Peripheral Immune Changes Research Articles

Loss of vagal integrity disrupts immune components of the microbiota-gut-brain axis and inhibits the effect of Lactobacillus rhamnosus on behavior and the corticosterone stress response

The vagus nerve is one of the major signalling components between the gut microbiota and brain. However, the exact relationship between gut-brain signaling along the vagus and the effects of gut microbes on brain function and behaviour is unclear. In particular, the relationship between the vagus nerve and immune signaling, that also appears to play a critical role in microbiota-gut-brain communication, has not been delineated. The aim of the present study was to determine the effect of subdiaphragmatic vagotomy on peripheral and central immune changes associated with the anxiolytic actions of L.rhamnosus. Male mice underwent vagotomy or sham surgery, followed by administration of L.rhamnosus for 14 days. L.rhamnosus administration following sham surgery resulted in reduced anxiety-like behaviour, and an attenuation of the hypothalamic-pituitary-adrenal axis (HPA axis), as indicated by reduced plasma corticosterone after acute restraint stress. These effects were associated with an increase in splenic T regulatory cells and a decrease in activated microglia in the hippocampus. The anxiolytic effects, HPA modulation and increase in T regulatory cells were prevented by vagotomy, whereas vagotomy alone led to a significant increase in activated microglia in the hippocampus that was not altered with L.rhamnosus treatment. Thus, both microbe induced and constitutive vagal signaling influences critical immune components of the microbiota-gut-brain axis. These findings suggest that, rather than acting as a direct neural link to the central nervous system, the role of the vagus nerve in gut-microbe to brain signalling is as an integral component of a bi-directional neuroimmunoendocrine pathway.

Alterations in circulating extracellular vesicles underlie social stress-induced behaviors in mice.

Chronic stress induces peripheral and intracerebral immune changes and inflammation, contributing to neuropathology and behavioral abnormalities relevant to psychiatric disorders such as depression. Although the pathological implication of many peripheral factors such as pro‐inflammatory cytokines, hormones, and macrophages has been demonstrated, the roles of circulating extracellular vesicles (EVs) for chronic stress mechanisms remain poorly investigated. Here, we report that chronic social defeat stress (CSDS)‐induced social avoidance phenotype, assessed by a previously untested three‐chamber social approach test, can be distinguished by multiple pro‐inflammatory cytokines and EV‐associated molecular signatures in the blood. We found that the expression patterns of miRNAs distinguished the CSDS‐susceptible mice from the CSDS‐resilient mice. Social avoidance behavior scores were also estimated with good accuracy by the expression patterns of multiple EV‐associated miRNAs. We also demonstrated that EVs enriched from the CSDS‐susceptible mouse sera upregulated the production of pro‐inflammatory cytokines in the LPS‐stimulated microglia‐like cell lines. Our results indicate the role of circulating EVs and associated miRNAs in CSDS susceptibility, which may be related to pro‐inflammatory mechanisms underlying stress‐induced neurobehavioral outcomes.

Monocyte markers correlate with immune and neuronal brain changes in REM sleep behavior disorder

Synucleinopathies are neurodegenerative diseases with both central and peripheral immune responses. However, whether the peripheral immune changes occur early in disease and their relation to brain events is yet unclear. Isolated rapid-eye-movement (REM) sleep behavior disorder (iRBD) can precede synucleinopathy-related parkinsonism and provides a prodromal phenotype to study early Parkinson's disease events. In this prospective case-control study, we describe monocytic markers in a cohort of iRBD patients that were associated with the brain-imaging markers of inflammation and neuronal dysfunction. Using 11C-PK11195 positron emission tomography (PET), we previously showed increased immune activation in the substantia nigra of iRBD patients, while 18F-DOPA PET detected reduced putaminal dopaminergic function. Here we describe that patients' blood monocytic cells showed increased expression of CD11b, while HLA-DR expression was decreased compared to healthy controls. The iRBD patients had increased classical monocytes and mature natural killer cells. Remarkably, the levels of expression of Toll-like receptor 4 (TLR4) on blood monocytes in iRBD patients were positively correlated with nigral immune activation measured by 11C-PK11195 PET and negatively correlated with putaminal 18F-DOPA uptake; the opposite was seen for the percentage of CD163+ myeloid cells. This suggesting a deleterious role for TLR4 and, conversely, a protective one for the CD163 expression. We show an association between peripheral blood monocytes and brain immune and dopaminergic changes in a synucleinopathy-related disorder, thus suggesting a cross-talk among periphery and brain during the disease.

