Cronobacter sakazakii Infection in Early Postnatal Rats Impaired Contextual-Associated Learning: a Putative Role of C5a-Mediated NF-κß and ASK1 Pathways.

This study was designed to test whether the Cronobacter sakazakii infection-impaired contextual learning and memory are mediated by the activation of the complement system; subsequent activation of inflammatory signals leads to alternations in serotonin transporter (SERT). To test this, rat pups (postnatal day, PND 15) were treated with either C. sakazakii (107 CFU) or Escherichia coli OP50 (107 CFU) or Luria bertani broth (100 µL) through oral gavage and allowed to stay with their mothers until PND 24. Experimental groups' rats were allowed to explore (PNDs 31-35) and then trained in contextual learning task (PNDs 36-43). Five days after training, individuals were tested for memory retention (PNDs 49-56). Observed behavioural data showed that C. sakazakii infection impaired contextual-associative learning and memory. Furthermore, our analysis showed that C. sakazakii infection activates complement system complement anaphylatoxin (C5a) (a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS1)) and mitogen-activated protein kinase kinase1 (MEKK1). Subsequently, MEKK1 induces pro-inflammatory signals possibly through apoptosis signal-regulating kinase-1 (ASK-1), c-Jun N-terminal kinase (JNK1/3) and protein kinase B gamma (AKT-3). In parallel, activated nuclear factor kappa-light-chain-enhancer B cells (NF-κB) induces interleukin-6 (IL-6) and IFNα-1, which may alter the level of serotonin transporter (SERT). Observed results suggest that impaired contextual learning and memory could be correlated with C5a-mediated NF-κß and ASK1 pathways.

Contribution of endogenous antibodies to learning deficits and astrocytosis in human P301S mutant tau transgenic mice.

Antibodies have been explored extensively as a potential therapeutic for Alzheimer's disease, where amyloid-ß (Aß) peptides and the tau protein deposit in patient brains. While the major focus of antibody-based therapy development was on Aß, arguably with limited success in clinical trials, targeting tau has become an emerging strategy, possibly extending therapies to dementias with isolated tau pathology. Interestingly, low titres of autoantibodies to pathological tau have been described in humans and transgenic mouse models, but their pathophysiological relevance remained elusive. Here, we used two independent approaches to deplete the B-cell lineage and hence antibody formation in human P301S mutant tau transgenic mice, TAU58/2. TAU58/2 mice were either crossed with the B-cell-deficient Ighm knockout line (muMT-/-) or treated with anti-CD20 antibodies that target B-cell precursors. In both models, B-cell depletion significantly reduced astrocytosis in TAU58/2 mice. Only when B-cells were absent throughout life, in TAU58/2.muMT-/- mice, were spatial learning deficits moderately aggravated while motor performance improved as compared to B-cell-competent TAU58/2 mice. This was associated with changes in brain region-specific tau solubility. No other relevant behavioural or neuropathological changes were observed in TAU58/2 mice in the absence of B-cells/antibodies. Taken together, our data suggests that the presence of antibodies throughout life contributes to astrocytosis in TAU58/2 mice and limits learning deficits, while other deficits and neuropathological changes appear to be independent of the presence of B-cells/antibodies.

Sulforaphane Alleviates Lipopolysaccharide-induced Spatial Learning and Memory Dysfunction in Mice: The Role of BDNF-mTOR Signaling Pathway.

