IgE, IgE Receptors and Anti-IgE Biologics: Protein Structures and Mechanisms of Action.

The evolution of IgE in mammals added an extra layer of immune protection at body surfaces to provide a rapid and local response against antigens from the environment. The IgE immune response employs potent expulsive and inflammatory forces against local antigen provocation, at the risk of damaging host tissues and causing allergic disease. Two well-known IgE receptors, the high-affinity FcεRI and low-affinity CD23, mediate the activities of IgE. Unlike other known antibody receptors, CD23 also regulates IgE expression, maintaining IgE homeostasis. This mechanism evolved by adapting the function of the complement receptor CD21. Recent insights into the dynamic character of IgE structure, its resultant capacity for allosteric modulation, and the potential for ligand-induced dissociation have revealed previously unappreciated mechanisms for regulation of IgE and IgE complexes. We describe recent research, highlighting structural studies of the IgE network of proteins to analyze the uniquely versatile activities of IgE and anti-IgE biologics.

Quantification approaches for magnetic resonance imaging following intravenous gadolinium injection: A window into brain-wide glymphatic function.

The glymphatic system is a brain-wide network of perivascular pathways along which cerebrospinal fluid and interstitial fluid rapidly exchange, facilitating solute and waste clearance from the brain parenchyma. The characterization of this exchange process in humans has relied primarily upon serial magnetic resonance imaging following intrathecal gadolinium-based contrast agent injection. However, less invasive approaches are needed. Here, we administered a gadolinium-based contrast agent intravenously in eight healthy participants and acquired magnetic resonance imaging scans prior to and 30, 90, 180, and 360 min post contrast injection. Using a region-of-interest approach, we observed that peripheral tissues and blood vessels exhibited high enhancement at 30 min after contrast administration, likely reflecting vascular and peripheral interstitial distribution of the gadolinium-based contrast agent. Ventricular, grey matter and white matter enhancement peaked at 90 min, declining thereafter. Using k-means clustering, we identify distinct distribution volumes reflecting the leptomeningeal perivascular network, superficial grey matter and deep grey/white matter that exhibit a sequential enhancement pattern consistent with parenchymal contrast enhancement via the subarachnoid cerebrospinal fluid compartment. We also outline the importance of correcting for (otherwise automatic) autoscaling of signal intensities, which could potentially lead to misinterpretation of gadolinium-based contrast agent distribution kinetics. In summary, we visualize and quantify delayed tissue enhancement following intravenous administration of gadolinium-based contrast agent in healthy human participants.

White Matter Microstructure of the Cerebellar Peduncles Is Associated with Balance Performance during Sensory Re-Weighting in People with Multiple Sclerosis.

People with multiple sclerosis (PwMS) exhibit impaired balance during different sensory environments and poor cerebellar peduncle microstructure. We aimed to examine associations between microstructures of the superior, middle and inferior cerebellar peduncles (CP) with visual, vestibular, and proprioceptive-based balance in PwMS. Twenty-seven PwMS and twenty-nine healthy controls (HC) underwent MRI and balance assessments. We assessed CP microstructure with radial diffusivity (RD) and fractional anisotropy (FA) and balance with center of pressure-derived measures of path length and root mean square of sway during proprioceptive (C2), visual (C3), and vestibular (C4) balance conditions of the modified clinical test of sensory integration on balance (mCTSIB). PwMS exhibited significantly lower FA (p < 0.001) and greater RD (p < 0.001) across all CP and greater path length (p < 0.05) in the mCTSIB compared with HC. In PwMS, significant associations were detected between inferior CP white matter microstructure and proprioceptive-based balance control (rho = -0.43, p < 0.05) and middle CP white matter microstructure and visual-based balance control (rho = 0.39, p < 0.05). PwMS may rely more on cerebellar-regulated proprioceptive- and visual-based balance control than HC.

The effect of shoe cushioning on gait and balance in females with multiple sclerosis.