30580 A TL1 Approach to Assessing Peripheral Immune Changes in PTSD

ABSTRACT IMPACT: We present preliminary data and an outlined approach to assess peripheral immune changes associated with PTSD in a clinical setting and in a pre-clinical rat model of PTSD. OBJECTIVES/GOALS: We report our methodology and findings indicating a relationship between CNS dopamine signaling and peripheral immune cell populations and propose to extend this methodology to a PTSD patient population to elucidate immune-brain connections in this disorder. METHODS/STUDY POPULATION: Using an IRB-approved protocol in collaboration with a board-certified psychiatrist, we will recruit PTSD patients undergoing treatment, newly diagnosed drug-naiive PTSD patients, and age-matched healthy controls. Flow cytometry will be used for immunophenotyping on blood samples from each group. To complement this data, we will also measure serum cytokine levels in each group. In order to elucidate the connection between the observed immunophenotypes in the PTSD population and CNS neurotransmitters levels, we will employ a rodent model of PTSD and high-pressure liquid chromatography to measure dopamine levels in tandem with peripheral immune changes. RESULTS/ANTICIPATED RESULTS: In both humans and rodents with low CNS dopamine, an expansion of monocyte-derived suppressor cells was observed via flow cytometry. We anticipate that human PTSD patients will exhibit a similar expansion in suppressive immune cells’‘ in agreement with existing literature suggesting a chronic inflammatory state in PTSD. Moreover, in an animal model of PTSD we anticipate an inverse correlation between the CNS dopamine levels and the size of the immune suppressor cell population. DISCUSSION/SIGNIFICANCE OF FINDINGS: Our findings will indicate whether altered dopamine neurotransmission underlies peripheral immune system changes in the context of PTSD models and human patients. Thus, these findings will provide an alternative avenue for future investigations on the role of the immune system in PTSD.

Abstract PS12-19: Title:peripheral blood immuneimpactsin arandomizedphase iiclinical trial ofprogrammed death 1 (pd-1) blockadecombined with platinum-based chemotherapy in patients with metastatic triple negative breast cancer (mtnbc)

