Central tolerance shapes the neutralizing B cell repertoire against a persisting virus in its natural host.

Viral mimicry of host cell structures has been postulated to curtail the B cell receptor (BCR) repertoire against persisting viruses through tolerance mechanisms. This concept awaits, however, experimental testing in a setting of natural virus-host relationship. We engineered mouse models expressing a monoclonal BCR specific for the envelope glycoprotein of lymphocytic choriomeningitis virus (LCMV), a naturally persisting mouse pathogen. When the heavy chain of the LCMV-neutralizing antibody KL25 was paired with its unmutated ancestor light chain, most B cells underwent receptor editing, a behavior reminiscent of autoreactive clones. In contrast, monoclonal B cells expressing the same heavy chain in conjunction with the hypermutated KL25 light chain did not undergo receptor editing but exhibited low levels of surface IgM, suggesting that light chain hypermutation had lessened KL25 autoreactivity. Upon viral challenge, these IgMlow cells were not anergic but up-regulated IgM, participated in germinal center reactions, produced antiviral antibodies, and underwent immunoglobulin class switch as well as further affinity maturation. These studies on a persisting virus in its natural host species suggest that central tolerance mechanisms prune the protective antiviral B cell repertoire.

Tract- and gray matter- based spatial statistics show white matter and gray matter microstructural differences in autistic males.

Background: Autism spectrum disorder (ASD) is a neurodevelopmental condition commonly studied in the context of early childhood. As ASD is a life-long condition, understanding the characteristics of brain microstructure from adolescence into adulthood and associations to clinical features is critical for improving outcomes across the lifespan. In the current work, we utilized Tract Based Spatial Statistics (TBSS) and Gray Matter Based Spatial Statistics (GBSS) to examine the white matter (WM) and gray matter (GM) microstructure in neurotypical (NT) and autistic males. Methods: Multi-shell diffusion MRI was acquired from 78 autistic and 81 NT males (12-to-46-years) and fit to the DTI and NODDI diffusion models. TBSS and GBSS were performed to analyze WM and GM microstructure, respectively. General linear models were used to investigate group and age-related group differences. Within the ASD group, relationships between WM and GM microstructure and measures of autistic symptoms were investigated. Results: All dMRI measures were significantly associated with age across WM and GM. Significant group differences were observed across WM and GM. No significant age-by-group interactions were detected. Within the ASD group, positive relationships with WM microstructure were observed with ADOS-2 Calibrated Severity Scores. Conclusion: Using TBSS and GBSS our findings provide new insights into group differences of WM and GM microstructure in autistic males from adolescence into adulthood. Detection of microstructural differences across the lifespan as well as their relationship to the level of autistic symptoms will deepen to our understanding of brain-behavior relationships of ASD and may aid in the improvement of intervention options for autistic adults.

Organizational Health Literacy as a Tool for Health Equity: Application in a High-Risk Infant Follow-Up Program.

BACKGROUND: Healthy People 2030 emphasizes personal health literacy (individual skills) and organizational health literacy-the degree to which organizations equitably enable individuals to find, understand, and use information and services to inform health-related decisions and actions for themselves and others. However, research on the latter is in the early stages. METHODS: This study describes an organizational health literacy assessment in a U.S. urban academic children's hospital. A variety of evidence-based health literacy assessments were used to assess patient information materials and the environment, including institutional practices, navigation, culture and language, and communication. Trained interviewers and analysts reached consensus for all assessments. RESULTS: Information Items: SMOG scores (n = 9) ranged from 7th- to 14th-grade reading level (average = 11.3). PEMAT-P scores (n = 9) ranged from 43.8% to 93.8% understandability and 0% to 80% actionability. CDC CCI scores (literacy demand) (n = 6) ranged from 18.2% to 58.8% (≥90% = excellent). SAM scores (suitability) (n = 6) fell in the "adequate" range (43.2-58.3%). The PMOSE/IKIRSCH scores (complexity) (n = 3) noted low-moderate difficulty. Apter's Hierarchy (n = 4) revealed three numeracy domains (50% = descriptive purposes and decision-making, 100% = interpreting information). Organization-level: Walking interviews highlighted organizational facilitators and barriers related to the pre-visit and visit environments. HLE2 domain scores ranged from 52% to 68%. CONCLUSIONS: Organizational health literacy demands far outweigh the average literacy skills of adults in the U.S. (patients and staff). Findings can be used to hone quality improvement and other processes to focus on structural solutions to increase health equity.