Gait and balance deficits are significant concerns for people with multiple sclerosis (MS). Shoe cushioning can influence mobility and balance, but its effect on walking and balance remains unknown in MS. This study aimed to determine how shoe cushioning affects gait and balance in females with MS (FwMS). We hypothesized that extra cushioning would improve gait but reduce balance performance. FwMS performed gait (n = 18) and balance (n = 17) assessments instrumented using inertial sensors in two different shoe conditions: a standard-cushioned and an extra-cushioned shoe. Care was taken to ensure minimal differences between shoe types other than midsole cushioning, but shoe construction was not identical between conditions. Spatiotemporal gait parameters were assessed during a 2-min walk test, while postural sway measures were evaluated using the modified Clinical Test of Sensory Interaction and Balance. In the extra-cushioned shoe, FwMS spent less time in the double support and stance phase with more time in the single support and swing phase. No differences in stride length, gait speed, or elevation at midswing were observed between shoe conditions. Decreased path length, RMS sway, and sway velocity were observed in the extra-cushioned shoe. No differences were observed in the gait cycle's spatial composition between shoe conditions, but FwMS demonstrated improvements in the gait cycle's temporal parameters and postural sway in the extra-cushioned shoe. This may suggest a less cautious walking strategy and improved balance when wearing a shoe with extra cushioning.

Virtual time-to-contact identifies balance deficits better than traditional metrics in people with multiple sclerosis.

Multiple sclerosis (MS) is a neurodegenerative disease that negatively affects the quality of electrical signaling throughout the central nervous system. Although impaired postural control is one of the most common symptoms in people with MS (PwMS), commonly reported metrics such as center of pressure (CoP) path length and velocity have not been great predictors of fall risk. A relatively new metric, known as virtual time-to-contact (VTC), is a measurement that uses the instantaneous position, velocity and acceleration of the CoP, to predict how long it would take the CoP to reach the boundary of the base of support for every data point in a trial. While the VTC metric has shown promising results in PwMS, there are still inconsistencies in how VTC is reported. Thus, the purpose of this work was to compare VTC to commonly reported measures of postural balance control to identify the most appropriate metric(s) for assessing balance impairments unique to PwMS. A group of patients with MS and a group of neurologically healthy controls performed a static balance task with both eyes open and eyes closed. The VTC minimum values (minima) were the best at detecting balance performance differences between conditions and between study groups. In addition, VTC minima was the best at detecting proprioceptive weaknesses in PwMS, assessed via the Romberg ratio. These results suggest that the VTC minima may be better than traditional metrics at detecting balance impairments unique to PwMS as well as proprioceptive deficits within this population.

Setting boundaries: Utilization of time to boundary for objective evaluation of the balance error scoring system.

Subjective evaluations of balance performance, like the modified Balance Error Scoring System (mBESS), are highly popular. Alternatively, quantitative measures may offer additional clarity in identifying balance dysfunction. A novel measure to define balance impairments is time to boundary (TTB), which represents the amount of time available to make corrective postural adjustments prior to the centre of pressure (CoP) reaching the edge of the base of support. The purpose of this investigation was to assess TTB and traditional measures of CoP displacement of young adults performing the mBESS on a BTrackS balance plate. Path length and TTB were calculated in anterior-posterior (AP) and medio-lateral (ML) directions, respectively. AP and ML path lengths were largest in Single stance (109.2 & 118.1 cm, respectively) and smallest in Dual stance (27.1 & 36.4 cm, respectively). The average AP and ML TTBs were higher in Dual (10.67 & 7.27 s, respectively) compared to Single (3.54 & 1.20 s, respectively) or Tandem (10.11 & 1.94 s, respectively) stances, and lower in Single stance compared to Tandem. Given the effect sizes for TTB were greater than those of path length in both directions, TTB more adequately differentiates these stance conditions than path length or subjective scores.

Transcallosal Control of Bilateral Actions.

The corpus callosum is an important neural structure for controlling and coordinating bilateral movements of the upper limbs; however, there remains a substantial lack of knowledge regarding its association with lower limb control. We argue that transcallosal structure is an integral neural mechanism underlying control of the lower limbs and callosal degradation is a key contributor to mobility declines.

Ontogeny of human IgE-expressing B cells and plasma cells.