Abstract Background: PD-1 blockade has shown promising clinical activity in mTNBC. We designed an investigator-initiated multi-center clinical trial consisting of a Safety run-in, into a randomized phase II trial of combination pembrolizumab (P) with carboplatin (C) and gemcitabine (G) in patients with mTNBC. A detailed characterization of peripheral immune cell changes may help in understanding responses in mTNBC to immune checkpoint inhibition. Correlative studies for the purpose of understanding the effect of combining chemotherapy (CT) simultaneously with checkpoint inhibition on the peripheral immune response are planned as part of this clinical trial. Methods: Patients with a diagnosis of mTNBC are recruited to this trial with a Safety Run-in (N = 6 subjects), followed by a randomized design of C + G with/without P (2:1 randomization, N = 75). Treatment consists of P 200 mg on day 1 of each 21-day cycle, and C (AUC2) + G (800mg/m2) on days 1 and 8 for cohort A, and C (AUC2) + G (800mg/m2) for cohort B. Patients are consented for a peripheral blood (PB) collection pre-treatment on day 1 of cycle 1, and post-treatment on day 1 of cycle 3, in order to phenotype immune changes by flow-cytometry. Results: A total of 60 patients have been consented, 42 patients were enrolled (6 on safety run-in, 36 on the randomized part II). Of those on the randomized part II, blood samples from 17 patients have been analyzed from cycle 1 day 1 and cycle 3 day 3. A decreased expression of PD-1 on effector and memory subsets of both CD4+ and CD8+ T cells from C1D1 to C3D1 was observed in blood from both cohorts, especially cohort A. We found an increased % NK, CD4+ T and CD8+ T cell subsets expressing the activation marker, CD69, in cohort A, but not cohort B, reflecting activation by pembrolizumab.​ There was a parallel increased expression of the proliferative marker, Ki67, in CD56bright (immature) NK cells and effector memory CD8+ T cells in blood from C1D1 to C3D1 in cohort A. We also found an increased % CD56bright (immature) NK and effector memory CD4+ T cells expressing the exhaustion marker, CD39, which was consistent with increased expression of the activation marker, CD69. Conclusions: Although comprising a limited number of patients in this early analysis, our correlative studies found evidence for effective immune stimulation upon combining CT with the PD-1 blockade. The randomized nature of this trial, with our planned pre and post treatment blood collection will be helpful in understanding response to immune check point inhibition combined with chemotherapy in mTNBC. Correlation with absolute lymphocyte counts and outcomes data is planned and will be presented. Citation Format: Elias Obeid, Judy Fang, Alex W McFarlane, IV, Irina Shchaveleva, Shauna Souchuck, Kerry S Campbell, Lori J Goldstein. Title:peripheral blood immuneimpactsin arandomizedphase iiclinical trial ofprogrammed death 1 (pd-1) blockadecombined with platinum-based chemotherapy in patients with metastatic triple negative breast cancer (mtnbc) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS12-19.

COVID-19 immune features revealed by a large-scale single-cell transcriptome atlas

A dysfunctional immune response in coronavirus disease 2019 (COVID-19) patients is a recurrent theme impacting symptoms and mortality, yet a detailed understanding of pertinent immune cells is not complete. We applied single-cell RNA sequencing to 284 samples from 196 COVID-19 patients and controls and created a comprehensive immune landscape with 1.46 million cells. The large dataset enabled us to identify that different peripheral immune subtype changes are associated with distinct clinical features, including age, sex, severity, and disease stages of COVID-19. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA was found in diverse epithelial and immune cell types, accompanied by dramatic transcriptomic changes within virus-positive cells. Systemic upregulation of S100A8/A9, mainly by megakaryocytes and monocytes in the peripheral blood, may contribute to the cytokine storms frequently observed in severe patients. Our data provide a rich resource for understanding the pathogenesis of and developing effective therapeutic strategies for COVID-19.

Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer's disease

AbstractBackgroundAlzheimer’s disease (AD) is an incurable neurodegenerative disorder in which neuroinflammation plays a critical function. Yet, little is known about the contribution of the adaptive immune response in AD. Here we used integrated analyses of multiple cohorts to identify peripheral and central adaptive immune changes in AD.MethodFirst, we performed mass cytometry of peripheral blood mononuclear cells and discovered an immune signature of AD consisting of increased numbers of CD8+ T effector memory CD45RA+ (TEMRA) cells.ResultIn a second cohort, we found that CD8+ TEMRA cells were negatively associated with cognition. Furthermore, single cell RNA sequencing revealed their enhanced T cell receptor (TCR) signaling. Notably, by utilizing multiple single cell TCR sequencing strategies on a third cohort, we discovered clonally expanded CD8+ TEMRA cells in patient cerebrospinal fluid (CSF). Finally, we used machine learning, cloning, and peptide screens to demonstrate specificity of clonally expanded AD CSF TCRs to two separate Epstein‐Barr virus antigens.ConclusionThese results reveal a novel blood‐CSF adaptive immune response in AD and provide evidence of clonal, antigen‐experienced T cells patrolling the intrathecal space of brains affected by age‐related neurodegeneration.

