MIA model. MIA-exposed offspring demonstrate subtle changes in cognitive development paired with marked reductions in frontal gray and white matter, further supporting the association between prenatal immune challenge and alterations in offspring neurodevelopment.
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http://dx.doi.org/10.1523/JNEUROSCI.0378-21.2021DOI Listing
October 2021

The influence of sex, genotype, and dose on serum and hippocampal cytokine levels in juvenile mice developmentally exposed to a human-relevant mixture of polychlorinated biphenyls.

Curr Res Toxicol 2020 Jun 10;1:85-103. Epub 2020 Sep 10.

Department of Molecular Biosciences, University of California, Davis, School of Veterinary Medicine, Davis, CA 95616, USA.

Polychlorinated biphenyls (PCBs) are pervasive environmental contaminants implicated as risk factors for neurodevelopmental disorders (NDDs). Immune dysregulation is another NDD risk factor, and developmental PCB exposures are associated with early life immune dysregulation. Studies of the immunomodulatory effects of PCBs have focused on the higher-chlorinated congeners found in legacy commercial mixtures. Comparatively little is known about the immune effects of contemporary, lower-chlorinated PCBs. This is a critical data gap given recent reports that lower-chlorinated congeners comprise >70% of the total PCB burden in serum of pregnant women enrolled in the MARBLES study who are at increased risk for having a child with an NDD. To examine the influence of PCBs, sex, and genotype on cytokine levels, mice were exposed throughout gestation and lactation to a PCB mixture in the maternal diet, which was based on the 12 most abundant PCBs in sera from MARBLES subjects. Using multiplex array, cytokines were quantified in the serum and hippocampus of weanling mice expressing either a human gain-of-function mutation in ryanodine receptor 1 (T4826I mice), a human CGG premutation repeat expansion in the fragile X mental retardation gene 1 (CGG mice), or both mutations (DM mice). Congenic wildtype (WT) mice were used as controls. There were dose-dependent effects of PCB exposure on cytokine concentrations in the serum but not hippocampus. Differential effects of genotype were observed in the serum and hippocampus. Hippocampal cytokines were consistently elevated in T4826I mice and also in WT animals for some cytokines compared to CGG and DM mice, while serum cytokines were usually elevated in the mutant genotypes compared to the WT group. Males had elevated levels of 19 cytokines in the serum and 4 in the hippocampus compared to females, but there were also interactions between sex and genotype for 7 hippocampal cytokines. Only the chemokine CCL5 in the serum showed an interaction between PCB dose, genotype, and sex. Collectively, these findings indicate differential influences of PCB exposure and genotype on cytokine levels in serum and hippocampal tissue of weanling mice. These results suggest that developmental PCB exposure has chronic effects on baseline serum, but not hippocampal, cytokine levels in juvenile mice.
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http://dx.doi.org/10.1016/j.crtox.2020.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8294704PMC
June 2020

Sexually dimorphic neuroanatomical differences relate to ASD-relevant behavioral outcomes in a maternal autoantibody mouse model.

Mol Psychiatry 2021 Jul 21. Epub 2021 Jul 21.

Department of Internal Medicine, Division of Rheumatology, Allergy, and Clinical Immunology, University of California, Davis, CA, USA.

Immunoglobulin G (IgG) autoantibodies reactive to fetal brain proteins in mothers of children with ASD have been described by several groups. To understand their pathologic significance, we developed a mouse model of maternal autoantibody related ASD (MAR-ASD) utilizing the peptide epitopes from human autoantibody reactivity patterns. Male and female offspring prenatally exposed to the salient maternal autoantibodies displayed robust deficits in social interactions and increased repetitive self-grooming behaviors as juveniles and adults. In the present study, neuroanatomical differences in adult MAR-ASD and control offspring were assessed via high-resolution ex vivo magnetic resonance imaging (MRI) at 6 months of age. Of interest, MAR-ASD mice displayed significantly larger total brain volume and of the 159 regions examined, 31 were found to differ significantly in absolute volume (mm) at an FDR of <5%. Specifically, the absolute volumes of several white matter tracts, cortical regions, and basal nuclei structures were significantly increased in MAR-ASD animals. These phenomena were largely driven by female MAR-ASD offspring, as no significant differences were seen with either absolute or relative regional volume in male MAR-ASD mice. However, structural covariance analysis suggests network-level desynchronization in brain volume in both male and female MAR-ASD mice. Additionally, preliminary correlational analysis with behavioral data relates that volumetric increases in numerous brain regions of MAR-ASD mice were correlated with social interaction and repetitive self-grooming behaviors in a sex-specific manner. These results demonstrate significant sex-specific effects in brain size, regional relationships, and behavior for offspring prenatally exposed to MAR-ASD autoantibodies relative to controls.
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http://dx.doi.org/10.1038/s41380-021-01215-wDOI Listing
July 2021

A profile and review of findings from the Early Markers for Autism study: unique contributions from a population-based case-control study in California.

Mol Autism 2021 03 18;12(1):24. Epub 2021 Mar 18.

Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA.

Background: The Early Markers for Autism (EMA) study is a population-based case-control study designed to learn more about early biologic processes involved in ASD.

Methods: Participants were drawn from Southern California births from 2000 to 2003 with archived prenatal and neonatal screening specimens. Across two phases, children with ASD (n = 629) and intellectual disability without ASD (ID, n = 230) were ascertained from the California Department of Developmental Services (DDS), with diagnoses confirmed according to DSM-IV-TR criteria based on expert clinical review of abstracted records. General population controls (GP, n = 599) were randomly sampled from birth certificate files and matched to ASD cases by sex, birth month and year after excluding individuals with DDS records. EMA has published over 20 papers examining immune markers, endogenous hormones, environmental chemicals, and genetic factors in association with ASD and ID. This review summarizes the results across these studies, as well as the EMA study design and future directions.

Results: EMA enabled several key contributions to the literature, including the examination of biomarker levels in biospecimens prospectively collected during critical windows of neurodevelopment. Key findings from EMA include demonstration of elevated cytokine and chemokine levels in maternal mid-pregnancy serum samples in association with ASD, as well as aberrations in other immune marker levels; suggestions of increased odds of ASD with prenatal exposure to certain endocrine disrupting chemicals, though not in mixture analyses; and demonstration of maternal and fetal genetic influence on prenatal chemical, and maternal and neonatal immune marker and vitamin D levels. We also observed an overall lack of association with ASD and measured maternal and neonatal vitamin D, mercury, and brain-derived neurotrophic factor (BDNF) levels.

Limitations: Covariate and outcome data were limited to information in Vital Statistics and DDS records. As a study based in Southern California, generalizability for certain environmental exposures may be reduced.