BACKGROUND: IgE-expressing (IgE+ ) plasma cells (PCs) provide a continuous source of allergen-specific IgE that is central to allergic responses. The extreme sparsity of IgE+ cells in vivo has confined their study almost entirely to mouse models. OBJECTIVE: To characterize the development pathway of human IgE+ PCs and to determine the ontogeny of human IgE+ PCs. METHODS: To generate human IgE+ cells, we cultured tonsil B cells with IL-4 and anti-CD40. Using FACS and RT-PCR, we examined the phenotype of generated IgE+ cells, the capacity of tonsil B-cell subsets to generate IgE+ PCs and the class switching pathways involved. RESULTS: We have identified three phenotypic stages of IgE+ PC development pathway, namely (i) IgE+ germinal centre (GC)-like B cells, (ii) IgE+ PC-like 'plasmablasts' and (iii) IgE+ PCs. The same phenotypic stages were also observed for IgG1+ cells. Total tonsil B cells give rise to IgE+ PCs by direct and sequential switching, whereas the isolated GC B-cell fraction, the main source of IgE+ PCs, generates IgE+ PCs by sequential switching. PC differentiation of IgE+ cells is accompanied by the down-regulation of surface expression of the short form of membrane IgE (mIgES ), which is homologous to mouse mIgE, and the up-regulation of the long form of mIgE (mIgEL ), which is associated with an enhanced B-cell survival and expressed in humans, but not in mice. CONCLUSION: Generation of IgE+ PCs from tonsil GC B cells occurs mainly via sequential switching from IgG. The mIgEL /mIgES ratio may be implicated in survival of IgE+ B cells during PC differentiation and allergic disease.

Low first-trimester PAPP-A in IVF (fresh and frozen-thawed) pregnancies, likely due to a biological cause.

PURPOSE: The purpose of this study is to confirm a difference in the first-trimester screen maternal biochemistry and false-positive rates (FPR) between pregnancies conceived spontaneously and those conceived via assisted reproductive technologies (ART). METHODS: Retrospective analysis of the complete population of women (17,889 pregnancies) who had undergone first-trimester screening between January 2004 and September 2009 at three private ultrasound clinics in Queensland, Australia was used in the study. The age, gestation, method of conception, ultrasound markers, biochemistry markers (PAPP-A, fß-hCG), and type of biochemical analyzer platform (Brahms Kryptor, Immulite 2000) data was collated. Univariate analysis of variance (ANOVA), Spearman's rank nonparametric correlation analysis, and Binary Logistic Regression analysis were used to analyze data. Spontaneous pregnancies were used as controls. Results were considered significant when the p value was less than 0.05. RESULTS: After exclusions, 16,363 singleton pregnancies, including 1543 conceived via ART, were analyzed. Results from the two biochemistry platforms, Brahms Kryptor and Immulite 2000 were significantly different (p < 0.001); thus, the data was divided for analysis purposes. PAPP-A was universally significantly lower in IVF pregnancies compared to spontaneously conceived pregnancies (p < 0.001). Using the Brahms Kryptor platform, ICSI was associated with significantly decreased PAPP-A (p < 0.046), and a significantly increased FPR (p = 0.012). CONCLUSIONS: Consistent with previous studies IVF pregnancies had significantly lower PAPP-A levels supporting the need to appropriately adjust the combined first-trimester screening (cFTS) risk algorithm for IVF conceptions. The Brahms Kryptor and Immulite 2000 platforms are significantly different; however, the universally lower PAPP-A findings support the hypothesis that the lower PAPP-A is due to a biological cause.

One Health approach to controlling a Q fever outbreak on an Australian goat farm.

A recent outbreak of Q fever was linked to an intensive goat and sheep dairy farm in Victoria, Australia, 2012-2014. Seventeen employees and one family member were confirmed with Q fever over a 28-month period, including two culture-positive cases. The outbreak investigation and management involved a One Health approach with representation from human, animal, environmental and public health. Seroprevalence in non-pregnant milking goats was 15% [95% confidence interval (CI) 7-27]; active infection was confirmed by positive quantitative PCR on several animal specimens. Genotyping of Coxiella burnetii DNA obtained from goat and human specimens was identical by two typing methods. A number of farming practices probably contributed to the outbreak, with similar precipitating factors to the Netherlands outbreak, 2007-2012. Compared to workers in a high-efficiency particulate arrestance (HEPA) filtered factory, administrative staff in an unfiltered adjoining office and those regularly handling goats and kids had 5·49 (95% CI 1·29-23·4) and 5·65 (95% CI 1·09-29·3) times the risk of infection, respectively; suggesting factory workers were protected from windborne spread of organisms. Reduction in the incidence of human cases was achieved through an intensive human vaccination programme plus environmental and biosecurity interventions. Subsequent non-occupational acquisition of Q fever in the spouse of an employee, indicates that infection remains endemic in the goat herd, and remains a challenge to manage without source control.