T-cell-B-cell collaboration in the lung.

Collaboration between T and B cells in secondary lymphoid organs is a crucial component of adaptive immunity, but lymphocytes also persist in other tissues. Recent studies have examined T-cell-B-cell interactions in nonlymphoid tissues such as the lung. CD4+ T- resident helper cells (TRH) remain in the lung after influenza infection and support both resident CD8 T cells and B cells. Multiple lung-resident B-cell subsets (B-resident memory (BRM)) that exhibit spatial and phenotypic diversity have also been described. Though not generated by all types of infection, inducible bronchus-associated lymphoid tissue offers a logical place for T and B cells to interact. Perturbations to BRM and TRH cells elicit effects specific to Immunoglobulin A (IgA) production, an antibody isotype with privileged access to mucosa. Understanding the interplay of lymphocytes in mucosal tissues, which can be insulated from systemic immune responses, may improve the design of future vaccines and therapies.

Abundance and Dynamics of Small Mammals in New Zealand: Sequential Invasions into an Island Ecosystem Like No Other.

New Zealand had no people or four-footed mammals of any size until it was colonised by Polynesian voyagers and Pacific rats in c. 1280 AD. Between 1769 and 1920 AD, Europeans brought three more species of commensal rats and mice, and three predatory mustelids, plus rabbits, house cats hedgehogs and Australian brushtail possums. All have in turn invaded the whole country and many offshore islands in huge abundance, at least initially. Three species are now reduced to remnant populations, but the other eight remain widely distributed. They comprise an artificial but interacting and fully functional bottom-up predator-prey system, responding at all levels to interspecific competition, habitat quality and periodic resource pulsing.

Magnesium sensing via LFA-1 regulates CD8+ T cell effector function.

The relevance of extracellular magnesium in cellular immunity remains largely unknown. Here, we show that the co-stimulatory cell-surface molecule LFA-1 requires magnesium to adopt its active conformation on CD8+ T cells, thereby augmenting calcium flux, signal transduction, metabolic reprogramming, immune synapse formation, and, as a consequence, specific cytotoxicity. Accordingly, magnesium-sufficiency sensed via LFA-1 translated to the superior performance of pathogen- and tumor-specific T cells, enhanced effectiveness of bi-specific T cell engaging antibodies, and improved CAR T cell function. Clinically, low serum magnesium levels were associated with more rapid disease progression and shorter overall survival in CAR T cell and immune checkpoint antibody-treated patients. LFA-1 thus directly incorporates information on the composition of the microenvironment as a determinant of outside-in signaling activity. These findings conceptually link co-stimulation and nutrient sensing and point to the magnesium-LFA-1 axis as a therapeutically amenable biologic system.

Longitudinal Stability of Intellectual Functioning in Autism Spectrum Disorder: From Age 3 Through Mid-adulthood.

Intelligence (IQ) scores are used in educational and vocational planning for individuals with autism spectrum disorder (ASD) yet little is known about the stability of IQ throughout development. We examined longitudinal age-related IQ stability in 119 individuals with ASD (3-36 years of age at first visit) and 128 typically developing controls. Intelligence measures were collected over a 20-year period. In ASD, Full Scale (FSIQ) and Verbal (VIQ) Intelligence started lower in childhood and increased at a greater rate with age relative to the control group. By early adulthood, VIQ and working memory stabilized, whereas nonverbal and perceptual scores continued to change. Our results suggest that in individuals with ASD, IQ estimates may be dynamic in childhood and young adulthood.