Peripheral immune activation could cause neuroinflammation, leading to a series of central nervous system (CNS) disorders, such as spatial learning and memory dysfunction. However, its pathogenic mechanism and therapeutic strategies are not yet determined. The present study aimed to investigate the therapeutic effects of sulforaphane (SFN) on lipopolysaccharide (LPS)-induced spatial learning and memory dysfunction, and tried to elucidate its relationship with the role of hippocampal brain-derived neurotrophic factor (BDNF)-mammalian target of rapamycin (mTOR) signaling pathway. Intraperitoneal injection of LPS for consecutive 7 days to mice caused abnormal behaviors in Morris water maze test (MWMT), while systemic administration of SFN notably reversed the abnormal behaviors. In addition, hippocampal levels of inflammatory cytokines, synaptic proteins, BDNF-tropomyosin receptor kinase B (TrkB) and mTOR signaling pathways were altered in the processes of LPS-induced cognitive dysfunction and SFN's therapeutic effects. Furthermore, we found that ANA-12 (a TrkB inhibitor) or rapamycin (a mTOR inhibitor) could block the beneficial effects of SFN on LPS-induced cognitive dysfunction, and that hippocampal levels of synaptic proteins, BDNF-TrkB and mTOR signaling pathways were also notably changed. In conclusion, the results of the present study suggest that SFN could elicit improving effects on LPS-induced spatial learning and memory dysfunction, which is likely related to the regulation of hippocampal BDNF-mTOR signaling pathway.

Antenatal and Neonatal Antecedents of Executive Dysfunctions in Extremely Preterm Children.

To find out why children born extremely preterm are at heightened risk of executive dysfunctions, the authors assessed 716 children who were 10 years old born extremely preterm whose IQ was ≥ 70. A working memory dysfunction (n = 169), an inhibition dysfunction (n = 360), a switching dysfunction (355), and all 3 (executive dysfunction; n = 107) were defined on the basis of Z-scores ≤ -1 on the Differential Ability Scales-II Working Memory composite, and/or on the NEPSY-II Inhibition-Inhibition and Inhibition-Switching subtests. All risk profiles include an indicator of socioeconomic disadvantage. The risk profile of each of the 3 individual dysfunctions includes an indicator of the newborn's immaturity, and the risk profiles of the inhibition dysfunction and switching dysfunction also include an indicator of inflammation. Only the switching dysfunction was associated with fetal growth restriction. The risk factors for executive dysfunction can be subsumed under the 4 themes of socioeconomic disadvantage, immaturity/vulnerability, inflammation, and fetal growth restriction.

Effects of sustained i.c.v. infusion of lupus CSF and autoantibodies on behavioral phenotype and neuronal calcium signaling.

Systemic lupus erythematosus (SLE) is a potentially fatal autoimmune disease that is often accompanied by brain atrophy and diverse neuropsychiatric manifestations of unknown origin. More recently, it was observed that cerebrospinal fluid (CSF) from patients and lupus-prone mice can be neurotoxic and that acute administration of specific brain-reactive autoantibodies (BRAs) can induce deficits in isolated behavioral tasks. Given the chronic and complex nature of CNS SLE, the current study examines broad behavioral performance and neuronal Ca2+ signaling in mice receiving a sustained infusion of cerebrospinal fluid (CSF) from CNS SLE patients and putative BRAs (anti-NR2A, anti-ribosomal P, and anti-α-tubulin). A 2-week intracerebroventricular (i.c.v.) infusion of CSF altered home-cage behavior and induced olfactory dysfunction, excessive immobility in the forced swim test, and perseveration in a learning task. Conversely, sustained administration of purified BRAs produced relatively mild, both inhibitory and stimulatory effects on olfaction, spatial learning/memory, and home-cage behavior. In vitro studies revealed that administration of some CSF samples induces a rapid influx of extracellular Ca2+ into murine neurons, an effect that could be partially mimicked with the commercial anti-NR2A antibody and blocked with selective N-methyl-D-aspartate (NMDA) receptor antagonists. The current findings confirm that the CSF from CNS SLE patients can be neuroactive and support the hypothesis that intrathecal BRAs induce synergistically diverse effects on all domains of behavior. In addition, anti-NMDA receptor antibodies may alter Ca2+ homeostasis of central neurons, thus accounting for excitotoxicity and contributing to the heterogeneity of psychiatric manifestations in CNS SLE and other autoantibody-related brain disorders.