Conclusions: Results across EMA studies support the importance of the prenatal and neonatal periods in ASD etiology, and provide evidence for the role of the maternal immune response during pregnancy. Future directions for EMA, and the field of ASD in general, include interrogation of mechanistic pathways and examination of combined effects of exposures.
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http://dx.doi.org/10.1186/s13229-021-00429-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7977191PMC
March 2021

Sequential perturbations to mouse corticogenesis following in utero maternal immune activation.

Elife 2021 Mar 5;10. Epub 2021 Mar 5.

Center for Neuroscience, UC Davis, Davis, United States.

In utero exposure to maternal immune activation (MIA) is an environmental risk factor for neurodevelopmental and neuropsychiatric disorders. Animal models provide an opportunity to identify mechanisms driving neuropathology associated with MIA. We performed time-course transcriptional profiling of mouse cortical development following induced MIA via poly(I:C) injection at E12.5. MIA-driven transcriptional changes were validated via protein analysis, and parallel perturbations to cortical neuroanatomy were identified via imaging. MIA-induced acute upregulation of genes associated with hypoxia, immune signaling, and angiogenesis, by 6 hr following exposure. This acute response was followed by changes in proliferation, neuronal and glial specification, and cortical lamination that emerged at E14.5 and peaked at E17.5. Decreased numbers of proliferative cells in germinal zones and alterations in neuronal and glial populations were identified in the MIA-exposed cortex. Overall, paired transcriptomic and neuroanatomical characterization revealed a sequence of perturbations to corticogenesis driven by mid-gestational MIA.
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http://dx.doi.org/10.7554/eLife.60100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979158PMC
March 2021

Risk assessment analysis for maternal autoantibody-related autism (MAR-ASD): a subtype of autism.

Mol Psychiatry 2021 05 22;26(5):1551-1560. Epub 2021 Jan 22.

Department of Internal Medicine, Division of Rheumatology, Allergy, and Clinical Immunology, One Shields Avenue, University of California, Davis, CA, 95616, USA.

The incidence of autism spectrum disorder (ASD) has been rising, however ASD-risk biomarkers remain lacking. We previously identified the presence of maternal autoantibodies to fetal brain proteins specific to ASD, now termed maternal autoantibody-related (MAR) ASD. The current study aimed to create and validate a serological assay to identify ASD-specific maternal autoantibody patterns of reactivity against eight previously identified proteins (CRMP1, CRMP2, GDA, NSE, LDHA, LDHB, STIP1, and YBOX) that are highly expressed in developing brain, and determine the relationship of these reactivity patterns with ASD outcome severity. We used plasma from mothers of children diagnosed with ASD (n = 450) and from typically developing children (TD, n = 342) to develop an ELISA test for each of the protein antigens. We then determined patterns of reactivity a highly significant association with ASD, and discovered several patterns that were ASD-specific (18% in the training set and 10% in the validation set vs. 0% TD). The three main patterns associated with MAR ASD are CRMP1 + GDA (ASD% = 4.2 vs. TD% = 0, OR 31.04, p = <0.0001), CRMP1 + CRMP2 (ASD% = 3.6 vs. TD% = 0, OR 26.08, p = 0.0005) and NSE + STIP1 (ASD% = 3.1 vs. TD% = 0, OR 22.82, p = 0.0001). Additionally, we found that maternal autoantibody reactivity to CRMP1 significantly increases the odds of a child having a higher Autism Diagnostic Observation Schedule (ADOS) severity score (OR 2.3; 95% CI: 1.358-3.987, p = 0.0021). This is the first report that uses machine learning subgroup discovery to identify with 100% accuracy MAR ASD-specific patterns as potential biomarkers of risk for a subset of up to 18% of ASD cases in this study population.
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http://dx.doi.org/10.1038/s41380-020-00998-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159732PMC
May 2021

Alterations in Retrotransposition, Synaptic Connectivity, and Myelination Implicated by Transcriptomic Changes Following Maternal Immune Activation in Nonhuman Primates.

Biol Psychiatry 2021 05 2;89(9):896-910. Epub 2020 Nov 2.

Department of Psychiatry, Center for Autism Research and Treatment, Los Angeles, California; Program in Neurobehavioral Genetics, Center for Autism Research and Treatment, Los Angeles, California; Department of Neurology, Center for Autism Research and Treatment, Los Angeles, California; Department of Human Genetics, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California. Electronic address:

Background: Maternal immune activation (MIA) is a proposed risk factor for multiple neuropsychiatric disorders, including schizophrenia. However, the molecular mechanisms through which MIA imparts risk remain poorly understood. A recently developed nonhuman primate model of exposure to the viral mimic poly:ICLC during pregnancy shows abnormal social and repetitive behaviors and elevated striatal dopamine, a molecular hallmark of human psychosis, providing an unprecedented opportunity for studying underlying molecular correlates.

Methods: We performed RNA sequencing across psychiatrically relevant brain regions (prefrontal cortex, anterior cingulate, hippocampus) and primary visual cortex for comparison from 3.5- to 4-year-old male MIA-exposed and control offspring-an age comparable to mid adolescence in humans.

Results: We identify 266 unique genes differentially expressed in at least one brain region, with the greatest number observed in hippocampus. Co-expression networks identified region-specific alterations in synaptic signaling and oligodendrocytes. Although we observed temporal and regional differences, transcriptomic changes were shared across first- and second-trimester exposures, including for the top differentially expressed genes-PIWIL2 and MGARP. In addition to PIWIL2, several other regulators of retrotransposition and endogenous transposable elements were dysregulated following MIA, potentially connecting MIA to retrotransposition.

Conclusions: Together, these results begin to elucidate the brain-level molecular processes through which MIA may impart risk for psychiatric disease.
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http://dx.doi.org/10.1016/j.biopsych.2020.10.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8052273PMC
May 2021

Maternal immune response and air pollution exposure during pregnancy: insights from the Early Markers for Autism (EMA) study.

J Neurodev Disord 2020 12 16;12(1):42. Epub 2020 Dec 16.

Division of Research, Kaiser Permanente of Northern California, Oakland, CA, USA.

Background: Perinatal exposure to air pollution and immune system dysregulation are two factors consistently associated with autism spectrum disorders (ASD) and other neurodevelopmental outcomes. However, little is known about how air pollution may influence maternal immune function during pregnancy.

Objectives: To assess the relationship between mid-gestational circulating levels of maternal cytokines/chemokines and previous month air pollution exposure across neurodevelopmental groups, and to assess whether cytokines/chemokines mediate the relationship between air pollution exposures and risk of ASD and/or intellectual disability (ID) in the Early Markers for Autism (EMA) study.