Formative online multiple-choice tests in nurse education: An integrative review.

AIM: The aim of this integrative review is to explore how formative online multiple-choice tests used in nurse education promote self-regulated learning and report on pedagogies that support their design. BACKGROUND: Online multiple-choice tests are widely used as learning and formative assessment tools in a range of educational contexts. However, little is known about how these tools are used to promote patterns of learner self-regulation. It is important that nurses and nursing students develop the capability to self-regulate learning to be effective lifelong learners and navigate complex and unfamiliar practice environments. DESIGN: A five-stage approach guided this integrative review: problem identification, literature search, data evaluation, data analysis and presentation. METHOD: A systematic search of ERIC, Web of Science, Ovid Medline, Scopus, PubMed, Embase and CINAHL was conducted in February 2021. Seventeen peer-reviewed papers were identified that discussed formative online multiple-choice tests in nurse education. Purposive sampling and ancestry searching identified an additional paper. Articles were analysed and sorted into themes of outcomes (presented as components of self-regulated learning theory) and pedagogy. RESULTS: Formative online multiple-choice tests are used with good effect in nurse education as measured by knowledge gain and exam performance, increased confidence and learner satisfaction. There was no literature that explored metacognitive outcomes and minimal literature considered behavioural outcomes. Pedagogy supporting the implementation of multiple-choice tests was lacking in most articles. CONCLUSIONS: Formative online multiple-choice tests are widely used with good effect in nurse education. However, opportunities for further research on how these tools can encourage metacognition and self-regulatory behaviours is warranted.

Vaccine-elicited CD4 T cells prevent the deletion of antiviral B cells in chronic infection.

Chronic viral infections subvert protective B cell immunity. An early type I interferon (IFN-I)-driven bias to short-lived plasmablast differentiation leads to clonal deletion, so-called "decimation," of antiviral memory B cells. Therefore, prophylactic countermeasures against decimation remain an unmet need. We show that vaccination-induced CD4 T cells prevented the decimation of naïve and memory B cells in chronically lymphocytic choriomeningitis virus (LCMV)-infected mice. Although these B cell responses were largely T independent when IFN-I was blocked, preexisting T help assured their sustainability under conditions of IFN-I-driven inflammation by instructing a germinal center B cell transcriptional program. Prevention of decimation depended on T cell-intrinsic Bcl6 and Tfh progeny formation. Antigen presentation by B cells, interactions with antigen-specific T helper cells, and costimulation by CD40 and ICOS were also required. Importantly, B cell-mediated virus control averted Th1-driven immunopathology in LCMV-challenged animals with preexisting CD4 T cell immunity. Our findings show that vaccination-induced Tfh cells represent a cornerstone of effective B cell immunity to chronic virus challenge, pointing the way toward more effective B cell-based vaccination against persistent viral diseases.

Randomized controlled trial of stress reduction with meditation and health education in black men and women with high normal and normal blood pressure.