Novel 3q27.2-qter deletion in a patient with Diamond-Blackfan anemia and immunodeficiency: Case report and review of literature.

3q27.2-qter deletion syndromes feature an overlapping set of terminal and interstitial deletions with variable congenital malformations. Diamond-Blackfan anemia (DBA) is etiologically heterogeneous disorder in which one cause is dominant mutations of the RPL35A gene on 3q29. We report a child with a 3q27.2-qter deletion that contains the RPL35A gene. She had clinical and laboratory features consistent with DBA and as well, an unexplained immunodeficiency disorder. Given these unusual findings, we reviewed other patients in the literature with overlapping genomic deletions. In addition, we evaluated our patient for the immunodeficiency disorder, RIDDLE syndrome, due to recessive mutations in the RNF168 gene on 3q29. A PubMed search for case reports of 3q27.2-qter overlapping deletions was performed. To determine if RPL35A was in the deletion region, the chromosomal regions reported were mapped to genomic regions using the UCSC Genome Browser. We identified 85 overlapping deletions, of which six included the RPL35A gene and all should be had DBA. Interestingly, none of the reported cases had immunodeficiency. To evaluate RIDDLE syndrome (radiosensitivity, immunodeficiency, dysmorphic features, and learning difficulties), we sequenced the remaining RNF168 gene and examined her fibroblast culture for a DNA double strand break repair deficiency. These results were normal, indicating that the immunodeficiency is unlikely to result from a RNF168 deficiency. We show that RPL35A haploinsufficiency is a cause of DBA and we report a novel case with 3q27.2-qter deletion and immunodeficiency. The etiology for the immunodeficiency remains unsolved and could be caused by an unknown gene effect or consequent to the DBA phenotype.

FFPM, a PDE4 inhibitor, reverses learning and memory deficits in APP/PS1 transgenic mice via cAMP/PKA/CREB signaling and anti-inflammatory effects.

Thus far, phosphodiesterase-4 (PDE4) inhibitors have not been approved for application in Alzheimer's disease (AD) in a clinical setting due to severe side effects, such as nausea and vomiting. In this study, we investigated the effect of FFPM, a novel PDE4 inhibitor, on learning and memory abilities, as well as the underlying mechanism in the APP/PS1 mouse model of AD. Pharmacokinetic studies have revealed that FFPM efficiently permeates into the brain, and reached peak values in plasma 2 h after orally dosing. A 3-week treatment with FFPM, at doses of 0.25 mg/kg and 0.5 mg/kg, significantly improved the learning and memory abilities of APP/PS1 transgenic mice in the Morris water maze and the Step-down passive avoidance task. Interestingly, we found that while rolipram (0.5 mg/kg) reduced the duration of the α2 adrenergic receptor-mediated anesthesia induced by xylazine/ketamine, FFPM (0.5 mg/kg) or the vehicle did not have an evident effect. FFPM increased the cAMP, PKA and CREB phosphorylation and BDNF levels, and reduced the NF-κB p65, iNOS, TNF-α and IL-1ß levels in the hippocampi of APP/PS1 trangenic mice, as observed by ELISA and Western blot analysis. Taken together, our data demonstrated that the reversal effect of FFPM on cognitive deficits in APP/PS1 transgenic mice might be related to stimulation of the cAMP/PKA/CREB/BDNF pathway and anti-inflammatory effects. Moreover, FFPM appears to have potential as an effective PDE4 inhibitor in AD treatment with little emetic potential.

Involvement of interleukin-1 in lipopolysaccaride-induced microglial activation and learning and memory deficits.