Intrinsic properties of germinal center-derived B cells promote their enhanced class switching to IgE.

BACKGROUND: Research on the origins and development of human IgE-expressing (IgE(+) ) cells is required for understanding the pathogenesis of allergy and asthma. These studies have been thwarted by the rarity of IgE(+) cells in vivo and the low frequency of class switch recombination (CSR) to IgE ex vivo. To determine the main source of IgE(+) cells, we investigated the relation between the phenotypic composition of tonsil B cells and the CSR to IgE ex vivo. METHODS: Human tonsil B cells were analyzed by flow cytometry (FACS) and cultured with IL-4 and anti-CD40 to induce CSR to IgE. Naïve, germinal center (GC), early GC (eGC), and memory tonsil B cells were isolated by FACS, and their capacities for IL-4 and anti-CD40 signaling, cell proliferation, and de novo class switching to IgE were analyzed by RT-PCR and FACS. RESULTS: B cells from different tonsils exhibited varying capacities for CSR to IgE ex vivo. This was correlated with the percentage of eGC B cells in the tonsil at the outset of the culture. Despite relatively poor cell viability, eGC and GC B-cell cultures produced the highest yields of IgE(+) cells compared to naïve and memory B-cell cultures. The main factors accounting for this result were the strength of IL-4R and CD40 signaling and relative rates of cell proliferation. CONCLUSIONS: This study shows that the maturation state of tonsil B cells determines their capacity to undergo class switching to IgE ex vivo, with the GC-derived B cells yielding the highest percentage of IgE(+) cells.

Inhibition of allergen-dependent IgE activity by antibodies of the same specificity but different class.

IgG4 purified from patients undergoing specific allergen immunotherapy inhibits the activities of the serum IgE in in vitro assays and is thought to reduce the symptoms of the disease. However, it is not known whether this is related to an intrinsic property of this subclass or only the allergen specificity. We tested the hypothesis that allergen specificity is the critical determinant for this activity using a panel of antibodies with identical specificity but different subclasses. The different antibodies were all able to inhibit the activity of IgE to the same extent. We demonstrate that specificity is the dominant factor determining the ability of an antibody to block allergen-dependent IgE activity.

Human IgE against the major allergen Bet v 1--defining an epitope with limited cross-reactivity between different PR-10 family proteins.

BACKGROUND: The interaction between IgE and allergen is a key event at the initiation of an allergic response, and its characteristics have substantial effects on the clinical manifestation. Despite this, the molecular details of the interaction between human IgE and the major birch allergen Bet v 1, one of the most potent tree allergens, still remain poorly investigated. OBJECTIVE: To isolate Bet v 1-specific human monoclonal IgE and characterize their interaction with the allergen. METHODS: Recombinant human IgE were isolated from a combinatorial antibody fragment library and their interaction with Bet v 1 assessed using various immunological assays. The structure of one such IgE in the single-chain fragment variable format was determined using X-ray crystallography. RESULTS: We present four novel Bet v 1-specific IgE, for one of which we solve the structure, all with their genetic origin in the IGHV5 germline gene, and demonstrate that they target two non-overlapping epitopes on the surface of Bet v 1, thereby fulfilling the basic criteria for FcεRI cross-linkage. We further define these epitopes and for one epitope pinpoint single amino acid residues important for the interaction with human IgE. This provides a potential explanation, at the molecular level, for the differences in recognition of isoforms of Bet v 1 and other allergens in the PR-10 protein family displayed by IgE targeting this epitope. Finally, we present the first high-resolution structure of a human allergen-specific IgE fragment in the single-chain fragment variable (scFv) format. CONCLUSIONS AND CLINICAL RELEVANCE: We here display the usefulness of allergen-specific human monoclonal IgE as a tool in studies of the crucial molecular interaction taking place at the initiation of an allergic response. Such studies may aid us in development of better diagnostic tools and guide us in the development of new therapeutic compounds.