BACKGROUND: Black men and women suffer from disparities in morbidity and mortality from hypertension, cardiovascular disease, and currently, COVID-19. These conditions are associated with social determinants of health and psychosocial stress. While previous trials demonstrated that stress reduction with meditation lowered BP in the grade I range in Black adults, there is a paucity of evidence for high normal and normal BP. OBJECTIVE: This randomized controlled trial was conducted to evaluate the effect of stress reduction with the Transcendental Meditation (TM) technique in Black adults with high normal BP and normal BP using international classifications. METHODS: A total of 304 Black men and women with high normal (130-139/85-89 mm Hg) and normal BP (120-129/80-84 mm Hg) were randomized to either TM or health education (HE) groups. BP was recorded at 3, 6, 9, 12, 24, 30 and 36 months after baseline. Linear mixed model analysis was conducted to compare the BP change between TM and HE participants in the high-normal BP and normal-BP groups. Survival analysis for hypertensive events was conducted. RESULTS: After an average of 19.9 ± 11.1 months follow-up, TM participants in the high-normal BP group showed significantly lower posttest SBP (-3.33 mm Hg, p = 0.045). There was no difference in DBP (-0.785 mm Hg, p = 0.367) compared to HE participants. In the normal BP group, the SBP and DBP were not different between the TM and HE participants. The hazard ratio for hypertensive events was 0.52 (p = 0.15) in the high normal BP group (7 TM vs 13 HE) with no difference in the normal BP group. CONCLUSION: This RCT found that meditation lowered systolic BP in Black men and women with high normal BP but not in normal BP participants. These results may be relevant to reducing health disparities in CVD and related co-morbidities.

Opposing effects of T cell receptor signal strength on CD4 T cells responding to acute versus chronic viral infection.

A hallmark of adaptive immunity is CD4 T cells' ability to differentiate into specialized effectors. A long-standing question is whether T cell receptor (TCR) signal strength can dominantly instruct the development of Th1 and T follicular helper (Tfh) cells across distinct infectious contexts. We characterized the differentiation of murine CD4 TCR transgenic T cells responding to altered peptide ligand lymphocytic choriomeningitis viruses (LCMV) derived from acute and chronic parental strains. We found that TCR signal strength exerts opposite and hierarchical effects on the balance of Th1 and Tfh cells responding to acute versus persistent infection. TCR signal strength correlates positively with Th1 generation during acute but negatively during chronic infection. Weakly activated T cells express lower levels of markers associated with chronic T cell stimulation and may resist functional inactivation. We anticipate that the panel of recombinant viruses described herein will be valuable for investigating a wide range of CD4 T cell responses.

T resident helper cells promote humoral responses in the lung.

Influenza is a deadly and costly infectious disease, even during flu seasons when an effective vaccine has been developed. To improve vaccines against respiratory viruses, a better understanding of the immune response at the site of infection is crucial. After influenza infection, clonally expanded T cells take up permanent residence in the lung, poised to rapidly respond to subsequent infection. Here, we characterized the dynamics and transcriptional regulation of lung-resident CD4+ T cells during influenza infection and identified a long-lived, Bcl6-dependent population that we have termed T resident helper (TRH) cells. TRH cells arise in the lung independently of lymph node T follicular helper cells but are dependent on B cells, with which they tightly colocalize in inducible bronchus-associated lymphoid tissue (iBALT). Deletion of Bcl6 in CD4+ T cells before heterotypic challenge infection resulted in redistribution of CD4+ T cells outside of iBALT areas and impaired local antibody production. These results highlight iBALT as a homeostatic niche for TRH cells and advocate for vaccination strategies that induce TRH cells in the lung.

TB or not to be: what specificities and impact do antibodies have during tuberculosis?

Tuberculosis, an infectious disease caused by Mycobacterium tuberculosis (Mtb), is a major cause of global morbidity and mortality. The primary barrier to the development of an effective tuberculosis vaccine is our failure to fully understand the fundamental characteristics of a protective immune response. There is an increasing evidence that mobilization of antibody and B cell responses during natural Mtb infection and vaccination play a role in host protection. Several studies have assessed the levels of Mtb-specific antibodies induced during active disease as well as the potential of monoclonal antibodies to modulate bacterial growth in vitro and in vivo. A major limitation of these studies, however, is that the specific antigens capable of eliciting humoral responses are largely unknown. As a result, information about antibody dynamics and function, which might fundamentally transform our understanding of host Mtb immunity, is missing. Importantly, Mtb infection also induces the recruitment, accumulation and colocalization of B and T cells in the lung, which are positively correlated with protection in humans and animal models of disease. These ectopic lymphoid tissues generally support local germinal center reactions for the proliferation and ongoing selection of effector and memory B cells in the mucosa. Efforts to leverage such responses for human health, however, require a more complete understanding of how antibodies and B cells contribute to the local and systemic host Mtb immunity.