Methods: EMA is a population-based, nested case-control study which linked archived maternal serum samples collected during weeks 15-19 of gestation for routine prenatal screening, birth records, and Department of Developmental Services (DDS) records. Children receiving DDS services for ASD without intellectual disability (ASD without ID; n = 199), ASD with ID (ASD with ID; n = 180), ID without ASD (ID; n = 164), and children from the general population (GP; n = 414) with no DDS services were included in this analysis. Serum samples were quantified for 22 cytokines/chemokines using Luminex multiplex analysis technology. Air pollution exposure for the month prior to maternal serum collection was assigned based on the Environmental Protection Agency's Air Quality System data using the maternal residential address reported during the prenatal screening visit.

Results: Previous month air pollution exposure and mid-gestational maternal cytokine and chemokine levels were significantly correlated, though weak in magnitude (ranging from - 0.16 to 0.13). Ten pairs of mid-pregnancy immune markers and previous month air pollutants were significantly associated within one of the child neurodevelopmental groups, adjusted for covariates (p < 0.001). Mid-pregnancy air pollution was not associated with any neurodevelopmental outcome. IL-6 remained associated with ASD with ID even after adjusting for air pollution exposure.

Conclusion: This study suggests that maternal immune activation is associated with risk for neurodevelopmental disorders. Furthermore, that prenatal air pollution exposure is associated with small, but perhaps biologically relevant, effects on maternal immune system function during pregnancy. Additional studies are needed to better evaluate how prenatal exposure to air pollution affects the trajectory of maternal immune activation during pregnancy, if windows of heightened susceptibility can be identified, and how these factors influence neurodevelopment of the offspring.
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http://dx.doi.org/10.1186/s11689-020-09343-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745402PMC
December 2020

Nonlethal Plasmodium yoelii Infection Drives Complex Patterns of Th2-Type Host Immunity and Mast Cell-Dependent Bacteremia.

Infect Immun 2020 11 16;88(12). Epub 2020 Nov 16.

Department of Entomology, Plant Pathology, and Nematology, University of Idaho, Moscow, Idaho, USA

Malaria strongly predisposes to bacteremia, which is associated with sequestration of parasitized red blood cells and increased gastrointestinal permeability. The mechanisms underlying this disruption are poorly understood. Here, we evaluated the expression of factors associated with mast cell activation and malaria-associated bacteremia in a rodent model. C57BL/6J mice were infected with 17XNL, and blood and tissues were collected over time to assay for circulating levels of bacterial 16S DNA, IgE, mast cell protease 1 (Mcpt-1) and Mcpt-4, Th1 and Th2 cytokines, and patterns of ileal mastocytosis and intestinal permeability. The anti-inflammatory cytokines (interleukin-4 [IL-4], IL-6, and IL-10) and MCP-1/CCL2 were detected early after 17XNL infection. This was followed by the appearance of IL-9 and IL-13, cytokines known for their roles in mast cell activation and growth-enhancing activity as well as IgE production. Later increases in circulating IgE, which can induce mast cell degranulation, as well as Mcpt-1 and Mcpt-4, were observed concurrently with bacteremia and increased intestinal permeability. These results suggest that 17XNL infection induces the production of early cytokines that activate mast cells and drive IgE production, followed by elevated IgE, IL-9, and IL-13 that maintain and enhance mast cell activation while disrupting the protease/antiprotease balance in the intestine, contributing to epithelial damage and increased permeability.
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http://dx.doi.org/10.1128/IAI.00427-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7671899PMC
November 2020

Baseline immunoreactivity before pregnancy and poly(I:C) dose combine to dictate susceptibility and resilience of offspring to maternal immune activation.

Brain Behav Immun 2020 08 23;88:619-630. Epub 2020 Apr 23.

Center for Neuroscience, University of California, Davis, United States. Electronic address:

Despite the potential of rodent models of maternal immune activation (MIA) to identify new biomarkers and therapeutic interventions for a range of psychiatric disorders, current approaches using these models ignore two of the most important aspects of this risk factor for human disease: (i) most pregnancies are resilient to maternal viral infection and (ii) susceptible pregnancies can lead to different combinations of phenotypes in offspring. Here, we report two new sources of variability-the baseline immunoreactivity (BIR) of isogenic females prior to pregnancy and differences in immune responses in C57BL/6 dams across vendors-that contribute to resilience and susceptibility to distinct combinations of behavioral and biological outcomes in offspring. Similar to the variable effects of human maternal infection, MIA in mice does not cause disease-related phenotypes in all pregnancies and a combination of poly(I:C) dose and BIR predicts susceptibility and resilience of pregnancies to aberrant repetitive behaviors and alterations in striatal protein levels in offspring. Even more surprising is that the intermediate levels of BIR and poly(I:C) dose are most detrimental to offspring, with higher BIR and poly(I:C) doses conferring resilience to measured phenotypes in offspring. Importantly, we identify the BIR of female mice as a biomarker before pregnancy that predicts which dams will be most at risk as well as biomarkers in the brains of newborn offspring that correlate with changes in repetitive behaviors. Together, our results highlight considerations for optimizing MIA protocols to enhance rigor and reproducibility and reveal new factors that drive susceptibility of some pregnancies and resilience of others to MIA-induced abnormalities in offspring.
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http://dx.doi.org/10.1016/j.bbi.2020.04.061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415552PMC
August 2020

Translational opportunities in the prenatal immune environment: Promises and limitations of the maternal immune activation model.

Neurobiol Dis 2020 07 9;141:104864. Epub 2020 Apr 9.

The MIND Institute, University of California, Davis, United States of America; Rheumatology/Allergy and Clinical Immunology, University of California, Davis, United States of America.

The prenatal environment, and in particular, the maternal-fetal immune environment, has emerged as a targeted area of research for central nervous system (CNS) diseases with neurodevelopmental origins. Converging evidence from both clinical and preclinical research indicates that changes in the maternal gestational immune environment can alter fetal brain development and increase the risk for certain neurodevelopmental disorders. Here we focus on the translational potential of one prenatal animal model - the maternal immune activation (MIA) model. This model stems from the observation that a subset of pregnant women who are exposed to infection during pregnancy have an increased risk of giving birth to a child who will later be diagnosed with a neurodevelopmental disorder, such as autism spectrum disorder (ASD) or schizophrenia (SZ). The preclinical MIA model provides a system in which to explore causal relationships, identify underlying neurobiological mechanisms, and, ultimately, develop novel therapeutic interventions and preventative strategies. In this review, we will highlight converging evidence from clinical and preclinical research that links changes in the maternal-fetal immune environment with lasting changes in offspring brain and behavioral development. We will then explore the promises and limitations of the MIA model as a translational tool to develop novel therapeutic interventions. As the translational potential of the MIA model has been the focus of several excellent review articles, here we will focus on what is perhaps the least well developed area of MIA model research - novel preventative strategies and therapeutic interventions.
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http://dx.doi.org/10.1016/j.nbd.2020.104864DOI Listing
July 2020

Biodistribution and toxicity of epitope-functionalized dextran iron oxide nanoparticles in a pregnant murine model.