We have developed an animal model of learning and memory impairment associated with activation of microglia in the mouse brain. Injection of lipopolysaccharide into the CA1 region of the mouse hippocampus resulted in an increased production of inflammatory cytokines, such as interleukin-1ß. Immunostaining for interleukin-1ß revealed an increase in the signal at 6 hr after lipopolysaccharide injection. Immunopositive cells for interleukin-1ß were colocalized with those immunopositive for CD11b. When subacute lipopolysaccharide treatment (20 µg/2 µl/injection, bilaterally for 5 consecutive days) was performed, long-term activation of microglia and learning and memory deficits as evaluated using a step-through passive avoidance test were observed in the wild-type mice. Gene expression of the N-methyl-D-aspartate receptor NR1 and NR2A subunits was also decreased by the lipopolysaccharide treatment. In contrast, activation of microglia and the associated behavioral deficits were not observed in mice lacking interleukin-1α and -1ß following the subacute lipopolysaccharide treatment, together with little change in the gene expression of NR1 and NR2A subunits. However, the subacute lipopolysaccharide treatment produced almost similar changes in those parameters in the tumor necrosis factor-α knockout mice as in the wild-type animals. The injection of interleukin-1ß neutralizing antibody with lipopolysaccharide for 5 consecutive days resulted in the improvement of lipopolysaccharide-induced learning and memory deficits. These findings suggest that the expression of interleukin-1 plays an important role in lipopolysaccharide-induced activation of microglia and the associated functional deficits in learning and memory.

Relación entre el sistema fibrinolítico y las enfermedades neurológicas / Relationship between fibrinolytic system and neurological diseases

Introducción. El sistema fibrinolítico, o sistema del plasminógeno, se compone de una serie de moléculas que convierten el plasminógeno en su forma activa plasmina, la cual es capaz de participar en múltiples procesos fisiopatológicos. Objetivo. Realizar una revisión de la bibliografía y analizar la relación entre el sistema fibrinolítico y las enfermedades neurológicas y sus posibles implicaciones terapéuticas al respecto. Desarrollo. El sistema fibrinolítico se ha involucrado en muy diversas patologías. Aunque tradicionalmente se pensaba que su relación con las enfermedades neurológicas era escasa, en los últimos años se han establecido importantes nexos de unión. De esta forma, el sistema fibrinolítico parece estar involucrado no solamente en enfermedades cerebrovasculares, sino también en la epilepsia, enfermedades neurodegenerativas, como la enfermedad de Alzheimer, enfermedades de perfil inflamatorio, como la esclerosis múltiple, alteraciones del sistema dopaminérgico, trastornos del aprendizaje o enfermedades del sistema nervioso periférico. Diferentes genotipos de los componentes de este sistema se han mostrado como factores protectores o de riesgo para el desarrollo de estas enfermedades, y la información acumulada a este respecto está aumentando sustancialmente. Conclusiones. Un mayor conocimiento de las relaciones entre el sistema fibrinolítico con las enfermedades neurológicas podría aclarar ciertos puntos sobre su fisiopatología y también suponer futuras líneas de prevención y tratamiento (AU)

Introduction. The fibrinolytic system, also named plasminogen system is formed by a group of molecules that transforms plasminogen in its active form plasmine, which is able to participate in a number of pathophysiological processes. Aim. To carry out a review of the literature and an analysis of the relationship between fibrinolytic system and neurological diseases and its potential therapeutic implications.Development. The fibrinolytic system has been involved in many different pathologies. Although its role in neurological diseases has always been thought to be scarce, many relations have been recently established. This way, fibrinolytic system seems to be involved not only in cerebrovascular diseases but also in epilepsy, inflammatory diseases such as multiple sclerosis, alterations of the dopaminergic system, learning disorders and several lesions of the peripheral nervous system. Different genotypes of several components of this system have been related as risk or protector factors to the development of these neurological diseases and information to this respect is rapidly increasing. Conclusions. A better knowledge about the relations between the fibrinolytic system and neurological diseases could clarify several aspects about their pathophysiology and it could suppose future prevention and treatment lines (AU)

Hippocampal CA1 atrophy and synaptic loss during experimental autoimmune encephalomyelitis, EAE.