Splenic sympathetic signaling contributes to acute neutrophil infiltration of the injured spinal cord

BackgroundAlterations in the immune system are a complication of spinal cord injury (SCI) and have been linked to an excessive sympathetic outflow to lymphoid organs. Still unknown is whether these peripheral immune changes also contribute for the deleterious inflammatory response mounted at the injured spinal cord.MethodsWe analyzed different molecular outputs of the splenic sympathetic signaling for the first 24 h after a thoracic compression SCI. We also analyzed the effect of ablating the splenic sympathetic signaling to the innate immune and inflammatory response at the spleen and spinal cord 24 h after injury.ResultsWe found that norepinephrine (NE) levels were already raised at this time-point. Low doses of NE stimulation of splenocytes in vitro mainly affected the neutrophils’ population promoting an increase in both frequency and numbers. Interestingly, the interruption of the sympathetic communication to the spleen, by ablating the splenic nerve, resulted in reduced frequencies and numbers of neutrophils both at the spleen and spinal cord 1 day post-injury.ConclusionCollectively, our data demonstrates that the splenic sympathetic signaling is involved in the infiltration of neutrophils after spinal cord injury. Our findings give new mechanistic insights into the dysfunctional regulation of the inflammatory response mounted at the injured spinal cord.

Clonally expanded CD8 T cells patrol Alzheimer’s cerebrospinal fluid

Abstract Alzheimer’s disease (AD) is an incurable neurodegenerative disorder in which neuroinflammation plays a critical function. Yet, little is known about the contribution of the adaptive immune response in AD. Here we used integrated analyses of multiple cohorts to identify peripheral and central adaptive immune changes in AD. First, we performed mass cytometry of peripheral blood mononuclear cells and discovered an immune signature of AD consisting of increased numbers of CD8+ T effector memory CD45RA+ (TEMRA) cells. In a second cohort, we found that CD8+ TEMRA cells were negatively associated with cognition. Furthermore, single cell RNA sequencing revealed their enhanced T cell receptor (TCR) signaling. Notably, by utilizing multiple single cell TCR sequencing strategies on a third cohort, we discovered clonally expanded CD8+ TEMRA cells in patient cerebrospinal fluid (CSF). Finally, we used machine learning, cloning, and peptide screens to demonstrate specificity of clonally expanded AD CSF TCRs to two separate Epstein-Barr virus antigens. These results reveal a novel blood-CSF adaptive immune response in AD and provide evidence of clonal, antigen-experienced T cells patrolling the intrathecal space of brains affected by age-related neurodegeneration.

Inflammation, Hippocampal Volume, and Therapeutic Outcome following Electroconvulsive Therapy in Depressive Patients: A Pilot Study

Introduction: Electroconvulsive therapy (ECT) influences the concentration of peripheral inflammatory markers, such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). In which way this immune effect contributes to the impact of ECT on the central nervous system in depression remains unknown. Objective: The aim of this study was to examine whether the hippocampal volumetric increase in depressed patients treated with ECT is related to changes in peripheral IL-6 and TNF-α levels. Methods: IL-6 and TNF-α plasma levels were measured in 62 patients 1 week before and after an acute course of ECT. Hippocampal volumes were analyzed in a magnetic resonance imaging (MRI) subsample of 13 patients at the same time points. Results: A significant decrease in IL-6 levels was observed in the total sample and a significant increase in hippocampal volume in the MRI subsample. The reduction of peripheral IL-6 correlated with an increase in total hippocampal volume. A more limited decrease of TNF-α correlated with a more limited increase of both the total and left hippocampus volumes. Conclusion: This pilot study is the first to highlight the link between peripheral immune changes and hippocampal volume increase following ECT. Further research is required to conclude whether ECT indeed exerts its central effect on the brain via changes of peripheral inflammatory markers.

