The effect of abatacept on T-cell activation is not long-lived in vivo.

Abatacept, a co-stimulatory blocker comprising the extracellular portion of human CTLA-4 linked to the Fc region of IgG1, is approved for the treatment of rheumatoid arthritis. By impairing the interaction between CD28 on T cells and CD80/CD86 on APCs, its mechanisms of action include the suppression of follicular T helper cells (preventing the breach of self-tolerance in B cells), inhibition of cell cycle progression holding T cells in a state described as 'induced naïve' and reduction in DC conditioning. However, less is known about how long these inhibitory effects might last, which is a critical question for therapeutic use in patients. Herein, employing a murine model of OVA-induced DTH, we demonstrate that the effect of abatacept is short-lived in vivo and that the inhibitory effects diminish markedly when treatment is ceased.

Homicide Manner-of-Death Classification in Arrest-Related Death.

ABSTRACT: Multiple studies have documented various factors that influence or determine forensic pathologist classification of manner of death. There do not appear to be any published studies on manner of death classification specifically regarding arrest-related deaths (ARDs). The goal of this study was to consider a large body of cases of nonfirearm ARDs to analyze the homicide classification with regards to numerous decedent and practitioner (medical examiner/coroner [ME/C]) variables. We analyzed 1145 US autopsy reports from the years 2006-2020, inclusive, and considered decedent variables of age, ethnicity, height, weight, body mass index, toxicology, and mention of a conducted electrical weapon and ME/C influence variables of gender, country region, and year. We found that the homicide classification likelihood increased by a factor of 1.04-1.05 per year, 1.34-1.37 for a female medical examiner, and 1.4-1.5 going from Southern states to Western states. There is an increasing trend for ME/C to label nonfirearm ARDs as homicides in the United States. The homicide classification is more common in Western states and less common in Southern states, and it was more common with a female ME/C.

Improved multimodal prediction of progression from MCI to Alzheimer's disease combining genetics with quantitative brain MRI and cognitive measures.

INTRODUCTION: There is a pressing need for non-invasive, cost-effective tools for early detection of Alzheimer's disease (AD). METHODS: Using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), Cox proportional models were conducted to develop a multimodal hazard score (MHS) combining age, a polygenic hazard score (PHS), brain atrophy, and memory to predict conversion from mild cognitive impairment (MCI) to dementia. Power calculations estimated required clinical trial sample sizes after hypothetical enrichment using the MHS. Cox regression determined predicted age of onset for AD pathology from the PHS. RESULTS: The MHS predicted conversion from MCI to dementia (hazard ratio for 80th versus 20th percentile: 27.03). Models suggest that application of the MHS could reduce clinical trial sample sizes by 67%. The PHS alone predicted age of onset of amyloid and tau. DISCUSSION: The MHS may improve early detection of AD for use in memory clinics or for clinical trial enrichment. HIGHLIGHTS: A multimodal hazard score (MHS) combined age, genetics, brain atrophy, and memory. The MHS predicted time to conversion from mild cognitive impairment to dementia. MHS reduced hypothetical Alzheimer's disease (AD) clinical trial sample sizes by 67%. A polygenic hazard score predicted age of onset of AD neuropathology.

Review: Unravelling the Role of DNA Sensing in Alum Adjuvant Activity.

Public interest in vaccines is at an all-time high following the SARS-CoV-2 global pandemic. Currently, over 6 billion doses of various vaccines are administered globally each year. Most of these vaccines contain Aluminium-based adjuvants (alum), which have been known and used for almost 100 years to enhance vaccine immunogenicity. However, despite the historical use and importance of alum, we still do not have a complete understanding of how alum works to drive vaccine immunogenicity. In this article, we critically review studies investigating the mechanisms of action of alum adjuvants, highlighting some of the misconceptions and controversies within the area. Although we have emerged with a clearer understanding of how this ubiquitous adjuvant works, we have also highlighted some of the outstanding questions in the field. While these may seem mainly of academic interest, developing a more complete understanding of these mechanisms has the potential to rationally modify and improve the immune response generated by alum-adjuvanted vaccines.