J Biomed Mater Res A 2020 05 26;108(5):1186-1202. Epub 2020 Feb 26.

Department of Biomedical Engineering, University of California Davis, Davis, California, USA.

In pursuit of a preventive therapeutic for maternal autoantibody-related (MAR) autism, we assessed the toxicity, biodistribution, and clearance of a MAR specific peptide-functionalized dextran iron oxide nanoparticle system in pregnant murine dams. We previously synthesized ~15 nm citrate-coated dextran iron oxide nanoparticles (DIONPs), surface-modified with polyethylene glycol and MAR peptides to produce systems for nanoparticle-based autoantibody reception and entrapments (SNAREs). First, we investigated their immunogenicity and MAR lactate dehydrogenase B antibody uptake in murine serum in vitro. To assess biodistribution and toxicity, as well as systemic effects, we performed in vivo clinical and post mortem pathological evaluations. We observed minimal production of inflammatory cytokines-interleukin 10 (IL-10) and IL-12 following in vitro exposure of macrophages to SNAREs. We established the maximum tolerated dose of SNAREs to be 150 mg/kg at which deposition of iron was evident in the liver and lungs by histology and magnetic resonance imaging but no concurrent evidence of liver toxicity or lung infarction was detected. Further, SNAREs exhibited slower clearance from the maternal blood in pregnant dams compared to DIONPs based on serum total iron concentration. These findings demonstrated that the SNAREs have a prolonged presence in the blood and are safe for use in pregnant mice as evidenced by no associated organ damage, failure, inflammation, and fetal mortality. Determination of the MTD dose sets the basis for future studies investigating the efficacy of our nanoparticle formulation in a MAR autism mouse model.
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http://dx.doi.org/10.1002/jbm.a.36893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8259460PMC
May 2020

T cell populations in children with autism spectrum disorder and co-morbid gastrointestinal symptoms.

Brain Behav Immun Health 2020 Feb 26;2:100042. Epub 2020 Jan 26.

Department of Medical Microbiology and Immunology, University of California Davis, Davis, CA, USA.

Children with ASD are more likely to experience gastrointestinal (GI) symptoms than typically-developed children. Numerous studies have reported immune abnormalities and inflammatory profiles in the majority of individuals with ASD. Immune dysfunction is often hypothesized as a driving factor in many GI diseases and it has been suggested that it is more apparent in children with ASD that exhibit GI symptoms. In this study we sought to characterize peripheral T cell subsets in children with and without GI symptoms, compared to healthy typically-developing children. Peripheral blood mononuclear cells were isolated from participants, who were categorized into three groups: children with ASD who experience GI symptoms (n ​= ​14), children with ASD who do not experience GI symptoms (n ​= ​10) and typically-developing children who do not experience GI symptoms (n ​= ​15). In order to be included in the GI group, GI symptoms such as diarrhea, constipation, and/or pain while defecating, had to be present in the child regularly for the past 6 months; likewise, in order to be placed in the no GI groups, bowel movements could not include the above symptoms present throughout development. Cells were assessed for surface markers and intracellular cytokines to identify T cell populations. Children with ASD and GI symptoms displayed elevated T17 populations (0.757% ​± ​0.313% compared to 0.297% ​± ​0.197), while children with ASD who did not experience GI symptoms showed increased frequency of T2 populations (2.02% ​± ​1.08% compared to 1.01% ​± ​0.58%). Both ASD groups showed evidence of reduced gut homing regulatory T cell populations compared to typically developing children (ASD:1.93% ​± ​0.75% and ASD:1.85% ​± ​0.89 compared to 2.93% ​± ​1.16%). Children with ASD may have deficits in immune regulation that lead to differential inflammatory T cell subsets that could be linked to associated co-morbidities.
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http://dx.doi.org/10.1016/j.bbih.2020.100042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8474588PMC
February 2020

Effects of cytokines on nuclear factor-kappa B, cell viability, and synaptic connectivity in a human neuronal cell line.

Mol Psychiatry 2021 03 21;26(3):875-887. Epub 2020 Jan 21.

Department of Molecular Biosciences, University of California, Davis, CA, USA.

Maternal infection during pregnancy is associated with increased risk of psychiatric and neurodevelopmental disorders (NDDs). Experimental animal models demonstrate that maternal immune activation (MIA) elevates inflammatory cytokine levels in the maternal and fetal compartments and causes behavioral changes in offspring. Individual cytokines have been shown to modulate neurite outgrowth and synaptic connectivity in cultured rodent neurons, but whether clinically relevant cytokine mixtures similarly modulate neurodevelopment in human neurons is not known. To address this, we quantified apoptosis, neurite outgrowth, and synapse number in the LUHMES human neuronal cell line exposed to varying concentrations of: (1) a mixture of 12 cytokines and chemokines (EMA) elevated in mid-gestational serum samples from mothers of children with autism and intellectual disability; (2) an inflammatory cytokine mixture (ICM) comprised of five cytokines elevated in experimental MIA models; or (3) individual cytokines in ICM. At concentrations that activated nuclear factor-kappa B (NF-κB) in LUHMES cells, EMA and ICM induced caspase-3/7 activity. ICM altered neurite outgrowth, but only at concentrations that also reduced cell viability, whereas ICM reduced synapse number independent of changes in cell viability. Individual cytokines in ICM phenocopied the effects of ICM on NF-κB activation and synaptic connectivity, but did not completely mimic the effects of ICM on apoptosis. These results demonstrate that clinically relevant cytokine mixtures modulate apoptosis and synaptic density in developing human neurons. Given the relevance of these neurodevelopmental processes in NDDs, our findings support the hypothesis that cytokines contribute to the adverse effects of MIA on children.
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http://dx.doi.org/10.1038/s41380-020-0647-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371517PMC
March 2021

Neonatal Thyroid Stimulating Hormone and Subsequent Diagnosis of Autism Spectrum Disorders and Intellectual Disability.

Autism Res 2020 03 10;13(3):444-455. Epub 2019 Dec 10.

Kaiser Permanente Division of Research, Oakland, California.