Over half of multiple sclerosis (MS) patients experience cognitive deficits, including learning and memory dysfunction, and the mechanisms underlying these deficits remain poorly understood. Neuronal injury and synaptic loss have been shown to occur within the hippocampus in other neurodegenerative disease models, and these pathologies have been correlated with cognitive impairment. Whether hippocampal abnormalities occur in MS models is unknown. Using experimental autoimmune encephalomyelitis (EAE), we evaluated hippocampal neurodegeneration and inflammation during disease. Hippocampal pathology began early in EAE disease course, and included decreases in CA1 pyramidal layer volume, loss of inhibitory interneurons and increased cell death of neurons and glia. It is interesting to note that these effects occurred in the presence of chronic microglial activation, with a relative paucity of infiltrating blood-borne immune cells. Widespread diffuse demyelination occurred in the hippocampus, but there was no significant decrease in axonal density. Furthermore, there was a significant reduction in pre-synaptic puncta and synaptic protein expression within the hippocampus, as well as impaired performance on a hippocampal-dependent spatial learning task. Our results demonstrate that neurodegenerative changes occur in the hippocampus during autoimmune-mediated demyelinating disease. This work establishes a preclinical model for assessing treatments targeted toward preventing hippocampal neuropathology and dysfunction in MS.

Can T-cell deficiency affect spatial learning ability following toluene exposure?

OBJECTIVE: The present studywas designed to investigate the possible role of T cells in spatial learning ability in mouse after toluene exposure. METHOD: Eight-week-old male wild-type (WT) and nude mice of BALB/c strain were exposed to toluene (0, 9 and 90 ppm) in a nose-only exposure chamber for 30 min per day for 3 consecutive days and then once per week for 4 weeks. Twenty-four hours after the completion of exposure, we examined the spatial learning ability in each mouse using the Morris water maze apparatus. RESULTS: In the acquisition phase, a longer escape latency was observed in nude mice exposed to 90 ppm toluene on days 3 and 4 when compared with corresponding WT mice. However, the effect of toluene on the escape latency was not significant in nude mice. In the probe trial, WT mice exposed to 90 ppm toluene showed poor retention memory compared with the control group. In the reversal phase, we did not find any significant difference between groups. CONCLUSION: These results indicate that T-cell deficiency may affect spatial learning performance following toluene exposure.

Neonatal effects of maternal antiphospholipid syndrome.

Antiphospholipid antibodies (aPL) can impair the physiologic development of a fetus during pregnancy not only by causing thrombosis of the placental vessels, but also by directly binding throphoblast cells and modifying their functions. Consequently, the presence of aPL in pregnant women is linked to an increased rate of pregnancy complications. These include recurrent early miscarriages, late fetal losses, and hypertensive disorders of gestation. In this clinical setting, preeclampsia is usually early and severe and can be complicated by the syndrome of hemolysis, elevated liver enzymes, and low platelet count (HELLP syndrome). The close association between aPL and obstetric pathology supports the inclusion of these manifestations in the clinical classification criteria of antiphospholipid syndrome. About 30% of children born to mothers with aPL passively acquire these autoantibodies; fortunately, the occurrence of thrombosis seems extremely rare in these babies. The prospective ongoing studies of children born to antiphospholipid syndrome patients reassure us about their general good health; however, some data suggest that learning difficulties might occur, possibly related to in utero exposure to aPL.

Neuropsychological development of children born to patients with antiphospholipid syndrome.

