Aberrant B Cell Signaling in Autoimmune Diseases

Aberrant B cell signaling plays a critical in role in various systemic and organ-specific autoimmune diseases. This is supported by genetic evidence by many functional studies in B cells from patients or specific animal models and by the observed efficacy of small-molecule inhibitors. In this review, we first discuss key signal transduction pathways downstream of the B cell receptor (BCR) that ensure that autoreactive B cells are removed from the repertoire or functionally silenced. We provide an overview of aberrant BCR signaling that is associated with inappropriate B cell repertoire selection and activation or survival of peripheral B cell populations and plasma cells, finally leading to autoantibody formation. Next to BCR signaling, abnormalities in other signal transduction pathways have been implicated in autoimmune disease. These include reduced activity of several phosphates that are downstream of co-inhibitory receptors on B cells and increased levels of BAFF and APRIL, which support survival of B cells and plasma cells. Importantly, pathogenic synergy of the BCR and Toll-like receptors (TLR), which can be activated by endogenous ligands, such as self-nucleic acids, has been shown to enhance autoimmunity. Finally, we will briefly discuss therapeutic strategies for autoimmune disease based on interfering with signal transduction in B cells

Decreased BAFF Receptor Expression and Unaltered B Cell Receptor Signaling in Circulating B Cells from Primary Sjogren's Syndrome Patients at Diagnosis

Animal models of autoimmunity and human genetic association studies indicate that the dysregulation of B-cell receptor (BCR) signaling is an important driver of autoimmunity. We previously showed that in circulating B cells from primary Sjogren's syndrome (pSS) patients with high systemic disease activity, protein expression of the BCR signaling molecule Bruton's tyrosine kinase (BTK) was increased and correlated with T-cell infiltration in the target organ. We hypothesized that these alterations could be driven by increased B-cell activating factor (BAFF) levels in pSS. Here, we investigated whether altered BCR signaling was already present at diagnosis and distinguished pSS from non-SS sicca patients. Using (phospho-)flow cytometry, we quantified the phosphorylation of BCR signaling molecules, and investigated BTK and BAFF receptor (BAFFR) expression in circulating B cell subsets in an inception cohort of non-SS sicca and pSS patients, as well as healthy controls (HCs). We found that both BTK protein levels and BCR signaling activity were comparable among groups. Interestingly, BAFFR expression was significantly downregulated in pSS, but not in non-SS sicca patients, compared with HCs, and correlated with pSS-associated alterations in B cell subsets. These data indicate reduced BAFFR expression as a possible sign of early B cell involvement and a diagnostic marker for pSS

Aberrant B cell receptor signaling in naïve B cells from patients with idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a chronic and ultimately fatal disease in which an impaired healing response to recurrent micro-injuries is thought to lead to fibrosis. Recent findings hint at a role for B cells and autoimmunity in IPF pathogenesis. We previously reported that circulating B cells from a fraction of patients, compared with healthy controls, express increased levels of the signaling molecule Bruton’s tyrosine kinase (BTK). However, it remains unclear whether B cell receptor (BCR) signaling is altered in IPF. Here, we show that the response to BCR stimulation is enhanced in peripheral blood B cells from treatment-naïve IPF patients. We observed increased anti-immunoglobulin-induced phosphorylation of BTK and its substrate phospholipase Cγ2 (PLCγ2) in naïve but not in memory B cells of patients with IPF. In naïve B cells of IPF patients enhanced BCR signaling correlated with surface expression of transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI) but not B cell activating factor receptor (BAFFR), both of which provide pro-survival signals. Interestingly, treatment of IPF patients with nintedanib, a tyrosine kinase inhibitor with anti-fibrotic and anti-inflammatory activity, induced substantial changes in BCR signaling. These findings support the involvement of B cells in IPF pathogenesis and suggest that targeting BCR signaling has potential value as a treatment option.</p

The feasibility of working memory tablet tasks in predicting scholastic skills in classroom settings

Cognitive assessment in natural group settings facilitates data collection but poses threats to the validity. In this study, tablet‐based working memory (WM) tasks, the counting span, and reading span were used in predicting 12‐year‐old children's (N = 837) scholastic skills and fluid intelligence in a classroom with environmental noise. WM tasks had excellent internal consistency, correlated with scholastic skills, and accounted for more of the variance in cognitive performance (grade point average, fluid intelligence, scholastic skills) compared with individually administered (n = 190) digit span task. Furthermore, the multilevel analysis revealed that compared with the classrooms with no noise, when naturally occurring speech or nonspeech types of environmental noises were present during assessment, WM scores or the reliability estimates were not lower. In contrast, when both types of noises were present, the relationships between some of the WM and achievement scores were even stronger. Thus, assessments in natural classroom contexts may promote revealing the individual differences in WM.Peer reviewe

Can cognitive psychological research on reasoning enhance the discussion around moral judgments?