Hypothyroid conditions in early life, if left untreated, are associated with adverse neurodevelopmental outcomes, including intellectual disability (ID). However, evidence addressing the role of neonatal thyroid hormone insufficiencies in the altered neurobiology underlying autism spectrum disorders (ASD), particularly among its subphenotypes, is limited. We conducted a population-based, case-control study among a sample of children born during 2000-2003 in Southern California. We examined neonatal thyroid-stimulating hormone (TSH) measured during routine newborn screening among children later diagnosed with ASD (n = 518) or ID (n = 145) and general population (GP) controls (n = 399). TSH was further analyzed in relation to ASD subgroups of intellectual ability and onset type (early-onset ASD vs. ASD with regression) ascertained by expert review of developmental services records. Odds ratios (ORs) of the differences in TSH between groups were obtained from multivariate logistic regression. We examined neonatal TSH as continuous (ln-transformed) and as quartiles. We found no association between continuous neonatal TSH levels and ASD (adj-OR: 1.00, 95% CI: 0.79-1.26) nor ID (adj-OR = 1.01, 95% CI: 0.73-1.40). Among ASD subphenotypes, we observed a suggestive inverse trend between ASD with regression and TSH, though the association only reached statistical significance in the highest TSH quartile (adj-OR: 0.50, 95% CI: 0.26-0.98). While there was little evidence that neonatal TSH is related to overall ASD risk, more work is needed to understand the influence of thyroid hormones on ASD subphenotypes. Autism Res 2020, 13: 444-455. © 2019 International Society for Autism Research,Wiley Periodicals, Inc. LAY SUMMARY: Low levels of thyroid hormone at birth can negatively impact brain development. We studied whether newborn levels of thyroid stimulating hormone (TSH) were associated with autism spectrum disorder (ASD) and its subtypes in a sample of children born in California. Newborn TSH was not related to the overall risk of ASD or intellectual disability. However, the relationships of thyroid hormone levels at birth and specific subtypes of ASD, particularly ASD with developmental regression, may need more research.
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http://dx.doi.org/10.1002/aur.2247DOI Listing
March 2020

Peptides of neuron specific enolase as potential ASD biomarkers: From discovery to epitope mapping.

Brain Behav Immun 2020 02 5;84:200-208. Epub 2019 Dec 5.

Department of Internal Medicine, Division of Rheumatology, Allergy, and Clinical Immunology, University of California, One Shields Avenue, Davis, CA 95616, USA; UC Davis MIND Institute, 2825 50th St, Sacramento, CA 95817, USA. Electronic address:

Autism spectrum disorder (ASD) is an important health issue and affects 1 in 59 children in the US. Prior studies determined that maternal autoantibody related (MAR) autism is thought to be associated with ~23% of ASD cases. We previously identified seven MAR-specific autoantigens including CRMP1, CRMP2, GDA, LDHA, LDHB, STIP1, and YBX1. We subsequently described the epitope peptide sequences recognized by maternal autoantibodies for each of the seven ASD-specific autoantigens. The aim of the current study was to expand upon our previous work and identify additional antigens recognized by the ASD-specific maternal autoantibodies, as well as to map the unique ASD-specific epitopes using microarray technology. Fetal Rhesus macaque brain tissues were separated by molecular weight and a fraction containing bands between 37 and 45 kDa was analyzed using 2-D gel electrophoresis, followed by peptide mass mapping using MALDI-TOF MS and TOF/TOF tandem MS/MS. Using this methodology, Neuron specific enolase (NSE) was identified as a target autoantigen and selected for epitope mapping. The full NSE sequence was translated into 15-mer peptides with an overlap of 14 amino acids onto microarray slides and probed with maternal plasma from mothers with an ASD child and from mothers with a Typically Developing child (TD) (ASD = 27 and TD = 21). The resulting data were analyzed by T-test. We found 16 ASD-specific NSE-peptide sequences for which four sequences were statistically significant (p < 0.05) using both the t-test and SAM t-test: DVAASEFYRDGKYDL (p = 0.047; SAM score 1.49), IEDPFDQDDWAAWSK (p = 0.049; SAM score 1.49), ERLAKYNQLMRIEEE (p = 0.045; SAM score 1.57), and RLAKYNQLMRIEEEL (p = 0.017; SAM score 1.82). We further identified 5 sequences that were recognized by both ASD and TD antibodies suggesting a large immunodominant epitope (DYPVVSIEDPFDQDDWAAW). While maternal autoantibodies against the NSE protein are present both in mothers with ASD and mothers of TD children, there are several ASD-specific epitopes that can potentially be used as MAR ASD biomarkers. Further, studies including analysis of NSE as a target protein in combination with the previously identified MAR ASD autoantigens are currently underway.
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http://dx.doi.org/10.1016/j.bbi.2019.12.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7010557PMC
February 2020

Prenatal Stress and Maternal Immune Dysregulation in Autism Spectrum Disorders: Potential Points for Intervention.

Curr Pharm Des 2019 ;25(41):4331-4343

Department of Internal Medicine, Division of Rheumatology, Allergy, and Clinical Immunology, And the MIND Institute, University of California, Davis, CA, United States.

Background: Genetics is a major etiological contributor to autism spectrum disorder (ASD). Environmental factors, however, also appear to contribute. ASD pathophysiology due to gene x environment is also beginning to be explored. One reason to focus on environmental factors is that they may allow opportunities for intervention or prevention.

Methods And Results: Herein, we review two such factors that have been associated with a significant proportion of ASD risk, prenatal stress exposure and maternal immune dysregulation. Maternal stress susceptibility appears to interact with prenatal stress exposure to affect offspring neurodevelopment. We also explore how maternal stress may interact with the microbiome in the neurodevelopmental setting. Additionally, understanding of the impact of maternal immune dysfunction on ASD has recently been advanced by recognition of specific fetal brain proteins targeted by maternal autoantibodies, and identification of unique mid-gestational maternal immune profiles. This might also be interrelated with maternal stress exposure. Animal models have been developed to explore pathophysiology targeting each of these factors.

Conclusion: We are beginning to understand the behavioral, pharmacopathological, and epigenetic effects related to these interactions, and we are beginning to explore potential mitigating factors. Continued growth in understanding of these mechanisms may ultimately allow for the identification of multiple potential targets for prevention or intervention for this subset of environmental-associated ASD cases.
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http://dx.doi.org/10.2174/1381612825666191119093335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7100710PMC
June 2020

Acute peripheral immune activation alters cytokine expression and glial activation in the early postnatal rat brain.

J Neuroinflammation 2019 Oct 31;16(1):200. Epub 2019 Oct 31.

MIND Institute, University of California, Davis School of Medicine, Sacramento, CA, 95817, USA.

Background: Neuroinflammation can modulate brain development; however, the influence of an acute peripheral immune challenge on neuroinflammatory responses in the early postnatal brain is not well characterized. To address this gap in knowledge, we evaluated the peripheral and central nervous system (CNS) immune responses to a mixed immune challenge in early postnatal rats of varying strains and sex.