Non-O1, non-O139 Vibrio cholerae bacteraemia in an Australian population.

This retrospective case series identifies the largest cohort of non-O1, non-O139 Vibrio cholerae bacteraemia in an Australian population from 2000 to 2013. We examine the risk factors, epidemiology, clinical presentations and mortality of non-O1, non-O139 V. cholerae bacteraemia in Victoria and compare them with published cases in the literature. This case series highlights the pathogenic potential of non-O1, non-O139 V. cholerae and identifies possible associations with host (underlying chronic liver disease and malignancy) and environmental factors (contaminated water supply and raw seafood). Clinicians should be aware of the morbidity and mortality associated with invasive non-O1, non-O139 V. cholerae infections, particularly in immunocompromised patients.

A static posturography guide to implementing time-to-boundary.

The emergence of time-to-boundary provides an advanced representation of the spatiotemporal characteristics of postural control through the estimation of the time required for the center of pressure to reach the boundary of the base of support. Time-to-boundary has demonstrated its utility in several healthy and clinical adoptions; however, unknown inconsistencies among studies exist. Text and graphical representations understandably highlight idealistic standards, but new investigators to this measure are forced to wade through the same potential pitfalls that others have addressed, but the field has neglected to concatenate. The purpose of this communication is to share recent methodological advancements made to enhance time-to-boundary and describe the components of the time-to-boundary code that is being made publicly accessible for the first time. We anticipate future researchers who wish to apply this methodology to their data processing toolbox could utilize our script in full, with any deviations in potential future developments noted in clear fashion. Historically, researchers (including ourselves) have had to interpret text-based descriptions of the existing literature into quantitative steps in a computational mathematics script. In contrast to fixed process measures that do not require investigator input (e.g., path length), time-to-boundary poses two distinct but connected challenges to investigators. The coding process itself can be a hurdle for novices or practitioners. Second, transferring logical considerations such as robust, objective event detection routines must be defended in the review process. This comprehensive guide to time-to-boundary, as used in our applications, should enhance adoption and advance the comprehension of postural control.

The risk of cognitive decline and dementia in older adults diagnosed with COVID-19: A systematic review and meta-analysis.

BACKGROUND: Cognitive impairment can be caused by infections with various pathogens, including SARS-CoV-2. Research has yet to determine the true incidence and course of cognitive impairment in older adults following COVID-19. Furthermore, research has theorised that COVID-19 is associated with dementia progression and diagnosis but this association has yet to be fully described. METHODS: A systematic review was registered in Prospero and conducted on the databases PubMed, Embase, Ovid, CENTRAL and Cochrane Library. Studies reporting cognitive impairment and dementia outcomes in post-acute and post-COVID-19 patients aged ≥65 years, and which included control data, were included in this review. RESULTS: 15,124 articles were identified by the search strategy. After eliminating duplicate titles and completing title, abstracts and full-text review, 18 studies were included comprising of 412,957 patients with COVID-19 (46.63% male) and 411,929 patients without COVID-19 (46.59% male). The overall mean Montreal Cognitive Assessment (MoCA) score in COVID-19 patients was 23.34 out of 30 (95% CI [22.24, 24.43]). indicating cognitive impairment. The overall proportion of patients identified as having new onset cognitive impairment was 65% (95% CI [44, 81]). Subgroup analyses indicated that time since infection significantly improves overall MoCA score and reduces proportion of patients with cognitive impairment. CONCLUSION: This study indicates that cognitive impairment may be an important sequela of COVID-19. Further research with adequate sample sizes is warranted regarding COVID-19's association with new-onset dementia and dementia progression, and the effect of repeat infections. There is a need for development of diagnostic and management protocols for COVID-19 patients with cognitive impairment.

Distinct spatial landscapes in clear-cell renal cell carcinoma as revealed by whole transcriptome analysis.