Sex differences in Alzheimer's disease: plasma MMP-9 and markers of disease severity.

BACKGROUND: Studies have reported higher plasma matrix metalloproteinase-9 (MMP-9) levels in mild cognitive impairment (MCI) and Alzheimer's disease (AD). Despite evidence that MMP-9 activity and its influence on AD pathophysiology may be modulated by sex hormones, sex differences in the association between MMP-9 and AD biomarkers and cognition have not been explored. METHODS: Our sample included 238 amyloid-ß (Aß)-positive participants with MCI or AD dementia from the Alzheimer's Disease Neuroimaging Initiative (37.4% women, 74.6 ± 7.3 years). We used linear regression models to examine whether sex modified free and total plasma MMP-9 associations with CSF t-tau, p-tau181, and Aß42. We used linear mixed effects models to examine whether sex modified total and free plasma MMP-9 associations with cognition, using longitudinal Mini-Mental Status Examination (MMSE) and Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) data. RESULTS: Total and free MMP-9 levels did not differ by sex, but AD dementia patients had higher total MMP-9 levels than participants with MCI (ß = 0.06 [-0.11 to -0.01], p = 0.031). Sex modified the association of CSF t-tau with total (ß = 128.68 [55.37 to 201.99], p < 0.001) and free MMP-9 (ß = 98.61 [33.61 to 163.62], p = 0.003), whereby higher total and free MMP-9 correlated with higher CSF t-tau in women and lower CSF t-tau in men. Higher free MMP-9 correlated with lower CSF p-tau181 among men (ß = -14.98 [-27.37 to -2.58], p = 0.018), but not women. In participants with MCI, higher free MMP-9 levels were associated with higher CSF Aß42 among men (ß = 26.88 [4.03 to 49.73], p = 0.022) but not women. In the overall sample, higher free and total MMP-9 at baseline predicted worsening MMSE scores in women (ß = -2.10 [-3.97 to -0.27], p = 0.027 and ß = -2.24 [-4.32 to -0.18], p = 0.035) but not men. Higher free MMP-9 correlated with worse ADAS-cog scores (ß = 12.34 [3.02 to 21.65], p = 0.011) in women (ß = 12.34 [3.02 to 21.65], p = 0.011) but not men with AD dementia cross-sectionally but correlated with worsening ADAS-cog scores longitudinally only in men (ß = 8.98 [0.27 to 17.68], p = 0.042). CONCLUSIONS: MMP-9 may have more detrimental effects on AD-related pathological and cognitive changes in women. If replicated, our findings could help uncover potential mechanisms contributing to women's elevated susceptibility to AD.

Orally administered antigen can reduce or exacerbate pathology in an animal model of inflammatory arthritis dependent upon the timing of administration.

Currently, treatments for rheumatoid arthritis (RA) are focussed on management of disease symptoms rather than addressing the cause of disease, which could lead to remission and cure. Central to disease development is the induction of autoimmunity through a breach of self-tolerance. Developing approaches to re-establish antigen specific tolerance is therefore an important emerging area of RA research. A crucial step in this research is to employ appropriate animal models to test prospective antigen specific immunotherapies. In this short communication, we evaluate our previously developed model of antigen specific inflammatory arthritis in which ovalbumin-specific T cell receptor transgenic T cells drive breach of tolerance to endogenous antigens to determine the impact that the timing of therapy administration has upon disease progression. Using antigen feeding to induce tolerance we demonstrate that administration prior to articular challenge results in a reduced disease score as evidenced by pathology and serum antibody responses. By contrast, feeding antigen after initiation of disease had the opposite effect and resulted in the exacerbation of pathology. These preliminary data suggest that the timing of antigen administration may be key to the success of tolerogenic immunotherapies. This has important implications for the timing of potential tolerogenic therapies in patients.

Alzheimer's polygenic hazard score in SuperAgers: SuperGenes or SuperResilience?