Methods: On postnatal day 10 (P10), male and female Lewis and Brown Norway rats were injected intramuscularly with either a mix of bacterial and viral components in adjuvant, adjuvant-only, or saline. Immune responses were evaluated at 2 and 5 days post-challenge. Cytokine and chemokine levels were evaluated in serum and in multiple brain regions using a Luminex multiplex assay. Multi-factor ANOVAs were used to compare analyte levels across treatment groups within strain, sex, and day of sample collection. Numbers and activation status of astrocytes and microglia were also analyzed in the cortex and hippocampus by quantifying immunoreactivity for GFAP, IBA-1, and CD68 in fixed brain slices. Immunohistochemical data were analyzed using a mixed-model regression analysis.

Results: Acute peripheral immune challenge differentially altered cytokine and chemokine levels in the serum versus the brain. Within the brain, the cytokine and chemokine response varied between strains, sexes, and days post-challenge. Main findings included differences in T helper (Th) type cytokine responses in various brain regions, particularly the cortex, with respect to IL-4, IL-10, and IL-17 levels. Additionally, peripheral immune challenge altered GFAP and IBA-1 immunoreactivity in the brain in a strain- and sex-dependent manner.

Conclusions: These findings indicate that genetic background and sex influence the CNS response to an acute peripheral immune challenge during early postnatal development. Additionally, these data reinforce that the developmental time point during which the challenge occurs has a distinct effect on the activation of CNS-resident cells.
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http://dx.doi.org/10.1186/s12974-019-1569-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6822372PMC
October 2019

Towards a nanoparticle-based prophylactic for maternal autoantibody-related autism.

Nanomedicine 2019 10 23;21:102067. Epub 2019 Jul 23.

University of California, Davis, Department of Biomedical Engineering, Davis, CA, USA. Electronic address:

Recently, the causative agents of Maternal Autoantibody-Related (MAR) autism, pathological autoantibodies and their epitopic targets (e.g. lactate dehydrogenase B [LDH B] peptide), have been identified. Herein, we report on the development of Systems for Nanoparticle-based Autoantibody Reception and Entrapment (SNAREs), which we hypothesized could scavenge disease-propagating MAR autoantibodies from the maternal blood. To demonstrate this functionality, we synthesized 15 nm dextran iron oxide nanoparticles surface-modified with citric acid, methoxy PEG(10 kDa) amine, and LDH B peptide (33.8 μg peptide/cm). In vitro, we demonstrated significantly lower macrophage uptake for SNAREs compared to control NPs. The hallmark result of this study was the efficacy of the SNAREs to remove 90% of LDH B autoantibody from patient-derived serum. Further, in vitro cytotoxicity testing and a maximal tolerated dose study in mice demonstrated the safety of the SNARE formulation. This work establishes the feasibility of SNAREs as the first-ever prophylactic against MAR autism.
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http://dx.doi.org/10.1016/j.nano.2019.102067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7197945PMC
October 2019

An Exploratory Examination of Neonatal Cytokines and Chemokines as Predictors of Autism Risk: The Early Markers for Autism Study.

Biol Psychiatry 2019 08 15;86(4):255-264. Epub 2019 May 15.

Division of Rheumatology, Allergy, and Clinical Immunology, Department of Internal Medicine, University of California, Davis, Davis, California; MIND Institute, University of California, Davis, Davis, California. Electronic address:

Background: The identification of an early biomarker for autism spectrum disorder (ASD) would improve the determination of risk, leading to earlier diagnosis and, potentially, earlier intervention and improved outcomes.

Methods: Data were generated from the Early Markers for Autism study, a population-based case-control study of prenatal and neonatal biomarkers of ASD. Newborn bloodspots of children with ASD (n = 370), children with developmental delay (n = 140), and general population (GP) controls (n = 378) were analyzed for 42 different immune markers using a Luminex multiplex platform. Comparisons of immune marker concentrations between groups were examined using logistic regression and partial least squares discriminant analysis.

Results: Children with ASD had significantly increased neonatal levels of interleukin-6 (IL-6) and IL-8 compared with GP controls. An increase in IL-8 was especially significant in the ASD group with early onset compared with the GP group, with an adjusted odds ratio of 1.97 (95% confidence interval, 1.39-2.83; p = .00014). In addition, children with ASD had significantly elevated levels of eotaxin-1, interferon-γ, and IL-12p70 relative to children with developmental delay. We observed no significant differences in levels of immune markers between the developmental delay and GP groups.

Conclusions: Elevated levels of some inflammatory markers in newborn bloodspots indicated a higher degree of immune activation at birth in children who were subsequently diagnosed with ASD. The data from this exploratory study suggest that with further expansion, the development of neonatal bloodspot testing for cytokine/chemokine levels might lead to the identification of biomarkers that provide an accurate assessment of ASD risk at birth.
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http://dx.doi.org/10.1016/j.biopsych.2019.04.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6677631PMC
August 2019

A Prospective Study of Environmental Exposures and Early Biomarkers in Autism Spectrum Disorder: Design, Protocols, and Preliminary Data from the MARBLES Study.

Environ Health Perspect 2018 11;126(11):117004

UC Davis MIND (Medical Investigations of Neurodevelopmental Disorders) Institute, UC Davis, Davis, California, USA.

Background: Until recently, environmental factors in autism spectrum disorder (ASD) were largely ignored. Over the last decade, altered risks from lifestyle, medical, chemical, and other factors have emerged through various study designs: whole population cohorts linked to diagnostic and/or exposure-related databases, large case-control studies, and smaller cohorts of children at elevated risk for ASD.

Objectives: This study aimed to introduce the MARBLES (Markers of Autism Risk in Babies-Learning Early Signs) prospective study and its goals, motivate the enhanced-risk cohort design, describe protocols and main exposures of interest, and present initial descriptive results for the study population.

Methods: Families having one or more previous child with ASD were contacted before or during a pregnancy, and once the woman became pregnant, were invited to enroll. Data and biological samples were collected throughout pregnancy, at birth, and until the child's third birthday. Neurodevelopment was assessed longitudinally. The study began enrolling in 2006 and is ongoing.

Results: As of 30 June 2018, 463 pregnant mothers have enrolled. Most mothers ([Formula: see text]) were thirty years of age or over, including 7.9% who are fourty years of age or over. The sample includes 22% Hispanic and another 25% nonHispanic Black, Asian, or multiracial participants; 24% were born outside the United States. Retention is high: 84% of participants whose pregnancies did not end in miscarriage completed the study or are still currently active. Among children evaluated at 36 months of age, 24% met criteria for ASD, and another 25% were assessed as nonASD nontypical development.