Immune and Inflammatory Determinants Underlying Alzheimer’s Disease Pathology

This study examines the link between peripheral immune changes in perpetuation of the Alzheimer's disease (AD) neuropathology and cognitive deficits. Our research design using human AD patients and rodent model is supported by past evidence from genomic studies. We observed an active immune response against Aβ as indicated by the increased Aβ specific IgG antibody in the serum of AD and patients with mild cognitive impairments as compared to healthy controls. A similar increase in IgG and decrease in IgM antibody against Aβ was also confirmed in the 5xFAD mouse model of AD. More importantly, we observed a negative correlation between reduced IgM levels and cognitive dysfunction that manifested as impaired memory consolidation. Strong peripheral immune activation was supported by increased activation of microglia in the brain and macrophages in the spleen of AD mice compared to wild type control littermates. Furthermore, inflammatory cytokine IL-21 that is involved in antibody class switching was elevated in the plasma of AD patients and correlated positively with the IgG antibody levels. Concurrently, an increase in IL-21 and IL-17 was observed in spleen cells from AD mice. Further investigation revealed that proportions of T follicular helper (Tfh) cells that secrete IL-21 are increased in the spleen of AD mice. In contrast to Tfh, the frequency of B1 cells that produce IgM antibodies was reduced in AD mice. Altogether, these data indicate that in AD the immune tolerance to Aβ is compromised leading to chronic immune/inflammatory responses against Aβ that are detrimental and cause neuropathology. Graphical Abstract Healthy subjects are tolerant to Aβ and usually react weakly to it resulting the in the production of IgM class of antibodies that are efficient at clearing up self-antigens such as Aβ without causing inflammation. In contrast, Alzheimer's disease patients mount a strong immune response against Aβ probably in an effort to clear up excessive Aβ. There is enhanced production of inflammatory cytokines such as IL-21 as well as an increase in Tfh cells that cause antibody class switching form IgM to IgG. The strong immune response is inefficient at clearing up Aβ and instead exacerbates inflammation that causes AD neuropathology and cognitive dysfunction.

Pre-treatment T-cell subsets associate with fingolimod treatment responsiveness in multiple sclerosis

Biomarkers predicting fingolimod (FTY) treatment response in relapsing-remitting multiple sclerosis (RRMS) are lacking. Here, we performed extensive functional immunophenotyping using multiparametric flow cytometry to examine peripheral immune changes under FTY treatment and explore biomarkers of FTY treatment response. From among 135 RRMS patients who initiated FTY in a 2-year multicentre observational study, 36 were classified as ‘Active’ or ‘Stable’ based on clinical and/or radiological activity on-treatment. Flow cytometric analysis of immune cell subsets was performed on pre- and on-treatment peripheral blood mononuclear cells (PBMC) samples. Decreased absolute counts of B cells and most T-cell subsets were seen on-treatment. Senescent CD8 + T cells, CD56 + T cells, CD56dim natural killer cells, monocytes and dendritic cells were not reduced in number and hence relatively increased in frequency on-treatment. An unbiased multiparametric and traditional manual analysis of T-cell subsets suggested a higher pre-treatment frequency of CD4 + central memory T cells (TCM) in patients who were subsequently Active versus Stable on-treatment. Lower pre-treatment terminally differentiated effector memory (TEMRA) cell frequencies were also seen in the subsequently Active cohort. Together, our data highlight differential effects of FTY on peripheral immune cell subsets and suggest that pre-treatment T-cell subset frequencies may have value in predicting FTY treatment response.

Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer's disease.

Alzheimer's disease is an incurable neurodegenerative disorder in which neuroinflammation has a critical function1. However, little is known about the contribution of the adaptive immune response in Alzheimer's disease2. Here, using integrated analyses of multiple cohorts, we identify peripheral and central adaptive immune changes in Alzheimer's disease. First, we performed mass cytometry of peripheral blood mononuclear cells and discovered an immune signature of Alzheimer's disease that consists of increased numbers of CD8+ T effector memory CD45RA+ (TEMRA) cells. In a second cohort, we found that CD8+ TEMRA cells were negatively associated with cognition. Furthermore, single-cell RNA sequencing revealed that T cell receptor (TCR) signalling was enhanced in these cells. Notably, by using several strategies of single-cell TCR sequencing in a third cohort, we discovered clonally expanded CD8+ TEMRA cells in the cerebrospinal fluid of patients with Alzheimer's disease. Finally, we used machine learning, cloning and peptide screens to demonstrate the specificity of clonally expanded TCRs in the cerebrospinal fluid of patients with Alzheimer's disease to two separate Epstein-Barr virus antigens. These results reveal an adaptive immune response in the blood and cerebrospinal fluid in Alzheimer's disease and provide evidence of clonal, antigen-experienced T cells patrolling the intrathecal space of brains affected by age-related neurodegeneration.