Introduction: SuperAgers are individuals over age 80 with superior episodic memory, at a level consistent with individuals 20 to 30 years their junior and who seem to show resistance to age-related neurofibrillary degeneration. Here we examine whether low genetic risk for Alzheimer's disease (AD) contributes to SuperAgers' unusually high episodic memory performance in advanced age. Methods: The AD polygenic hazard score (PHS) was calculated for each SuperAger and cognitively normal participant and compared between groups. Results: A total of 37 SuperAgers (73% female, mean [standard deviation] 82.7 [2.8] years old) and 35 controls (54% female, 83.7 [4.3] years old) were included. There was no significant difference in the AD PHS between SuperAgers and cognitively normal controls. Discussion: Unusually successful cognitive aging cannot be simply explained by low polygenic risk for AD as assessed by common genetic variants. However, rare variants and common protective genetic factors may contribute to resistance or resilience. Highlights: SuperAging cannot be simply explained by low polygenic risk for Alzheimer's disease.Rare variants and common protective genetic factors may contribute to SuperAging.A protective factors polygenic score may uncover mechanisms for SuperAging.

Streptococcus pneumoniae Rapidly Translocate from the Nasopharynx through the Cribriform Plate to Invade the Outer Meninges.

The entry routes and translocation mechanisms of microorganisms or particulate materials into the central nervous system remain obscure We report here that Streptococcus pneumoniae (pneumococcus), or polystyrene microspheres of similar size, appear in the meninges of the dorsal cortex of mice within minutes of inhaled delivery. Recovery of viable bacteria from dissected tissue and fluorescence microscopy show that up to at least 72 h, pneumococci and microspheres were predominantly found in the outer of the two meninges: the pachymeninx. No pneumococci were found in blood or cerebrospinal fluid. Intravital imaging through the skull, aligned with flow cytometry showed recruitment and activation of LysM+ cells in the dorsal pachymeninx at 5 and 10 hours following intranasal infection. Imaging of the cribriform plate suggested that both pneumococci and microspheres entered through the foramina via an inward flow of fluid connecting the nose to the pachymeninx. Our findings bring new insight into the varied mechanisms of pneumococcal invasion of the central nervous system, but they are also pertinent to the delivery of drugs to the brain and the entry of airborne particulate matter into the cranium. IMPORTANCE Using two-photon imaging, we show that pneumococci translocate from the nasopharynx to the dorsal meninges of a mouse in the absence of any bacteria found in blood or cerebrospinal fluid. Strikingly, this takes place within minutes of inhaled delivery of pneumococci, suggesting the existence of an inward flow of fluid connecting the nasopharynx to the meninges, rather than a receptor-mediated mechanism. We also show that this process is size dependent, as microspheres of the same size as pneumococci can translocate along the same pathway, while larger size microspheres cannot. Furthermore, we describe the host response to invasion of the outer meninges. Our study provides a completely new insight into the key initial events that occur during the translocation of pneumococci directly from the nasal cavity to the meninges, with relevance to the development of intranasal drug delivery systems and the investigations of brain damage caused by inhaled air pollutants.

Requirement of preoperative blood typing for cholecystectomy and appendectomy: a systematic review.

PURPOSE: Blood typing, or group and save (G&S) testing, is commonly performed prior to cholecystectomy and appendectomy in many hospitals. In order to determine whether G&S testing is required prior to these procedures, we set out to evaluate the relevant literature and associated rates of perioperative blood transfusion. METHODS: Studies from January 1990 to June 2021 assessing the requirement of preoperative G&S testing for elective or emergency cholecystectomy and appendectomy were retrieved from MEDLINE, EMBASE and CINAHL databases. The search was performed on 6th July 2021 (PROSPERO registration number CRD42021267967). Number of patients, co-morbidities, operation performed, number of patients that underwent preoperative G&S testing, perioperative transfusion rates and financial costs were extracted. RESULTS: We initially screened 194 studies of which 15 retrospective studies, a total of 477,437 patients, specifically met the inclusion criteria. Ten studies reported on cholecystectomy, two studies on appendectomy and three studies included both procedures. Where reported, a total of 177,539/469,342 (37.8%) patients underwent preoperative G&S testing with a perioperative transfusion rate of 2.1% (range 0.0 to 2.1%). The main preoperative risk factors associated with perioperative blood transfusion identified include cardiovascular co-morbidity, coagulopathy, anaemia and haematological malignancy. All 15 studies concluded that routine G&S is not warranted. CONCLUSION: The current evidence suggests that G&S is not necessarily required for all patients undergoing cholecystectomy or appendectomy. Having a targeted G&S approach would reduce delays in elective and emergency lists, reduce the burden on the blood transfusion service and have financial implications.

