Humoral immunity is generated and maintained by antigen-specific antibodies that counter infectious pathogens. Plasma cells are the major producers of antibodies during and after infections, and each ...plasma cell produces some thousands of antibody molecules per second. This magnitude of secretion requires enormous quantities of amino acids and glycosylation sugars to properly build and fold antibodies, biosynthetic substrates to fuel endoplasmic reticulum (ER) biogenesis, and additional carbon sources to generate energy. Many of these processes are likely to be linked, thereby affording possibilities to improve vaccine design and to develop new therapies for autoimmunity. We review here aspects of plasma cell biology with an emphasis on recent studies and the relationships between intermediary metabolism, antibody production, and lifespan.
Plasma cells secrete enormous quantities of antibodies and play crucial roles in humoral immunity and autoimmunity. This secretory activity underlies very specific metabolic requirements in this cell type.
As B cells differentiate into plasma cells, marked changes in nutrient uptake and intermediary metabolism promote antibody synthesis and expansion of the ER.
Some of the same substrates used for antibody synthesis and ER biogenesis are also used to generate energy and prevent plasma cell apoptosis. Differences in nutrient uptake thus correlate with plasma cell lifespan and antibody secretion rates.
Expansion of the secretory apparatus in plasma cells triggers compensatory stress responses. Potential links between intermediary metabolism, ER stress, and plasma cell lifespan are starting to emerge.
Generation of CD8+ memory T cells requires metabolic reprogramming that is characterized by enhanced mitochondrial fatty-acid oxidation (FAO). However, where the fatty acids (FA) that fuel this ...process come from remains unclear. While CD8+ memory T cells engage FAO to a greater extent, we found that they acquired substantially fewer long-chain FA from their external environment than CD8+ effector T (Teff) cells. Rather than using extracellular FA directly, memory T cells used extracellular glucose to support FAO and oxidative phosphorylation (OXPHOS), suggesting that lipids must be synthesized to generate the substrates needed for FAO. We have demonstrated that memory T cells rely on cell intrinsic expression of the lysosomal hydrolase LAL (lysosomal acid lipase) to mobilize FA for FAO and memory T cell development. Our observations link LAL to metabolic reprogramming in lymphocytes and show that cell intrinsic lipolysis is deterministic for memory T cell fate.
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•Unlike Teff cells, memory T cells do not acquire substantial amounts of long-chain FA•Glucose supports mitochondrial FAO and OXPHOS in memory T cells•Memory T cells use LAL-mediated cell-intrinsic lipolysis to mobilize FA for FAO•T cell-intrinsic lysosomal lipolysis is important for memory T cell development
CD8+ memory T cells engage fatty-acid oxidation (FAO); however, the source of fatty acids that fuel FAO is unclear. O’Sullivan et al. show that memory T cells rely on glucose, and cell-intrinsic lipolysis to mobilize substrates, for FAO.
The FOXO3 and FOXM1 forkhead box transcription factors, functioning downstream of the essential PI3K-Akt, Ras-ERK and JNK/p38MAPK signalling cascades, are crucial for cell proliferation, ...differentiation, cell survival, senescence, DNA damage repair and cell cycle control. The development of resistance to both conventional and newly emerged molecularly targeted therapies is a major challenge confronting current cancer treatment in the clinic. Intriguingly, the mechanisms of resistance to ‘classical’ cytotoxic chemotherapeutics and to molecularly targeted therapies are invariably linked to deregulated signalling through the FOXO3 and FOXM1 transcription factors. This is owing to the involvement of FOXO3 and FOXM1 in the regulation of genes linked to crucial drug action-related cellular processes, including stem cell renewal, DNA repair, cell survival, drug efflux, and deregulated mitosis. A better understanding of the mechanisms regulating the FOXO3-FOXM1 axis, as well as their downstream transcriptional targets and functions, may render these proteins reliable and early diagnostic/prognostic factors as well as crucial therapeutic targets for cancer treatment and importantly, for overcoming chemotherapeutic drug resistance.