Repeated stress induces a pro-inflammatory state, increases amygdala neuronal and microglial activation, and causes anxiety in adult male rats

A link exists between immune function and psychiatric conditions, particularly depressive and anxiety disorders. Psychological stress is a powerful trigger for these disorders and stress influences immune state. However, the nature of peripheral immune changes after stress conflicts across studies, perhaps due to the focus on few measures of pro-inflammatory or anti-inflammatory processes. The basolateral amygdala (BLA) is critical for emotion, and plays an important role in the effects of stress on anxiety. As such, it may be a primary central nervous system (CNS) mediator for the effects of peripheral immune changes on anxiety after stress. Therefore, this study aimed to delineate the influence of stress on peripheral pro-inflammatory and anti-inflammatory aspects, BLA immune activation, and its impact on BLA neuronal activity. To produce a more encompassing view of peripheral immune changes, this study used a less restrictive approach to categorize and group peripheral immune changes. We found that repeated social defeat stress in adult male Sprague-Dawley rats increased the frequencies of mature T-cells positive for intracellular type 2-like cytokine and serum pro-inflammatory cytokines. Principal component analysis and hierarchical clustering was used to guide grouping of T-cells and cytokines, producing unique profiles. Stress shifted the balance towards a specific set that included mostly type 2-like T-cells and pro-inflammatory cytokines. Within the CNS component, repeated stress caused an increase of activated microglia in the BLA, increased anxiety-like behaviors across several assays, and increased BLA neuronal firing in vivo that was prevented by blockade of microglia activation. Because repeated stress can trigger anxiety states by actions in the BLA, and altered immune function can trigger anxiety, these results suggest that repeated stress may trigger anxiety-like behaviors by inducing a pro-inflammatory state in the periphery and the BLA. These results begin to uncover how stress may recruit the immune system to alter the function of brain regions critical to emotion.

Sex differences in the temporal development of pronociceptive immune responses in the tibia fracture mouse model.

Previously, distinct sex differences were observed in the pronociceptive role of spinal immune cells in neuropathic and inflammatory mouse pain models. Both peripheral and central innate and adaptive immune changes contribute to sensitization in the tibia fracture rodent model of complex regional pain syndrome, and the current study evaluated sex differences in the development of pronociceptive immune responses after fracture. At 4 and 7 weeks after fracture, the analgesic effects of a microglia inhibitor were tested in male and female mice, and polymerase chain reaction was used to measure inflammatory mediator expression in skin and spinal cord. The temporal progression of complex regional pain syndrome-like changes in male and female wild-type and muMT fracture mice lacking B cells and antibodies were evaluated, and IgM antibody deposition measured. Pronociceptive effects of injecting wild-type fracture mouse serum into muMT fracture mice were also tested in both sexes, and the role of sex hormones was evaluated in the postfracture development of pronociceptive immune responses. Long-lasting immune changes developed in the fracture limb and corresponding spinal cord of both male and female mice, including upregulated neuropeptide and cytokine signaling, microglial activation, and pronociceptive autoimmunity. These complex postfracture immune responses were sexually dichotomous and interacted in temporally evolving patterns that generated post-traumatic nociceptive sensitization in both sexes lasting for up to 5 months. Unfortunately, the redundancy and plasticity of these chronic post-traumatic immune responses suggest that clinical interventions focusing on any single specific pronociceptive immune change are likely to be ineffectual.

LncRNA Expression Profiling of Ischemic Stroke During the Transition From the Acute to Subacute Stage.