Sex differences in plasma p-tau181 associations with Alzheimer's disease biomarkers, cognitive decline, and clinical progression.

Studies have shown that women on the Alzheimer's disease (AD) continuum have more pathological tau in the brain and cerebrospinal fluid (CSF), than men. Some studies have found that higher levels of tau biomarkers are more strongly associated with clinical AD, cognitive decline and neurodegeneration in women than in men. Despite major developments in the use of plasma tau phosphorylated at threonine 181 (p-tau181) as an AD biomarker, it is unknown whether these sex differences apply to plasma p-tau181. In 1060 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants (47% women, 73.8 ± 7.6 years old), we examined sex differences in plasma p-tau181 levels and their association with other biomarkers, cognitive decline and incident AD. Linear regressions tested for an effect of sex on plasma p-tau181 levels and for plasma p-tau181 × sex interactions on CSF p-tau181, as well as entorhinal cortex tau, cortical amyloid-ß (Aß) deposition, and brain glucose metabolism, quantified using PET imaging. Linear mixed effects models tested for a sex × baseline plasma p-tau181 interaction on change in cognition over time. Finally, Cox models tested for a sex × plasma p-tau181 interaction on the risk of AD dementia in participants who were free of dementia at baseline. Despite similar plasma p-tau181 levels between sexes, women had lower brain glucose metabolism, greater brain Aß and entorhinal cortex tau deposition, higher CSF p-tau181 and faster cognitive decline in relation to higher baseline plasma p-tau181 levels compared with men. Among Aß positive, dementia-free participants, women had higher rates of incident AD dementia associated with increasing baseline plasma p-tau181 levels, relative to men. Our results suggest that sex may impact the clinical interpretation of plasma p-tau181 concentrations. If replicated, these findings could have important implications for the use of plasma p-tau181 as an accessible AD biomarker and screening tool for preventive and therapeutic clinical trials.

Sex and APOE ɛ4 modify the effect of cardiovascular risk on tau in cognitively normal older adults.

The interaction between APOE ɛ4 and vascular risk factors on cognitive function is stronger in women than in men. These effects may be mediated by the amount of tau pathology in the brain. Therefore, we examined whether APOE ɛ4 and sex modify cross-sectional associations between cardiovascular risk and tau deposition in cognitively normal older adults from the Alzheimer's Disease Neuroimaging Initiative. We calculated the Framingham Heart Study cardiovascular disease risk score for 141 participants (74 women, 47 APOE ɛ4 carriers) with complete medical history data, processed tau-PET data and a Clinical Dementia Rating global score of 0.0 at the time of the tau-PET scan, implying no significant cognitive or functional impairment. We used linear regression models to examine the effects of sex, APOE ɛ4, cardiovascular risk and their interactions on tau deposition in the entorhinal cortex, inferior temporal cortex and a composite meta-region of interest of temporal lobe areas. We found a significant three-way interaction among sex, APOE ɛ4 status and cardiovascular disease risk on tau deposition in the entorhinal cortex (ß = 0.04; 95% CI, 0.01-0.07; P = 0.008), inferior temporal cortex (ß = 0.02; 95% CI, 0.0-0.05; P = 0.029) and meta-region (ß = 0.02; 95% CI, 0.0-0.04; P = 0.042). After stratifying by APOE ɛ4 status to examine interactions between sex and cardiovascular disease risk on tau in APOE ɛ4 carriers and non-carriers, we found a significant two-way interaction between sex and cardiovascular disease risk on tau in the entorhinal cortex (ß = 0.05; 95% CI, 0.02-0.08; P = 0.001), inferior temporal cortex (ß = 0.03; 95% CI, 0.01-0.05; P =0.009) and meta-region (ß = 0.02; 95% CI, 0.01-0.04; P = 0.008) only among APOE ɛ4 carriers. In analyses stratified by sex, higher cardiovascular risk scores were associated with higher levels of tau in the entorhinal cortex (ß = 0.05; 95% CI, 0.02-0.08; P = 0.002), inferior temporal cortex (ß = 0.02; 95% CI, 0.0-0.05; P = 0.023) and meta-region (ß = 0.02; 95% CI, 0.01-0.04; P = 0.013) in female APOE ɛ4 carriers but not in male carriers. Our findings suggest that cognitively normal older women carrying at least one APOE ɛ4 allele, may be particularly vulnerable to the effects of cardiovascular disease risk on early tau deposition.