OBJECTIVE: To verify the occurrence of learning disabilities (LDs) in the offspring of women with primary antiphospholipid syndrome (APS) as a consequence of fetal exposure to maternal antiphospholipid antibodies (aPL), and to evaluate the impact of maternal chronic disease on children's development. METHODS: We studied 17 children of mothers with primary APS using a standardized intelligence test (Wechsler Intelligence Scale for Children, Revised), a specific LD battery of tests (Sartori, MT groups' test for reading ability, MT groups' test for math skills), and a questionnaire on behavioral and social characteristics (Child Behavior Checklist [CBCL]). Mothers were interviewed about their pregnancy and motherhood experience. RESULTS: All children had a normal intelligence level (full-scale intelligence quotient >85); 15 pregnancies occurred in mothers with IgG aPL. LDs were diagnosed in 4 children (26.7%), 2 boys and 2 girls. One of these children was born premature, with a brother also affected. Four children (26.7%) showed a higher risk to present problems on the CBCL total competence scale and 2 children (13.3%) on the CBCL total behavior scale. Two children were described as hyperactive (1 had an LD). All families had a good socioeconomic status and educational level. CONCLUSION: Besides prematurity and genetic and environmental factors, the genesis of LDs may also include in utero exposure to aPL, in agreement with described experimental models and patients with systemic lupus erythematosus. Socioeconomic status does not seem to influence the occurrence of LDs. A long-term multidisciplinary followup may improve quality of life in patients with primary APS and their children.

Reduced CXCL12/CXCR4 results in impaired learning and is downregulated in a mouse model of Alzheimer disease.

Alzheimer disease (AD) is characterized by the presence of plaques and tangles in parallel with progressive cognitive decline. The underlying cause of the cognitive decline is unknown. The purpose of this study was to identify factors that could affect learning and memory using the Tg2576 mouse model of AD. Un-biased GeneChip analysis at the time-point coinciding with the onset of behavioral deficits but prior to plaque deposition revealed that Tg2576 show altered gene expression for a number of molecules including the chemokine CXCL12. We show that this chemokine's mRNA, protein and receptor are downregulated in this mouse model coinciding with cognitive deficits. Furthermore, we demonstrate that CXCL12 levels are decreased in AD patients as compared to controls. To determine if CXCL12 might be related to impaired learning and memory, we chronically treated young non-transgenic mice with an antagonist to the CXCL12 receptor to simulate the reduction seen in transgenic animals. Treated animals showed selectively impaired learning and memory suggesting a potential role for this chemokine in cognitive functioning.

Anti-amyloid beta protein antibody passage across the blood-brain barrier in the SAMP8 mouse model of Alzheimer's disease: an age-related selective uptake with reversal of learning impairment.

Amyloid beta protein (Abeta) levels are elevated in the brain of Alzheimer's disease patients. Anti-Abeta antibodies can reverse the histologic and cognitive impairments in mice which overexpress Abeta. Passive immunization appears safer than vaccination and treatment of patients will likely require human rather than xenogenic antibodies. Effective treatment will likely require antibody to cross the blood-brain barrier (BBB). Unfortunately, antibodies typically cross the BBB very poorly and accumulate less well in brain than even albumin, a substance nearly totally excluded from the brain. We compared the ability of two anti-Abeta human monoclonal IgM antibodies, L11.3 and HyL5, to cross the BBB of young CD-1 mice to that of young and aged SAMP8 mice. The SAMP8 mouse has a spontaneous mutation that induces an age-related, Abeta-dependent cognitive deficit. There was preferential uptake of intravenously administered L11.3 in comparison to HyL5, albumin, and a control human monoclonal IgM (RF), especially by hippocampus and olfactory bulb in aged SAMP8 mice. Injection of L11.3 into the brains of aged SAMP8 mice reversed both learning and memory impairments in aged SAMP8 mice, whereas IgG and IgM controls were ineffective. Pharmacokinetic analysis predicted that an intravenous dose 1000 times higher than the brain injection dose would reverse cognitive impairments. This predicted intravenous dose reversed the impairment in learning, but not memory, in aged SAMP8 mice. In conclusion, an IgM antibody was produced that crosses the BBB to reverse cognitive impairment in a murine model of Alzheimer's disease.

Hippocampal damage in mouse and human forms of systemic autoimmune disease.