Conclusion: Few environmental studies of ASD prospectively obtain early-life exposure measurements. The MARBLES study fills this gap with extensive data and specimen collection beginning in pregnancy and has achieved excellent retention in an ethnically diverse study population. The 24% familial recurrence risk is consistent with recent reported risks observed in large samples of siblings of children diagnosed with ASD. https://doi.org/10.1289/EHP535.
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http://dx.doi.org/10.1289/EHP535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6371714PMC
November 2018

Variability in PolyIC induced immune response: Implications for preclinical maternal immune activation models.

J Neuroimmunol 2018 10 28;323:87-93. Epub 2018 Jun 28.

Department of Psychiatry and Behavioral Sciences, University of California, Davis, USA; The MIND Institute, University of California, Davis, USA; California National Primate Research Center, University of California, Davis, USA. Electronic address:

Maternal infection during pregnancy may increase the risk of offspring neurodevelopmental disorders. The preclinical Polyinosinic-polycytidylic acid (PolyIC) model has become one of the most widely used approaches in maternal immune activation (MIA) research. However, variability in molecular weight may impact the immune activating potential of PolyIC. Nulliparous rats injected with high molecular weight PolyIC exhibit pronounced cytokine response and sickness behavior that was not observed in rats injected low molecular weight PolyIC. Although an essential next step is to extend these studies to pregnant animals, the preliminary results suggest that PolyIC molecular weight is an important experimental design consideration.
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http://dx.doi.org/10.1016/j.jneuroim.2018.06.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6782055PMC
October 2018

Cross-genetic determination of maternal and neonatal immune mediators during pregnancy.

Genome Med 2018 08 22;10(1):67. Epub 2018 Aug 22.

Department of Psychiatry and Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA.

Background: The immune system plays a fundamental role in development during pregnancy and early life. Alterations in circulating maternal and neonatal immune mediators have been associated with pregnancy complications as well as susceptibility to autoimmune and neurodevelopmental conditions in later life. Evidence suggests that the immune system in adults not only responds to environmental stimulation but is also under strong genetic control.

Methods: This is the first genetic study of > 700 mother-infant pairs to analyse the circulating levels of 22 maternal mid-gestational serum-derived and 42 neonatal bloodspot-derived immune mediators (cytokines/chemokines) in the context of maternal and fetal genotype. We first estimated the maternal and fetal genome-wide SNP-based heritability (h) for each immune molecule and then performed genome-wide association studies (GWAS) to identify specific loci contributing to individual immune mediators. Finally, we assessed the relationship between genetic immune determinants and ASD outcome.

Results: We show maternal and neonatal cytokines/chemokines displaying genetic regulation using independent methodologies. We demonstrate that novel fetal loci for immune function independently affect the physiological levels of maternal immune mediators and vice versa. The cross-associated loci are in distinct genomic regions compared with individual-specific immune mediator loci. Finally, we observed an interaction between increased IL-8 levels at birth, autism spectrum disorder (ASD) status, and a specific maternal genotype.

Conclusions: Our results suggest that maternal and fetal genetic variation influences the immune system during pregnancy and at birth via distinct mechanisms and that a better understanding of immune factor determinants in early development may shed light on risk factors for developmental disorders.
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http://dx.doi.org/10.1186/s13073-018-0576-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6106874PMC
August 2018

Autism-specific maternal autoantibodies produce behavioral abnormalities in an endogenous antigen-driven mouse model of autism.

Mol Psychiatry 2020 11 28;25(11):2994-3009. Epub 2018 Jun 28.

Department of Internal Medicine, Division of Rheumatology, Allergy, and Clinical Immunology, University of California, Davis, CA, USA.

Immune dysregulation has been noted consistently in individuals with autism spectrum disorder (ASD) and their families, including the presence of autoantibodies reactive to fetal brain proteins in nearly a quarter of mothers of children with ASD versus <1% in mothers of typically developing children. Our lab recently identified the peptide epitope sequences on seven antigenic proteins targeted by these maternal autoantibodies. Through immunization with these peptide epitopes, we have successfully created an endogenous, antigen-driven mouse model that ensures a constant exposure to the salient autoantibodies throughout gestation in C57BL/6J mice. This exposure more naturally mimics what is observed in mothers of children with ASD. Male and female offspring were tested using a comprehensive sequence of behavioral assays, as well as measures of health and development highly relevant to ASD. We found that MAR-ASD male and female offspring had significant alterations in development and social interactions during dyadic play. Although 3-chambered social approach was not significantly different, fewer social interactions with an estrous female were noted in the adult male MAR-ASD animals, as well as reduced vocalizations emitted in response to social cues with robust repetitive self-grooming behaviors relative to saline treated controls. The generation of MAR-ASD-specific epitope autoantibodies in female mice prior to breeding created a model that demonstrates for the first time that ASD-specific antigen-induced maternal autoantibodies produced alterations in a constellation of ASD-relevant behaviors.
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http://dx.doi.org/10.1038/s41380-018-0126-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6310680PMC
November 2020

Maternal autoantibody related autism: mechanisms and pathways.

Mol Psychiatry 2019 02 22;24(2):252-265. Epub 2018 Jun 22.

Rheumatology/Allergy and Clinical Immunology, University of California, 451 E. Health Sciences Drive, Suite 6510 GBSF, Davis, CA, 95616, USA.

It has been estimated that autism spectrum disorder (ASD) now affects 1 in 59 children in the United States. Although the cause(s) of ASD remain largely unknown, it is becoming increasingly apparent that ASD can no longer be defined simply as a behavioral disorder, but is in effect a rather complex and highly heterogeneous biological disorder. Up until recently the brain was thought to be "immune privileged." However, it is now known that the immune system plays critical roles in the development and functioning of the brain throughout life. Recent evidence from multiple investigators has illustrated the deleterious role that dysregulation of the maternal immune system during gestation can play in the manifestation of changes in neurodevelopment, resulting in the development of neurobehavioral disorders such as ASD. One potential etiologic pathway through which the maternal immune system can interfere with neurodevelopment is through maternal autoantibodies that recognize proteins in the developing fetal brain. This mechanism of pathogenesis is now thought to lead to a subphenotype of ASD that has been termed maternal autoantibody related (MAR) ASD. This review provides an overview of the current research implicating the presence of brain-reactive maternal autoantibodies as a risk factor for MAR ASD.
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http://dx.doi.org/10.1038/s41380-018-0099-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6784837PMC
February 2019

Cytokine alterations in first-episode schizophrenia and bipolar disorder: relationships to brain structure and symptoms.

J Neuroinflammation 2018 May 26;15(1):165. Epub 2018 May 26.