Dissecting the molecular control of immune cell accumulation in the inflamed joint.

Mechanisms governing entry and exit of immune cells into and out of inflamed joints remain poorly understood. We sought herein to identify the key molecular pathways regulating such migration. Using murine models of inflammation in conjunction with mice expressing a photoconvertible fluorescent protein, we characterized the migration of cells from joints to draining lymph nodes and performed RNA-Seq analysis on isolated cells, identifying genes associated with migration and retention. We further refined the gene list to those specific for joint inflammation. RNA-Seq data revealed pathways and genes previously highlighted as characteristic of rheumatoid arthritis in patient studies, validating the methodology. Focusing on pathways associated with cell migration, adhesion, and movement, we identified genes involved in the retention of immune cells in the inflamed joint, namely junctional adhesion molecule A (JAM-A), and identified a role for such molecules in T cell differentiation in vivo. Thus, using a combination of cell-tracking approaches and murine models of inflammatory arthritis, we identified genes, pathways, and anatomically specific tissue signatures regulating cell migration in a variety of inflamed sites. This skin- and joint-specific data set will be an invaluable resource for the identification of therapeutic targets for arthritis and other inflammatory disorders.

Intranasal insulin modulates cerebrospinal fluid markers of neuroinflammation in mild cognitive impairment and Alzheimer's disease: a randomized trial.

Intranasal insulin (INI) has shown promise as a treatment for Alzheimer's disease (AD) in pilot clinical trials. In a recent phase 2 trial, participants with mild cognitive impairment (MCI) or AD who were treated with INI with one of two delivery devices showed improved cerebral spinal fluid (CSF) biomarker profiles and slower symptom progression compared with placebo. In the cohort which showed benefit, we measured changes in CSF markers of inflammation, immune function and vascular integrity and assessed their relationship with changes in cognition, brain volume, and CSF amyloid and tau concentrations. The insulin-treated group had increased CSF interferon-γ (p = 0.032) and eotaxin (p = 0.049), and reduced interleukin-6 (p = 0.048) over the 12 month trial compared to placebo. Trends were observed for increased CSF macrophage-derived chemokine for the placebo group (p = 0.083), and increased interleukin-2 in the insulin-treated group (p = 0.093). Insulin-treated and placebo groups showed strikingly different patterns of associations between changes in CSF immune/inflammatory/vascular markers and changes in cognition, brain volume, and amyloid and tau concentrations. In summary, INI treatment altered the typical progression of markers of inflammation and immune function seen in AD, suggesting that INI may promote a compensatory immune response associated with therapeutic benefit.

Revealing stromal and lymphoid sources of Col3a1-expression during inflammation using a novel reporter mouse.