Systemic lupus erythematosus (SLE) is frequently accompanied by neuropsychiatric (NP) and cognitive deficits of unknown etiology. By using autoimmune MRL-lpr mice as an animal model of NP-SLE, we examine the relationship between autoimmunity, hippocampal damage, and behavioral dysfunction. Fluoro Jade B (FJB) staining and anti-ubiquitin (anti-Ub) immunocytochemistry were used to assess neuronal damage in young (asymptomatic) and aged (diseased) mice, while spontaneous alternation behavior (SAB) was used to estimate the severity of hippocampal dysfunction. The causal relationship between autoimmunity and neuropathology was tested by prolonged administration of the immunosuppressive drug cyclophosphamide (CY). In comparison to congenic MRL +/+ controls, SAB acquisition rates and performance in the "reversal" trial were impaired in diseased MRL-lpr mice, suggesting limited use of the spatial learning strategy. FJB-positive neurons and anti-Ub particles were frequent in the CA3 region. Conversely, CY treatment attenuated the SAB deficit and overall FJB staining. Similarly to mouse brain, the hippocampus from a patient who died from NP-SLE showed reduced neuronal density in the CA3 region and dentate gyrus, as well as increased FJB positivity in these regions. Gliosis and neuronal loss were observed in the gray matter, and T lymphocytes and stromal calcifications were common in the choroid plexus. Taken together, these results suggest that systemic autoimmunity induces significant hippocampal damage, which may underlie affective and cognitive deficits in NP-SLE.

Effects of mothers' autoimmune disease during pregnancy on learning disabilities and hand preference in their children.

OBJECTIVES: To determine whether children (and particularly sons) of women with systemic lupus erythematosus (SLE) during pregnancy are more likely to have learning disabilities (LD) and be non-right-handed, and if maternal disease variables (ie, presence of maternal antibodies, disease activity level, and use of corticosteroids) predict the prevalence of LD in offspring. DESIGN: Case-controlled study with subjects matched by age and sex. PARTICIPANTS: We studied 58 children whose mothers had SLE during pregnancy and 58 children of healthy mothers. Measures Data collected included maternal disease variables in women with SLE during their pregnancies. All children took a standardized intelligence test (Wechsler Intelligence Scale for Children-III) and completed a modified version of the Edinburgh Hand Preference Questionnaire. They also took standardized tests of reading, arithmetic, and writing achievement. Learning disability was defined as having an academic achievement score of at least 1.5 SDs below the Full-Scale IQ. RESULTS: Sons of women with SLE were significantly more likely to have LD than daughters of women with SLE or children of either sex in the control group. Maternal SLE was not associated with non-right-handedness in sons or daughters. The presence of anti-Ro/La antibodies and disease activity (flare) in mothers during pregnancy were significantly related to higher prevalence of LD in offspring. CONCLUSIONS: Autoimmune disease in women during pregnancy is associated with an increased risk for LD in their sons. Maternal antibodies, particularly anti-Ro/La, likely affect the fetal brain of male offspring and result in later learning problems. These findings should promote greater awareness of the risk for LD in sons of women with autoimmune disease and the possible need for early educational intervention in those children.

Aberrant cytokine gene expression in the hippocampus in murine systemic lupus erythematosus.

Cytokines are important mediators of immune regulation and have been implicated in the pathogenesis of the neurological disturbances, which occur in up to sixty percent of patients with systemic lupus erythematosus (SLE). SLE is an autoimmune disease characterized by the presence of autoantibodies against nuclear antigens, including native DNA. Cytokines are thought to drive autoantibody production in lupus. Certain of the derangements in memory and learning described in human and experimental SLE map to the hippocampus. The current study examines the expression of cytokine genes in the hippocampus in lupus, using MRL-lpr/lpr mice as the experimental model. These mice spontaneously develop a SLE-like illness accompanied by disturbances in spatial learning. Our results suggest a potential role for proinflammatory cytokines in the cognitive aberrations observed in lupus.