In this article we will demonstrate how cognitive psychological research on reasoning and decision making could enhance discussions and theories of moral judgments. In the first part, we will present recent dual-process models of moral judgments and describe selected studies which support these approaches. However, we will also present data that contradict the model predictions, suggesting that approaches to moral judgment might be more complex. In the second part, we will show how cognitive psychological research on reasoning might be helpful in understanding moral judgments. Specifically, we will highlight approaches addressing the interaction between intuition and reflection. Our data suggest that a sequential model of engaging in deliberation might have to be revised. Therefore, we will present an approach based on Signal Detection Theory and on intuitive conflict detection. We predict that individuals arrive at the moral decisions by comparing potential action outcomes (e.g., harm caused and utilitarian gain) simultaneously. The response criterion can be influenced by intuitive processes, such as heuristic moral value processing, or considerations of harm caused

Cognitive Control and Individual Differences in Economic Ultimatum Decision-Making

Much publicity has been given to the fact that people's economic decisions often deviate from the rational predictions of standard economic models. In the classic ultimatum game, for example, most people turn down financial gains by rejecting unequal monetary splits. The present study points to neglected individual differences in this debate. After participants played the ultimatum game we tested for individual differences in cognitive control capacity of the most and least economic responders. The key finding was that people who were higher in cognitive control, as measured by behavioral (Go/No-Go performance) and neural (No-Go N2 amplitude) markers, did tend to behave more in line with the standard models and showed increased acceptance of unequal splits. Hence, the cognitively highest scoring decision-makers were more likely to maximize their monetary payoffs and adhere to the standard economic predictions. Findings question popular claims with respect to the rejection of standard economic models and the irrationality of human economic decision-making

Cognitive control in belief-laden reasoning during conclusion processing: An ERP study

Belief bias is the tendency to accept conclusions that are compatible with existing beliefs more frequently than those that contradict beliefs. It is one of the most replicated behavioral findings in the reasoning literature. Recently, neuroimaging studies using functional magnetic resonance imaging (fMRI) and event-related potentials (ERPs) have provided a new perspective and have demonstrated neural correlates of belief bias that have been viewed as supportive of dual-process theories of belief bias. However, fMRI studies have tended to focus on conclusion processing, while ERPs studies have been concerned with the processing of premises. In the present research, the electrophysiological correlates of cognitive control were studied among 12 subjects using high-density ERPs. The analysis was focused on the conclusion presentation phase and was limited to normatively sanctioned responses to valid–believable and valid–unbelievable problems. Results showed that when participants gave normatively sanctioned responses to problems where belief and logic conflicted, a more positive ERP deflection was elicited than for normatively sanctioned responses to nonconflict problems. This was observed from −400 to −200 ms prior to the correct response being given. The positive component is argued to be analogous to the late positive component (LPC) involved in cognitive control processes. This is consistent with the inhibition of empirically anomalous information when conclusions are unbelievable. These data are important in elucidating the neural correlates of belief bias by providing evidence for electrophysiological correlates of conflict resolution during conclusion processing. Moreover, they are supportive of dual-process theories of belief bias that propose conflict detection and resolution processes as central to the explanation of belief bias

The logic-bias effect: The role of effortful processing in the resolution of belief-logic conflict.

According to the default interventionist dual-process account of reasoning, belief-based responses to reasoning tasks are based on Type 1 processes generated by default, which must be inhibited in order to produce an effortful, Type 2 output based on the validity of an argument. However, recent research has indicated that reasoning on the basis of beliefs may not be as fast and automatic as this account claims. In three experiments, we presented participants with a reasoning task that was to be completed while they were generating random numbers (RNG). We used the novel methodology introduced by Handley, Newstead & Trippas (Journal of Experimental Psychology: Learning, Memory, and Cognition, 37, 28-43, 2011), which required participants to make judgments based upon either the validity of a conditional argument or the believability of its conclusion. The results showed that belief-based judgments produced lower rates of accuracy overall and were influenced to a greater extent than validity judgments by the presence of a conflict between belief and logic for both simple and complex arguments. These findings were replicated in Experiment 3, in which we controlled for switching demands in a blocked design. Across all three experiments, we found a main effect of RNG, implying that both instructional sets require some effortful processing. However, in the blocked design RNG had its greatest impact on logic judgments, suggesting that distinct executive resources may be required for each type of judgment. We discuss the implications of our findings for the default interventionist account and offer a parallel competitive model as an alternative interpretation for our findings