Background: Clear-cell renal cell carcinoma (ccRCC) is the most common and aggressive form of renal cancer and a paradigm of inter- and intratumor heterogeneity. We carried out an exploratory digital spatial profiling of the tumor interior and periphery of two ccRCC tumor specimens and mapped spatially the molecular and cellular composition of their tumor microenvironment and ecosystem. Materials and methods: Digital spatial profiling of the whole transcriptome of 19 regions of interest (ROIs) was carried out from two selected highly immunogenic stage pT3a/grade 3 (G3) and stage pT3a/grade 4 (G4) ccRCC. A total of 9-10 ROIs were selected from distinct areas from each tumor, including tumor interior and tumor periphery, and differences in gene expression were analyzed by RNA sequencing, pathway enrichment analysis, and cell deconvolution. Results: The distinct areas from the two locally advanced tumors displayed unique gene expression spatial patterns defining distinct biological pathways. Dimensional reduction analysis showed that the G3 ccRCC, compared to the G4 ccRCC, correlated with more variability between regions from the tumor interior and tumor periphery. Cell deconvolution analysis illustrated higher abundance of immune cells, including macrophages, myeloid dendritic cells, and CD4 T cells, and lower abundance of regulatory T cells in the tumor periphery compared to the tumor interior. Conclusions: Transcriptome spatial profiling revealed high inter- and intratumor heterogeneity in the analyzed tumors and provided information with potential clinical utility. This included the finding of less intratumor heterogeneity and more tumor-infiltrated T cells in the ccRCC tumor specimen with a higher grade.

Dynamic changes in perivascular space morphology predict signs of spaceflight-associated neuro-ocular syndrome in bed rest.

During long-duration spaceflight, astronauts experience headward fluid shifts and expansion of the cerebral perivascular spaces (PVS). A major limitation to our understanding of the changes in brain structure and physiology induced by spaceflight stems from the logistical difficulties of studying astronauts. The current study aimed to determine whether PVS changes also occur on Earth with the spaceflight analog head-down tilt bed rest (HDBR). We examined how the number and morphology of magnetic resonance imaging-visible PVS (MV-PVS) are affected by HDBR with and without elevated carbon dioxide (CO2). These environments mimic the headward fluid shifts, body unloading, and elevated CO2 observed aboard the International Space Station. Additionally, we sought to understand how changes in MV-PVS are associated with signs of Spaceflight Associated Neuro-ocular Syndrome (SANS), ocular structural alterations that can occur with spaceflight. Participants were separated into two bed rest campaigns: HDBR (60 days) and HDBR + CO2 (30 days with elevated ambient CO2). Both groups completed multiple magnetic resonance image acquisitions before, during, and post-bed rest. We found that at the group level, neither spaceflight analog affected MV-PVS quantity or morphology. However, when taking into account SANS status, persons exhibiting signs of SANS showed little or no MV-PVS changes, whereas their No-SANS counterparts showed MV-PVS morphological changes during the HDBR + CO2 campaign. These findings highlight spaceflight analogs as models for inducing changes in MV-PVS and implicate MV-PVS dynamic compliance as a mechanism underlying SANS. These findings may lead to countermeasures to mitigate health risks associated with human spaceflight.

Good times, bad times? An evaluation of event detection strategies in time to boundary postural assessments.

Time-to-boundary (TtB) is a popular balance metric that identifies minimum reaction times available to correct balance challenges during quiet standing. Minimum event criteria is a critical methodological consideration to determine physiologically relevant TtB outcomes yet selection methodology appears inconsistent and/or vaguely defined across studies. This study aimed to identify a robust, objective methodology to select meaningful TtB outcomes. Ninety-seven healthy adults stood quietly on a force platform with eyes open and feet together. Anterior-posterior (AP) and medial-lateral (ML) center-of-pressure data from 150 s were utilized to compute a TtB series. The MATLAB findpeaks function identified minima with and without a time delay following selected events and/or a vertical axis threshold. An individualized time delay excluded excessively large values that hold no clinically relevant information, and this effect was enhanced by a vertical threshold at 22 s. The absolute minimum TtB was unaffected by any findpeaks criteria. The recommendations implicated by these results will help improve clarity and consistency among TtB studies, thereby enhancing the applicability of clinical findings.