Durable antibody production after vaccination or infection is mediated by long-lived plasma cells (LLPCs). Pathways that specifically allow LLPCs to persist remain unknown. Through bioenergetic ...profiling, we found that human and mouse LLPCs could robustly engage pyruvate-dependent respiration, whereas their short-lived counterparts could not. LLPCs took up more glucose than did short-lived plasma cells (SLPCs) in vivo, and this glucose was essential for the generation of pyruvate. Glucose was primarily used to glycosylate antibodies, but glycolysis could be promoted by stimuli such as low ATP levels and the resultant pyruvate used for respiration by LLPCs. Deletion of Mpc2, which encodes an essential component of the mitochondrial pyruvate carrier, led to a progressive loss of LLPCs and of vaccine-specific antibodies in vivo. Thus, glucose uptake and mitochondrial pyruvate import prevent bioenergetic crises and allow LLPCs to persist. Immunizations that maximize these plasma cell metabolic properties might thus provide enduring antibody-mediated immunity.
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•LLPCs import more glucose than do short-lived plasma cells (SLPCs)•LLPCs primarily use glucose to glycosylate antibodies•Under metabolic stress, LLPCs but not SLPCs divert glucose to form pyruvate•Genetic ablation of mitochondrial pyruvate import shortens the lifespan of LLPCs
Durable antibody production after vaccination or infection is mediated by long-lived plasma cells (LLPCs), but specific pathways that allow LLPC persistence are unknown. Bhattacharya and colleagues show that LLPCs import and use glucose for antibody glycosylation, but in times of metabolic stress, they divert glucose to generate pyruvate for survival.
Stem cell therapies for nervous system disorders are hindered by a lack of accessible autologous sources of neural stem cells (NSCs). In this study, neural crest-derived Schwann cells are found to ...populate nerve fiber bundles (NFBs) residing in mouse and human subcutaneous adipose tissue (SAT). NFBs containing Schwann cells were harvested from mouse and human SAT and cultured in vitro. During in vitro culture, SAT-derived Schwann cells remodeled NFBs to form neurospheres and exhibited neurogenic differentiation potential. Transcriptional profiling determined that the acquisition of these NSC properties can be attributed to dedifferentiation processes in cultured Schwann cells. The emerging population of cells were termed SAT-NSCs because of their considerably distinct gene expression profile, cell markers, and differentiation potential compared to endogenous Schwann cells existing in vivo. SAT-NSCs successfully engrafted to the gastrointestinal tract of mice, migrated longitudinally and circumferentially within the muscularis, differentiated into neurons and glia, and exhibited neurochemical coding and calcium signaling properties consistent with an enteric neuronal phenotype. These cells rescued functional deficits associated with colonic aganglionosis and gastroparesis, indicating their therapeutic potential as a cell therapy for gastrointestinal dysmotility. SAT can be harvested easily and offers unprecedented accessibility for the derivation of autologous NSCs from adult tissues. Evidence from this study indicates that SAT-NSCs are not derived from mesenchymal stem cells and instead originate from Schwann cells within NFBs. Our data describe efficient isolation procedures for mouse and human SAT-NSCs and suggest that these cells have potential for therapeutic applications in gastrointestinal motility disorders.
Foot orthoses are widely used in runners with pronated feet, who are characterized with large forefoot abduction and arch deformation during gait. However, the relationship between the amount of ...forefoot and arch orthotic correction and the alterations in foot biomechanics remains unclear.
This study aimed to determine dose-response effects of foot orthoses with forefoot wedge and arch support components on the center of pressure (COP) trajectories and pressure distribution during running in symptomatic pronated feet.
Fifteen recreational runners participated in this study. A pressure plate was used to measure plantar pressures during running with control shoe only and ten foot orthoses, varying in forefoot wedges (5 levels) and arch supports (2 levels). The COP trajectory across the entire stance phase was compared between orthotic and control conditions using one-dimensional statistical parametric mapping. The differences in the force-time integral (FTI) and temporal variables were explored between conditions using repeated measures ANOVAs. The main effect of the two orthotic components and their interaction on tested variables were examined using two-way ANOVAs.