One of the earliest signs of dysregulation of the homeostatic process of fibrosis, associated with pathology in chronic conditions such as rheumatoid arthritis, is the overexpression of collagen type III (COL-3). Critically, there is still relatively little known regarding the identity of the cell types expressing the gene encoding COL-3 (Col3a1). Identifying and characterizing Col3a1-expressing cells during the development of fibrosis could reveal new targets for the diagnosis and treatment of fibrosis-related pathologies. As such, a reporter mouse expressing concomitantly Col3a1 and mKate-2, a fluorescent protein, was generated. Using models of footpad inflammation, we demonstrated its effectiveness as a tool to measure the expression of COL-3 during the repair process and provided an initial characterization of some of the stromal and immune cells responsible for Col3a1 expression.

Nanoalum adjuvanted vaccines: small details make a big difference.

Purified vaccine antigens offer important safety and reactogenicity advantages compared with live attenuated or whole killed virus and bacterial vaccines. However, they require the addition of adjuvants to induce the magnitude, duration and quality of immune response required to achieve protective immunity. Aluminium salts have been used as adjuvants in vaccines for almost a century. In the literature, they are often referred to as aluminium-based adjuvants (ABAs), or aluminium salt-containing adjuvants or more simply "alum". All these terms are used to group aluminium suspensions that are very different in terms of atomic composition, size, and shape. They differ also in stability, antigen-adsorption, and antigen-release kinetics. Critically, these parameters also have a profound effect on the character and magnitude of the immune response elicited. Recent findings suggest that, by reducing the size of aluminium from micro to nanometers, a more effective adjuvant is obtained, together with the ability to sterile filter the vaccine product. However, the behaviour of aluminium nanoparticles in vaccine formulations is different from microparticles, requiring specific formulation strategies, as well as a more detailed understanding of how formulation influences the immune response generated. Here we review the current state of art of aluminium nanoparticles as adjuvants, with a focus on their immunobiology, preparation methods, formulation optimisation and stabilisation.

Corrigendum: To the Skin and Beyond: The Immune Response to African Trypanosomes as They Enter and Exit the Vertebrate Host.

[This corrects the article DOI: 10.3389/fimmu.2020.01250.].

Preclinical models of arthritis for studying immunotherapy and immune tolerance.

Increasingly earlier identification of individuals at high risk of rheumatoid arthritis (RA) (eg, with autoantibodies and mild symptoms) improves the feasibility of preventing or curing disease. The use of antigen-specific immunotherapies to reinstate immunological self-tolerance represent a highly attractive strategy due to their potential to induce disease resolution, in contrast to existing approaches that require long-term treatment of underlying symptoms.Preclinical animal models have been used to understand disease mechanisms and to evaluate novel immunotherapeutic approaches. However, models are required to understand critical processes supporting disease development such as the breach of self-tolerance that triggers autoimmunity and the progression from asymptomatic autoimmunity to joint pain and bone loss. These models would also be useful in evaluating the response to treatment in the pre-RA period.This review proposes that focusing on immune processes contributing to initial disease induction rather than end-stage pathological consequences is essential to allow development and evaluation of novel immunotherapies for early intervention. We will describe and critique existing models in arthritis and the broader field of autoimmunity that may fulfil these criteria. We will also identify key gaps in our ability to study these processes in animal models, to highlight where further research should be targeted.

Sex differences in Alzheimer's disease: do differences in tau explain the verbal memory gap?

To determine if sex differences in verbal memory in AD are related to differences in extent or distribution of pathological tau, we studied 275 participants who were amyloid PET positive and carried clinical classifications of normal cognition, mild cognitive impairment (MCI) or dementia, and had tau (AV1451) PET. We compared tau distribution between men and women, and as a function of genetic risk. In MCI we further explored the relationship between quantity and distribution of tau in relation to verbal memory scores. Women had more tau burden overall, but this was driven by sex differences at the MCI stage. There was no significant difference in tau load by APOE e4 status. Within the MCI group the association between tau and performance in verbal memory tasks was stronger in women than men. The topography of the associations between tau and verbal memory also differed in MCI; women demonstrated stronger relationships between tau distribution and verbal memory performance, especially in the left hemisphere. These findings have implications for understanding tau distribution and spread, and in interpretation of verbal memory performance.