Regulation of autoreactive B cells during innate immune responses

A diverse repertoire of B cell specificities is critical to combat pathogenic threats, but this diversity is tinged with the threat of autoimmunity. Autoimmune diseases such as systemic lupus erythematosus (SLE) underscore the need for strict regulation of B cell activation during immune responses. Regulation of the adaptive immune response is dependent on B cell receptor (BCR) ligation, affinity of the BCR-antigen interaction, and the presence of costimulatory molecules. Mechanisms of central tolerance and peripheral tolerance eradicate B cells that inappropriately bind self-antigens. Autoreactive B cells that escape these mechanisms of tolerance and encounter antigen in the absence of costimulatory signals enter an unresponsive state known as anergy. Anergic B cells do not differentiate into plasma cells, activate transcription factors such as Blimp-1 and XBP-1, or secrete immunoglobulin (Ig). B cells can also be activated by toll-like receptor (TLR) ligands and contribute to the innate immune response, the first line of defense against pathogens. Bacterial and viral components are the archetypical TLR ligands, but endogenous DNA and RNA can also bind TLRs and activate the innate immune system. Therefore, it is critical to regulate the innate immune response to prevent autoimmunity, and this regulation requires unique mechanisms that are not necessarily dependent on BCR ligation. Ideally, these mechanisms would also discriminate between naive and chronically antigen-experienced B cells, allowing naive B cells to respond to threats while potentially autoreactive B cells remain quiescent. We have recently described a mechanism where antigen-experienced B cells are regulated by IL-6 and sCD40L released by dendritic cells (DCs) and macrophages (M[phi]s) during innate immune responses. Naive B cells are unaffected by these factors, permitting a robust immune response in the absence of autoimmunity. IL-6/sCD40L-mediated repression is dependent on ERK activation and "repressed" antigen-experienced cells exhibit a decrease in activated ERK in the nucleus. Identifying new targets for SLE therapies could enable specific regulation of antigen-experienced B cells instead of non-specific B cell depletion and immunosuppression

Linear Self-Motion Cues Support the Spatial Distribution and Stability of Hippocampal Place Cells

The vestibular system provides a crucial component of place-cell and head-direction cell activity [1-7]. Otolith signals are necessary for head-direction signal stability and associated behavior [8, 9], and the head-direction signal's contribution to parahippocampal spatial representations [10-14] suggests that place cells may also require otolithic information. Here, we demonstrate that self-movement information from the otolith organs is necessary for the development of stable place fields within and across sessions. Place cells in otoconia-deficient tilted mice showed reduced spatial coherence and formed place fields that were located closer to environmental boundaries, relative to those of control mice. These differences reveal an important otolithic contribution to place-cell functioning and provide insight into the cognitive deficits associated with otolith dysfunction

The regulation of autoreactive B cells during innate immune responses

Systemic lupus erythematosus (SLE) highlights the dangers of dysregulated B cells and the importance of initiating and maintaining tolerance. In addition to central deletion, receptor editing, peripheral deletion, receptor revision, anergy, and indifference, we have described a new mechanism of B cell tolerance wherein dendritic cells (DCs) and macrophages (MΦs) regulate autoreactive B cells during innate immune responses. In part, DCs and MΦs repress autoreactive B cells by releasing IL-6 and soluble CD40L (sCD40L). This mechanism is selective in that IL-6 and sCD40L do not affect Ig secretion by naïve cells during innate immune responses, allowing immunity in the absence of autoimmunity. In lupus-prone mice, DCs and MΦs are defective in secretion of IL-6 and sCD40L and cannot effectively repress autoantibody secretion suggesting that defects in DC/MΦ-mediated tolerance may contribute to the autoimmune phenotype. Further, these studies suggest that reconstituting DCs and MΦs in SLE patients might restore regulation of autoreactive B cells and provide an alternative to immunosuppressive therapies

Seasonal and Interannual Variations of Top-of-Atmosphere Irradiance and Cloud Cover over Polar Regions Derived from the CERES Data Set

The semi-direct effects of dust aerosols are analyzed over eastern Asia using 2 years (June 2002 to June 2004) of data from the Clouds and the Earth s Radiant Energy System (CERES) scanning radiometer and MODerate Resolution Imaging Spectroradiometer (MODIS) on the Aqua satellite, and 18 years (1984 to 2001) of International Satellite Cloud Climatology Project (ISCCP) data. The results show that the water path of dust-contaminated clouds is considerably smaller than that of dust-free clouds. The mean ice water path (IWP) and liquid water path (LWP) of dusty clouds are less than their dust-free counterparts by 23.7% and 49.8%, respectively. The long-term statistical relationship derived from ISCCP also confirms that there is significant negative correlation between dust storm index and ISCCP cloud water path. These results suggest that dust aerosols warm clouds, increase the evaporation of cloud droplets and further reduce cloud water path, the so-called semi-direct effect. The semi-direct effect may play a role in cloud development over arid and semi-arid areas of East Asia and contribute to the reduction of precipitation