A forefoot wedge, whether laterally or medially located, shifted the COP trajectory laterally during some subphases of running (p < 0.05), while using an arch support only had minimal effect on the COP. Almost all orthoses reduced the FTI on the 2nd metatarsal and medial heel, and only medial forefoot wedges reduced the FTI on the hallux. There was a linear effect of forefoot wedges on the medial-lateral COP displacements during the propulsion phase, but no interactions were found between two orthotic components.
These findings suggest that forefoot orthotic components rather than arch supports are effective in altering forefoot dynamics in runners with pronated feet. This study could have implications for foot orthotic prescription and running-related injury prevention for individuals with pronated feet.
•Forefoot wedges shifted the COP laterally during running.•Medial forefoot wedges reduced the plantar loading on the hallux.•Forefoot wedges had a linear effect on the COP during the propulsion phase.•Arch supports had minimal effects on the COP trajectory.•There was no interaction between forefoot wedges and arch supports on the COP.
The highly cross-linked thermosetting polymers used as adhesives and as the matrices of fibre composites for the construction of lightweight vehicles are very brittle, and finding effective ...toughening solutions for such engineering applications is a long-standing problem. An anhydride-cured thermosetting epoxy polymer has been modified by the addition of different wt% of silica nanoparticles, core–shell rubber particles and hybrids with equal wt% of both. The fracture energy was measured at ambient and low temperature (− 40 °C and − 80 °C) to understand the brittle fracture behaviour. The fracture and toughening mechanisms were identified by scanning electron microscopy of the fracture surfaces. Analytical models were used to predict the modulus and fracture energy; the predictions agreed very well with the measured values. Toughening using silica nanoparticles is especially efficient at low particle contents. This shows how epoxies can be toughened successfully for use in industrial and transport applications.
The present exploratory cross-sectional case-control study sought to develop a reliable and scalable screening tool for autism using a social robot. The robot HUMANE, installed with computer vision ...and linked with recognition technology, detected the direction of eye gaze of children. Children aged 3-8 (M = 5.52; N = 199) participated, 87 of whom had been confirmed with autism, 55 of whom were suspected to have autism, and 57 of whom were not considered to cause any concern for having autism. Before a session, a human experimenter instructed HUMANE to narrate a story to a child. HUMANE prompted the child to return his/her eye gaze to the robot if the child looked away, and praised the child when it re-established its eye gaze quickly after a prompt. The reliability of eye gaze detection was checked across all pairs of human raters and HUMANE and reached 0.90, indicating excellent interrater agreement. Using the pre-specified reference standard (Autism Spectrum Quotient), the sensitivity and specificity of the index tests (i.e., the number of robot prompts and duration of inattentiveness) reached 0.88 or above and the Diagnostic Odds Ratios were beyond 190. These results show that social robots may detect atypical eye patterns, suggesting a potential future for screening autism using social robots.
To identify early indications of waning antibody levels to the spike protein (S-antibody) after complete two-dose vaccination, we did a cross-sectional analysis of fully vaccinated adults (aged ≥18 ...years) who submitted capillary blood samples for Virus Watch, a longitudinal community cohort study in England and Wales.4 The study received ethical approval from the Hampstead NHS Health Research Authority Ethics Committee (20/HRA/2320). Sera were tested using Elecsys Anti-SARS-CoV-2 S and N electro-chemiluminescent immunoassays (Roche Diagnostics, Basel, Switzerland); the S assay targets total antibodies to the S1 subunit of the spike protein (range 0·4–25 000 units per mL U/mL), whereas the N assay targets total antibodies to the full-length nucleocapsid protein, which we took as a proxy for previous SARS-CoV-2 infection (specificity 99·8% 99·3–100).5 Serological results were linked with demographic and clinical information collected at enrolment and with weekly self-reported vaccination status. 605 adults submitted a valid sample on June 14–15, 2021. In the context of recent advice in support of booster vaccinations from the UK's Joint Committee on Vaccination and Immunisation,13 and given the potentially rapid S-antibody decline suggested by these data, heterologous regimens, which preliminary data suggest elicit stronger antibody and T-cell responses,14,15 might provide more durable immunity and greater protection against emerging variants.
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