Effects of cardiac rehabilitation with and without meditation on myocardial blood flow using quantitative positron emission tomography: A pilot study.

BACKGROUND: Psychosocial stress is recognized as a risk factor for coronary heart disease (CHD). High rates of CHD in African-Americans may be related to psychosocial stress. However, standard cardiac rehabilitation (CR) usually does not include a systematic stress-reduction technique. Previous studies suggest that the Transcendental Meditation (TM) technique may reduce CHD risk factors and clinical events. This pilot study explored the effects of standard CR with and without TM on a measure of CHD in African-American patients. METHODS: Fifty-six CHD patients were assigned to CR, CR + TM, TM alone, or usual care. Testing was done at baseline and after 12 weeks. The primary outcome was myocardial flow reserve (MFR) assessed by 13N-ammonia positron emission tomography (PET). Secondary outcomes were CHD risk factors. Based on guidelines for analysis of small pilot studies, data were analyzed for effect size (ES). RESULTS: For 37 patients who completed posttesting, there were MFR improvements in the CR + TM group (+20.7%; ES = 0.64) and the TM group alone (+12.8%; ES = 0.36). By comparison, the CR-alone and usual care groups showed modest changes (+ 5.8%; ES = 0.17 and - 10.3%; ES = - 0.31), respectively. For the combined TM group, MFR increased (+ 14%, ES = 0.56) compared to the combined non-TM group (- 2.0%, ES = - 0.08). CONCLUSIONS: These pilot data suggest that adding the TM technique to standard cardiac rehabilitation or using TM alone may improve the myocardial flow reserve in African-American CHD patients. These results may be applied to the design of controlled clinical trials to definitively test these effects. TRIAL REGISTRATION: ClinicalTrials.gov registration # NCT01810029.

Resident Memory T Cells Escape 'Home Quarantine'.

T resident memory (Trm) cells provide a first line of defense in non-lymphoid tissues. A new report in Nature Immunology by Fonseca et al. reveals that CD8+ Trm cells can give rise to circulating effector and memory T cells, but remain predisposed to migrate back into their tissue of origin.

Long-lived T follicular helper cells retain plasticity and help sustain humoral immunity.

CD4+ memory T cells play an important role in protective immunity and are a key target in vaccine development. Many studies have focused on T central memory (Tcm) cells, whereas the existence and functional significance of long-lived T follicular helper (Tfh) cells are controversial. Here, we show that Tfh cells are highly susceptible to NAD-induced cell death (NICD) during isolation from tissues, leading to their underrepresentation in prior studies. NICD blockade reveals the persistence of abundant Tfh cells with high expression of hallmark Tfh markers to at least 400 days after infection, by which time Tcm cells are no longer found. Using single-cell RNA-seq, we demonstrate that long-lived Tfh cells are transcriptionally distinct from Tcm cells, maintain stemness and self-renewal gene expression, and, in contrast to Tcm cells, are multipotent after recall. At the protein level, we show that folate receptor 4 (FR4) robustly discriminates long-lived Tfh cells from Tcm cells. Unexpectedly, long-lived Tfh cells concurrently express a distinct glycolytic signature similar to trained immune cells, including elevated expression of mTOR-, HIF-1-, and cAMP-regulated genes. Late disruption of glycolysis/ICOS signaling leads to Tfh cell depletion concomitant with decreased splenic plasma cells and circulating antibody titers, demonstrating both unique homeostatic regulation of Tfh and their sustained function during the memory phase of the immune response. These results highlight the metabolic heterogeneity underlying distinct long-lived T cell subsets and establish Tfh cells as an attractive target for the induction of durable adaptive immunity.