Ischemic stroke induces profound effects on the peripheral immune system, which may participate the infectious complications. However, the exact function and mechanism of immune reaction in stroke development are not well-elucidated. Recently, several long non-coding RNAs (LncRNAs) are reported to affect ischemic stroke process, especially the immunological response after stroke. In the present study, we investigated the profile of LncRNAs in human ischemic stroke during the transition from the acute to subacute stage, when the state of the peripheral immune system changes from activation to systemic immunosuppression. In this study, we analyzed the RNA-sequencing (RNA-seq) datasets obtained at two time points (24 h and 7 days) from the peripheral blood mononuclear cells of ischemic patients. Vascular risk factor-matched healthy adults were enrolled as controls. A total of 3,009 LncRNAs and 3,982 mRNAs were identified as differentially expressed 24 h after stroke. Furthermore, 2,034 LncRNAs and 1,641 mRNAs were detected to be differentially expressed on day 7. Bioinformatics analyses, including GO, KEGG pathway enrichment analysis, and network analysis, were performed for the identified dysregulated genes. Our study reveals that ischemic stroke can influence the expression of LncRNAs and mRNAs in the peripheral blood at both the acute and subacute stages; the level of LncRNAs in the antigen processing and presentation pathway was clearly upregulated at 24 h and had recovered to normal levels on day 7 after stroke. Moreover, inflammatory mediator regulation of TRP channels and GABAergic synapses were two specifically downregulated pathways on day 7 after stroke. Our findings provide a valuable resource for further study of the role of LncRNAs in peripheral immune system changes following ischemic stroke.

Abstract # 3185 Central immune alterations in a gestational stress animal model of postpartum depression

Postpartum depression (PPD) is a major public health problem that is experienced by15% of new mothers, but its causes remain unclear. Hormonal fluctuations have been posited to be the most important contributor to PPD, although peripheral immune changes have recently been observed in women with PPD. Little is known about neuroimmune alterations in PPD, thus we used an animal model of PPD incorporating gestational stress, a well-known risk factor, and evaluated the maternal neuroimmune system focusing on the medial prefrontal cortex (mPFC), a key mood-regulating brain region. Pregnant rats underwent chronic variable stress from gestation days (GD) 7–20 or were unstressed and then sacrificed at GD21 or postpartum day(P)8. Brain tissue levels IL-1beta, interferon (IFN) gamma, and TNFalpha, and insulin-like growth factor (IGF)1 transcripts, as well as the phagocytosis-related gene transcripts, CD68, integrin alpha M (ITGAM), complement components (C)3 and C1q, were assessed via qPCR. ELISA was performed on blood to assess peripheral cytokine levels. Gestational stress led to increased expression of IL-1B and IFNy in the mPFC at GD21, and increased expression of ITGAM and C1q, which suggests that stress leads to central inflammation as well as microglia-mediated synaptic remodeling. There was no effect of gestational stress on any genes at PD8, nor stress effects on peripheral cytokines. These data suggest that gestational stress impacts the maternal neuroimmune system, which may thereby contribute to PPD.

Anti-α4β1 Integrin Antibodies Attenuated Brain Inflammatory Changes in a Mouse Model of Alzheimer's Disease.