Early Preplasma Cells Define a Tolerance Checkpoint for Autoreactive B Cells

Ab-secreting plasma cells (PCs) are the effectors of humoral immunity. In this study, we describe regulation of autoreactive B cells specific for the ribonucleoprotein Smith (Sm) at an early pre-PC stage. These cells are defined by the expression of the PC marker CD138 and normal levels of CD19 and B220. They are present at a high frequency in normal mouse spleen and bone marrow, are Ag dependent, and are located predominantly along the T cell-B cell border and near bridging channels. Anti-Sm pre-PCs also occur at a high frequency in nonautoimmune mice and show additional phenotypic characteristics of PC differentiation. However, while some of these pre-PCs are Ab-secreting cells, those specific for Sm are not, indicating regulation. Consistent with this, anti-Sm pre-PCs have a higher turnover rate and higher frequency of cell death than those that do not bind Sm. Regulation of anti-Sm pre-PCs occurs upstream of the transcriptional repressor, B lymphocyte-induced maturation protein-1, expression. Regulation at this stage is overcome in autoimmune MRL/lpr mice and is accompanied by an altered B lymphocyte stimulator receptor profile. These data reveal a new B cell tolerance checkpoint that is overcome in autoimmunity

Receptor Cross-Talk Spatially Restricts p-ERK during TLR4 Stimulation of Autoreactive B Cells

To maintain tolerance, autoreactive B cells must regulate signal transduction from the B cell receptor and Toll-like receptors. We recently identified that dendritic cells and macrophages regulate autoreactive cells during TLR4 activation by releasing IL-6 and soluble CD40L (sCD40L). These cytokines selectively repress antibody secretion from autoreactive, but not antigenically naïve, B cells. How IL-6 and sCD40L repress autoantibody production is unknown. In this paper, we show that IL-6 and sCD40L are required for low-affinity/avidity autoreactive B cells to maintain tolerance through a mechanism involving receptor crosstalk between the BCR, TLR4, and the IL-6 receptor or CD40. We show that acute signaling through IL-6 receptor or CD40 integrates with chronic BCR-mediated ERK activation to restrict pERK from the nucleus and repress TLR4-induced Blimp-1 and XBP-1 expression. Tolerance is disrupted in 2-12H/MRL/lpr mice where IL-6 and sCD40L fail to spatially restrict pERK and fail to repress TLR4-induced Ig secretion. In the case of CD40, acute signaling in B cells from 2-12H/MRL/lpr mice is intact, but the chronic activation of pERK emanating from the BCR is attenuated. Re-establishing chronically active ERK through retroviral expression of constitutively active MEK1 restores tolerance upon sCD40L, but not IL-6, stimulation indicating that regulation by IL-6 requires another signaling effector. These data define the molecular basis for the regulation of low-affinity autoreactive B cells during TLR4 stimulation, they explain how autoreactive but not naïve B cells are repressed by IL-6 and sCD40L, and they identify B cell defects in lupus-prone mice that lead to TLR4-induced autoantibody production

Machine learning–based models incorporating social determinants of health vs traditional models for predicting in-hospital mortality in patients with heart failure

Importance: Traditional models for predicting in-hospital mortality for patients with heart failure (HF) have used logistic regression and do not account for social determinants of health (SDOH). Objective: To develop and validate novel machine learning (ML) models for HF mortality that incorporate SDOH. Design, Setting, and Participants: This retrospective study used the data from the Get With The Guidelines–Heart Failure (GWTG-HF) registry to identify HF hospitalizations between January 1, 2010, and December 31, 2020. The study included patients with acute decompensated HF who were hospitalized at the GWTG-HF participating centers during the study period. Data analysis was performed January 6, 2021, to April 26, 2022. External validation was performed in the hospitalization cohort from the Atherosclerosis Risk in Communities (ARIC) study between 2005 and 2014. Main Outcomes and Measures: Random forest-based ML approaches were used to develop race-specific and race-agnostic models for predicting in-hospital mortality. Performance was assessed using C index (discrimination), regression slopes for observed vs predicted mortality rates (calibration), and decision curves for prognostic utility. Results: The training data set included 123 634 hospitalized patients with HF who were enrolled in the GWTG-HF registry (mean [SD] age, 71 [13] years; 58 356 [47.2%] female individuals; 65 278 [52.8%] male individuals. Patients were analyzed in 2 categories: Black (23 453 [19.0%]) and non-Black (2121 [2.1%] Asian; 91 154 [91.0%] White, and 6906 [6.9%] other race and ethnicity). The ML models demonstrated excellent performance in the internal testing subset (n = 82 420) (C statistic, 0.81 for Black patients and 0.82 for non-Black patients) and in the real-world–like cohort with less than 50% missingness on covariates (n = 553 506; C statistic, 0.74 for Black patients and 0.75 for non-Black patients). In the external validation cohort (ARIC registry; n = 1205 Black patients and 2264 non-Black patients), ML models demonstrated high discrimination and adequate calibration (C statistic, 0.79 and 0.80, respectively). Furthermore, the performance of the ML models was superior to the traditional GWTG-HF risk score model (C index, 0.69 for both race groups) and other rederived logistic regression models using race as a covariate. The performance of the ML models was identical using the race-specific and race-agnostic approaches in the GWTG-HF and external validation cohorts. In the GWTG-HF cohort, the addition of zip code–level SDOH parameters to the ML model with clinical covariates only was associated with better discrimination, prognostic utility (assessed using decision curves), and model reclassification metrics in Black patients (net reclassification improvement, 0.22 [95% CI, 0.14-0.30]; P < .001) but not in non-Black patients. Conclusions and Relevance: ML models for HF mortality demonstrated superior performance to the traditional and rederived logistic regressions models using race as a covariate. The addition of SDOH parameters improved the prognostic utility of prediction models in Black patients but not non-Black patients in the GWTG-HF registry