Dynamics of the Coreceptor-LCK Interactions during T Cell Development Shape the Self-Reactivity of Peripheral CD4 and CD8 T Cells.

Overtly self-reactive T cells are removed during thymic selection. However, it has been recently established that T cell self-reactivity promotes protective immune responses. Apparently, the level of self-reactivity of mature T cells must be tightly balanced. Our mathematical model and experimental data show that the dynamic regulation of CD4- and CD8-LCK coupling establish the self-reactivity of the peripheral T cell pool. The stoichiometry of the interaction between CD8 and LCK, but not between CD4 and LCK, substantially increases upon T cell maturation. As a result, peripheral CD8+ T cells are more self-reactive than CD4+ T cells. The different levels of self-reactivity of mature CD8+ and CD4+ T cells likely reflect the unique roles of these subsets in immunity. These results indicate that the evolutionary selection pressure tuned the CD4-LCK and CD8-LCK stoichiometries, as they represent the unique parts of the proximal T cell receptor (TCR) signaling pathway, which differ between CD4+ and CD8+ T cells.

Stress Reduction in the Prevention of Left Ventricular Hypertrophy: A Randomized Controlled Trial of Transcendental Meditation and Health Education in Hypertensive African Americans.

Background: African Americans have disproportionately high rates of cardiovascular disease (CVD). Left ventricular hypertrophy (LVH) is an independent risk factor for CVD and may contribute to this disparity. Psychological stress contributes to LVH in African Americans and other populations. Objective: This study evaluated the effects of stress reduction with the Transcendental Meditation (TM) technique on preventing LVH in African American adults with hypertension. Setting: Martin Luther King Hospital - Charles R. Drew University of Medicine and Science, Los Angeles, CA. Method: In this trial, 85 African American adults (average 52.8 years) were randomly assigned to either TM program or health education (HE) control group and completed posttesting. Participants were tested at baseline and after six months for left ventricular mass index (LVMI) by M-mode echocardiography, blood pressure, psychosocial stress and behavioral factors. Change in outcomes was analyzed between groups by ANCOVA and within groups by paired t-test. Results: The TM group had significantly lower LVMI compared with the HE group (-7.55gm/m2, 95% CI -14.78 to -.34 gm/m2, P=.040). Both interventions showed significant within group reductions in BP, (SBP/DBP changes for TM: -5/ -3 mm Hg, and for HE: -7/-6 mm Hg, P=.028 to <.001) although between group changes were not significant. In addition, both groups showed significant reductions in anger (P=.002 to .001). There were no other changes in lifestyle factors. Conclusions: These findings indicate that stress reduction with TM was effective in preventing LVMI progression and thus may prevent LVH and associated CVD in high-risk African American patients.

Generalizability and reproducibility of functional connectivity in autism.

Background: Autism is hypothesized to represent a disorder of brain connectivity, yet patterns of atypical functional connectivity show marked heterogeneity across individuals. Methods: We used a large multi-site dataset comprised of a heterogeneous population of individuals with autism and typically developing individuals to compare a number of resting-state functional connectivity features of autism. These features were also tested in a single site sample that utilized a high-temporal resolution, long-duration resting-state acquisition technique. Results: No one method of analysis provided reproducible results across research sites, combined samples, and the high-resolution dataset. Distinct categories of functional connectivity features that differed in autism such as homotopic, default network, salience network, long-range connections, and corticostriatal connectivity, did not align with differences in clinical and behavioral traits in individuals with autism. One method, lag-based functional connectivity, was not correlated to other methods in describing patterns of resting-state functional connectivity and their relationship to autism traits. Conclusion: Overall, functional connectivity features predictive of autism demonstrated limited generalizability across sites, with consistent results only for large samples. Different types of functional connectivity features do not consistently predict different symptoms of autism. Rather, specific features that predict autism symptoms are distributed across feature types.