Background: Alzheimer’s disease (AD) is associated with age-associated central nervous sys-tem degeneration and dementia. This decline in the function correlates with deposition of Aβ peptide con-taining plaques and associated reactive gliosis. The inflammatory phenotype of microglia, in particular, is often considered detrimental to cognitive function in AD. In addition to the changes in the CNS, altered immune changes in the periphery have recently been observed in AD suggesting a critical immune-related communication between the periphery and the brain.Objective: We hypothesized that modulating the peripheral immune system may alter the proinflammatory gliosis associated with AD. Therapeutic antibodies against the α4β1 integrin receptor have been used clini-cally to attenuate the ability of various immune cells to adhere to endothelium and migrate into target tis-sues such as the intestines (Crohn’s disease) or brain (multiple sclerosis). We hypothesized that a similar peripheral antibody-based therapy would attenuate gliosis by altering immune cell infiltration or phenotype in peripheral organs and the brain using an APP/PS1 mouse model of Alzheimer’s disease.Method: Littermate control wild-type and APP/PS1 mice were tail vein injected with either saline, isotype control (IgG2b), or an antibody recognizing α4-integrin, anti-CD49d, once a week for 4 consecutive weeks. To understand CNS and peripheral immune changes, brains and spleen were used.Results/Conclusion: Our data suggests that the antibody therapy was able to reduce microgliosis, astro-gliosis, and synaptic changes in the APP/PS1 mice compared to isotype control injections without chang-ing amyloid-β plaque load. Interestingly, both isotype control and antibody therapy also reduced the number of proinflammatory cytokines in the spleen although changes in the brain were less robust. The anti-CD49d and isotype control treatments also reduced CD4 immunoreactivity in the brains, suggesting a possible mechanism for attenuation of inflammation in the brain. This data suggests that it is indeed feasi-ble to alter the immune component of AD brain changes using a clinically feasible strategy of delivering a particular subtype of IgG or epitope selective antibodies that target infiltration of the peripheral immune system.

Peripheral T Cells as a Biomarker for Oxygen-Ion-Radiation-Induced Social Impairments.

Exposure to galactic cosmic rays (GCR) poses an obstacle to successful deep space missions, including missions to the Moon or Mars. Previously, we and others have identified chronic cognitive impairments associated with GCR in rodent model systems. The persistent cognitive loss previously reported is indicative of global changes in different regions of the brain, including the prefrontal cortex and the hippocampus. It has been shown that both of these brain regions are involved in social functions. Here we demonstrate that four months after a single exposure to oxygen ionizing radiation, which is a component of GCR, adult male mice have social memory deficits. Importantly, we identified circulating levels of CD8 T cells as predictors of social behavioral changes. Thus, CD8 T cells could be used as a potential peripheral biomarker. To the best of our knowledge we demonstrate for the first time that GCR-induced impairments in social behavior are directly linked to peripheral immune changes. These results further advance our understanding of the challenges encountered during space exploration.

Abnormalities of age-related T cell senescence in Parkinson\u2019s disease

BackgroundA wealth of evidence implicates both central and peripheral immune changes as contributing to the pathogenesis of Parkinson’s disease (PD). It is critical to better understand this aspect of PD given that it is a tractable target for disease-modifying therapy. Age-related changes are known to occur in the immune system (immunosenescence) and might be of particular relevance in PD given that its prevalence rises with increasing age. We therefore sought to investigate this with respect to T cell replicative senescence, a key immune component of human ageing.MethodsPeripheral blood mononuclear cells were extracted from blood samples from 41 patients with mild PD (Hoehn and Yahr stages 1–2, mean (SD) disease duration 4.3 (1.2) years) and 41 age- and gender-matched controls. Immunophenotyping was performed with flow cytometry using markers of T lymphocyte activation and senescence (CD3, CD4, CD8, HLA-DR, CD38, CD28, CCR7, CD45RA, CD57, CD31). Cytomegalovirus (CMV) serology was measured given its proposed relevance in driving T cell senescence.ResultsMarkers of replicative senescence in the CD8+ population were strikingly reduced in PD cases versus controls (reduced CD57 expression (p = 0.005), reduced percentage of ‘late differentiated’ CD57loCD28hi cells (p = 0.007) and ‘TEMRA’ cells (p = 0.042)), whilst expression of activation markers (CD28) was increased (p = 0.005). This was not driven by differences in CMV seropositivity. No significant changes were observed in the CD4 population.ConclusionsThis study demonstrates for the first time that the peripheral immune profile in PD is distinctly atypical for an older population, with a lack of the CD8+ T cell replicative senescence which characterises normal ageing. This suggests that ‘abnormal’ immune ageing may contribute to the development of PD, and markers of T cell senescence warrant further investigation as potential biomarkers in this condition.