Department of Medical Microbiology and Immunology, University of California at Davis, 3146 Tupper Hall, 1 Shields Avenue, Davis, CA, 95616, USA.

Background: Over the past 30 years, evidence has been accumulating for an immunological component to schizophrenia etiology, including genetic links to the major histocompatibility complex, microglia activation, and dysregulated cytokine profiles. However, the degree of similarity in cytokine profiles for schizophrenia and bipolar disorder, as well as the relationship between cytokine levels and brain structure, is less well understood.

Methods: To address this, we recruited 69 first-episode schizophrenia-spectrum patients, 16 first-episode bipolar patients with psychotic features, and 53 healthy controls, from the UC Davis EDAPT clinic. Blood plasma was collected and analyzed for all participants with a subset of participants that also underwent structural MRI on a 1.5T GE scanner.

Results: Plasma levels of interleukin (IL)-1β, IL-2, IL-6, and interferon (IFN)-γ were elevated in schizophrenia patients compared to those in controls. Patients with bipolar disorder had elevated plasma IL-10 levels compared to controls, and the two patient groups did not differ significantly on any immunological measure. Percent whole-brain gray matter was inversely correlated with IFN-γ and IL-12 levels in patients with schizophrenia, with a trend relationship between IFN-γ and IL-12 and prefrontal cortical thickness. Furthermore, psychotic symptoms were positively related to IL-1β levels in individuals with schizophrenia.

Conclusions: These data suggest a partially overlapping pattern of elevated blood cytokine levels in patients with first-episode schizophrenia and bipolar disorder with psychotic features. Furthermore, our findings suggest that elevated pro-inflammatory cytokines may be particularly involved in schizophrenia etiology, given evidence of cytokine-related decreases in total gray matter.
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http://dx.doi.org/10.1186/s12974-018-1197-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5970482PMC
May 2018

Differential immune responses and microbiota profiles in children with autism spectrum disorders and co-morbid gastrointestinal symptoms.

Brain Behav Immun 2018 05 20;70:354-368. Epub 2018 Mar 20.

Department of Medical Microbiology and Immunology, University of California Davis, USA; MIND Institute, University of California Davis, USA; Children's Center for Environmental Health, University of California Davis, CA, USA. Electronic address:

Objectives: Many studies have reported the increased presence of gastrointestinal (GI) symptoms in children with autism spectrum disorders (ASD). Altered microbiome profiles, pro-inflammatory responses and impaired intestinal permeability have been observed in children with ASD and co-morbid GI symptoms, yet few studies have compared these findings to ASD children without GI issues or similarly aged typical developing children. The aim of this study was to determine whether there are biological signatures in terms of immune dysfunction and microbiota composition in children with ASD with GI symptoms.

Methods: Children were enrolled in one of four groups: ASD and GI symptoms of irregular bowel habits (ASD), children with ASD but without current or previous GI symptoms (ASD), typically developing children with GI symptoms (TD) and typically developing children without current or previous GI symptoms (TD). Peripheral blood mononuclear cells (PBMC) were isolated from the blood, stimulated and assessed for cytokine production, while stool samples were analyzed for microbial composition.

Results: Following Toll-Like receptor (TLR)-4 stimulation, the ASD group produced increased levels of mucosa-relevant cytokines including IL-5, IL-15 and IL-17 compared to ASD. The production of the regulatory cytokine TGFβ1 was decreased in the ASD group compared with both the ASD and TD groups. Analysis of the microbiome at the family level revealed differences in microbiome composition between ASD and TD children with GI symptoms; furthermore, a predictive metagenome functional content analysis revealed that pathways were differentially represented between ASD and TD subjects, independently of the presence of GI symptoms. The ASD also showed an over-representation of the gene encoding zonulin, a molecule regulating gut permeability, compared to the other groups.

Conclusions: Overall our findings suggest that children with ASD who experience GI symptoms have an imbalance in their immune response, possibly influenced by or influencing metagenomic changes, and may have a propensity to impaired gut barrier function which may contribute to their symptoms and clinical outcome.
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http://dx.doi.org/10.1016/j.bbi.2018.03.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5953830PMC
May 2018

Identification of the antigenic epitopes of maternal autoantibodies in autism spectrum disorders.

Brain Behav Immun 2018 03 28;69:399-407. Epub 2017 Dec 28.

Department of Internal Medicine, Division of Rheumatology, Allergy and Clinical Immunology, One Shields Avenue, University of California, Davis, CA 95616, USA; UC Davis MIND Institute, 2825 50th St, Sacramento, CA 95817, USA. Electronic address:

Several groups have described the presence of fetal brain-reactive maternal autoantibodies in the plasma of some mothers whose children have autism spectrum disorder (ASD). We previously identified seven autoantigens targeted by these maternal autoantibodies, each of which is expressed at significant levels in the developing brain and has demonstrated roles in typical neurodevelopment. To further understand the binding repertoire of the maternal autoantibodies, as well as the presence of any meaningful differences with respect to the recognition and binding of these ASD-specific autoantibodies to each of these neuronal autoantigens, we utilized overlapping peptide microarrays incubated with maternal plasma samples obtained from the Childhood Autism Risk from Genetics and Environment (CHARGE) Study. In an effort to identify the most commonly recognized (immunodominant) epitope sequences targeted by maternal autoantibodies for each of the seven ASD-specific autoantigens, arrays were screened with plasma from mothers with children across diagnostic groups (ASD and typically developing (TD)) that were positive for at least one antigen by western blot (N = 67) or negative control mothers unreactive to any of the autoantigens (N = 18). Of the 63 peptides identified with the discovery microarrays, at least one immunodominant peptide was successfully identified for each of the seven antigenic proteins using subsequent selective screening microarrays. Furthermore, while limited by our relatively small sample size, there were peptides that were distinctly recognized by autoantibodies relative to diagnosis For example, reactivity was observed exclusively in mothers of children of ASD towards several peptides, including the LDH-B peptides DCIIIVVSNPVDILT (9.1% ASD vs. 0% TD; odds ratio (95% CI) = 6.644 (0.355-124.384)) and PVAEEEATVPNNKIT (5.5% ASD vs. 0% TD; odds ratio (95% CI) = 4.067 (0.203-81.403)).These results suggest that there are differences in the binding repertoire between the antigen positive ASD and TD maternal samples. Further, the autoantibodies in plasma from mothers of children with ASD bound to a more diverse set of peptides, and there were specific peptide binding combinations observed only in this group. Future studies are underway to determine the critical amino acids necessary for autoantibody binding, which will be essential in developing a potential therapeutic strategy for maternal autoantibody related (MAR) ASD.
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http://dx.doi.org/10.1016/j.bbi.2017.12.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5857423PMC
March 2018
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