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Introduction: Genetic predisposition to autoimmune encephalitis with antibodies against N-methyl-D-aspartate receptor (NMDAR) is poorly understood. Given the diversity of associated environmental factors (tumors, infections), we hypothesized that human leukocyte antigen (HLA) and killer-cell immunoglobulin-like receptors (KIR), two extremely polymorphic gene complexes key to the immune system, might be relevant for the genetic predisposition to anti-NMDAR encephalitis. Notably, KIR are chiefly expressed by Natural Killer (NK) cells, recognize distinct HLA class I allotypes and play a major role in anti-tumor and anti-infection responses. Methods: We conducted a Genome Wide Association Study (GWAS) with subsequent control-matching using Principal Component Analysis (PCA) and HLA imputation, in a multi-ethnic cohort of anti-NMDAR encephalitis (n=479); KIR and HLA were further sequenced in a large subsample (n=323). PCAcontrolled logistic regression was then conducted for carrier frequencies (HLA and KIR) and copy number variation (KIR). HLA-KIR interaction associations were also modeled. Additionally, single cell sequencing was conducted in peripheral blood mononuclear cells from 16 cases and 16 controls, NK cells were sorted and phenotyped. Results: Anti-NMDAR encephalitis showed a weak HLA association with DRB1*01:01~DQA1*01:01~DQB1*05:01 (OR=1.57, 1.51, 1.45; respectively), and DRB1*11:01 (OR=1.60); these effects were stronger in European descendants and in patients without an underlying ovarian teratoma. More interestingly, we found increased copy number variation of KIR2DL5B (OR=1.72), principally due to an overrepresentation of KIR2DL5B*00201. Further, we identified two allele associations in framework genes, KIR2DL4*00103 (25.4% vs. 12.5% in controls, OR=1.98) and KIR3DL3*00302 (5.3% vs. 1.3%, OR=4.44). Notably, the ligands of these KIR2DL4 and KIR3DL3, respectively, HLA-G and HHLA2, are known to act as immune checkpoint with immunosuppressive functions. However, we did not find differences in specific KIR-HLA ligand interactions or HLA-G polymorphisms between cases and controls. Similarly, gene expression of CD56dim or CD56bright NK cells did not differ between cases and controls. Discussion: Our observations for the first time suggest that the HLA-KIR axis might be involved in anti-NMDAR encephalitis. While the genetic risk conferred by the identified polymorphisms appears small, a role of this axis in the pathophysiology of this disease appears highly plausible and should be analyzed in future studies. [ABSTRACT FROM AUTHOR]

Background: Preclinical studies suggest synergistic effects of maternal inflammatory exposures on offspring neurodevelopment, but human studies have been limited. Objectives: To examine the cumulative association and potential interactions between seven maternal exposures related to inflammation and child attention‐deficit/hyperactivity disorder (ADHD). Methods: We conducted a population‐based cohort study of children born from July 2001 to December 2011 in New South Wales, Australia, and followed up until December 2014. Seven maternal exposures were identified from birth data and hospital admissions during pregnancy: autoimmune disease, asthma, hospitalization for infection, mood or anxiety disorder, smoking, hypertension, and diabetes. Child ADHD was identified from stimulant prescription records. Multivariable Cox regression assessed the association between individual and cumulative exposures and ADHD and potential interaction between exposures, controlling for potential confounders. Results: The cohort included 908,770 children, one‐third (281,724) with one or more maternal exposures. ADHD was identified in 16,297 children (incidence 3.5 per 1000 person‐years) with median age of 7 (interquartile range 2) years at first treatment. Each exposure was independently associated with ADHD, and risk increased with additional exposures: one exposure (hazard ratio (HR) 1.59, 95% confidence interval (CI) 1.54, 1.65), two exposures (HR 2.25, 95% CI 2.13, 2.37), and three or more exposures (HR 3.28, 95% CI 2.95, 3.64). Positive interaction was found between smoking and infection. The largest effect size was found for cumulative exposure of asthma, infection, mood or anxiety disorder, and smoking (HR 6.12, 95% CI 3.47, 10.70). Conclusions: This study identifies cumulative effects of multiple maternal exposures related to inflammation on ADHD, most potentially preventable or modifiable. Future studies should incorporate biomarkers of maternal inflammation and consider gene–environment interactions. [ABSTRACT FROM AUTHOR]

Janus kinase (JAK) 1 inhibition represents a precision medicine approach in the treatment of Aicardi–Goutières syndrome (AGS), through targeting of type I interferon‐mediated cell signalling. Blood interferon mRNAseq has been proposed as a biomarker of disease with utility in therapeutic monitoring. Objective cerebrospinal fluid (CSF) biomarkers tracking treatment efficacy are currently lacking. Here, we report a retrospective case series of 13 patients (median age 6y, range 2y 6mo–17y; five females, eight males) with AGS demonstrating significantly elevated CSF neopterin levels at first sampling (median 200nmol/L, range 45–2024nmol/L), compared to 13 age‐matched controls with non‐inflammatory neurological conditions (median 23nmol/L, range 5–34nmol/L, p<0.001). Five patients with AGS treated with JAK inhibitors demonstrated a median 81.5% reduction of CSF neopterin (range –36% to –88% change from baseline), compared to eight untreated patients with AGS demonstrating a median 7% reduction in CSF neopterin (range –63% to +117% change) (p=0.047). Our data indicate a biological effect of JAK inhibitors, and the potential role of CSF neopterin as a biomarker of treatment response. [ABSTRACT FROM AUTHOR]

Background: Autoimmune conditions are associated with adverse pregnancy and offspring outcomes; however, the prevalence in pregnant women is not well understood. Estimates based on administrative data alone may underestimate prevalence. Methods: A cross-sectional survey of women attending a tertiary referral hospital for antenatal care in December 2018–February 2019 and review of the hospital's maternity database of women giving birth from October 2017–June 2018 to estimate autoimmune disease prevalence. Results: A total of 400 women completed surveys (78% response rate) and 41 (10.3%) reported an autoimmune disease, most commonly Hashimoto's thyroiditis (2.8%) and psoriasis (2.5%). From the maternity database, 112 of 2756 women giving birth (4.1%) had a recorded autoimmune disease, most commonly Hashimoto's thyroiditis (1.3%) followed by coeliac disease, Graves' disease, and immune thrombocytopenic purpura (all 0.4%). Conclusion: Autoimmune disease prevalence in pregnant women is higher when self-reported and may be more common than previously reported using administrative data. [ABSTRACT FROM AUTHOR]

Epidemiological studies, animal models, and case-control studies indicate maternal immune activation may be an important factor involved in disease expression of autism spectrum disorder (ASD), Tourette syndrome, and obsessive-compulsive disorder (OCD). We report eight children (mean age 6y 6mo [range 4-15y]; six males and two females) referred over a 2-year period with at least one of these neurodevelopmental disorders plus a maternal history of thyroid autoimmunity. Seven of eight children presented with an abrupt onset of neuropsychiatric symptoms (OCD [n=6], tics [n=5], and/or psychosis [n=1]), associated with an autistic or global regression. Four children had a pre-existing diagnosis of ASD. Six presentations were preceded by infection, and symptoms followed a relapsing-remitting course in seven children. All children responded to immunomodulatory treatment as indicated by a reduction in psychiatric symptoms, and seven children were also managed with conventional treatment with additional improvement. We propose that maternal autoimmunity can activate fetal microglia or alter transcription of neurodevelopmental vulnerability and/or immune genes in utero, and is an environmental factor that increases the expression and severity of neurodevelopmental problems, and susceptibility to deteriorations after infectious or stress stimuli. WHAT THIS PAPER ADDS: Maternal thyroid autoimmunity may represent a risk factor for neuropsychiatric disorders in offspring. Atypical neuropsychiatric features in these children may be due to maternal immune activation in utero. [ABSTRACT FROM AUTHOR]

Sediment grain size, and specifically changes in the percent mud content (i.e. the fraction <63 µm) over time is often used as an indicator of estuarine environmental health. Using sediment samples from three distinct estuarine systems, we determined that different analytical methods (laser diffraction and wet sieving) gave significantly different results in terms of percent mud content. These differences are also ecologically meaningful when considering the influence of mud on estuarine macrofauna. We propose an approach to measuring sediment grain size termed Environmentally Available Sediment (EAS), which advocates for the measurement of the sediment that biota are directly exposed to. For the purposes of environmental monitoring, it is also essential to monitor sediment grain size in a repeatable way which is likely to be achieved using consistent (or no) pre-treatment and the use of a measurement technique that is unlikely to change over time, e.g. wet sieving. [ABSTRACT FROM AUTHOR]

Declines in bivalve populations have been quite common worldwide, often associated with coastal development, pollution and climate change. In addition to the impacts of these chronic stressors, occasional mass mortality events may have severe consequences on ecosystem services and biodiversity. In this study, we examined the impact of a mass mortality event of the clam (Austrovenus stutchburyi) on an estuarine food web and the grazing pressure exerted by the bivalve population. In February 2009, c. 60% of the clam population died in Whangateau Harbour, New Zealand. Population clearance rate calculations suggest that the clam population do not exert significant top-down control on phytoplankton biomass in the estuary, and thus the impact of the mortality event on bivalve grazing pressure was less severe than the reduction in abundance would suggest. A trophic model shows that phytoplankton play a limited role in the estuary food web, which is instead dominated by microphytobenthos and clams. This study highlights the importance of microphytobenthos in shallow estuaries, and the application of the trophic model is a useful tool that can identify key components of the ecosystem and could help inform monitoring programmes. [ABSTRACT FROM PUBLISHER]