CTLA-4 and Autoimmunity: New Twists in the Tale

CTLA-4 has long been associated with control of autoimmunity. A recent study by Sharpe and colleagues explores this relationship in a model that enables conditional deletion of CTLA-4 in adult mice, with some surprising new conclusions

The course of mental health problems in children presenting with abdominal pain in general practice

Objective. To investigate the course of mental health problems in children presenting to general practice with abdominal pain and to evaluate the extent to which abdominal pain characteristics during follow-up predict the presence of mental health problems at 12 months' follow-up. Design. A prospective cohort study with one-year follow-up. Setting. 53 general practices in the Netherlands, between May 2004 and March 2006. Subjects. 281 children aged 4-17 years. Main outcome measures. The presence of a depressive problem, an anxiety problem, and multiple non-specific somatic symptoms at follow-up and odds ratios of duration, frequency, and severity of abdominal pain with these mental health problems at follow-up. Results. A depressive problem persisted in 24/74 children (32.9%; 95% CI 22.3-44.9%), an anxiety problem in 13/43 (30.2%; 95% CI 17.2-46.1%) and the presence of multiple non-specific somatic symptoms in 75/170 children (44.1%; 95% CI 36.7-51.6%). None of the abdominal pain characteristics predicted a depressive or an anxiety problem at 12 months' follow-up. More moments of moderate to severe abdominal pain predicted the presence of multiple nonspecific somatic symptoms at follow-up. Conclusions. In one-third of the children presenting to general practice for abdominal pain, anxiety and depressive problems persist during one year of follow-up. Characteristics of the abdominal pain during the follow-up period do not predict anxiety or depressive problems after one-year follow-up. We recommend following over time children seen in primary care with abdominal pain

EFIS Lecture: Understanding the CTLA-4 checkpoint in the maintenance of immune homeostasis

The past 20 years have heralded fascinating developments in the field of CTLA-4 biology. The CTLA-4 protein is a critical negative regulator of T cell immunity and its absence provokes severe lymphoproliferative disease. In a surprising twist, the generation of mixed bone marrow chimeric mice revealed that CTLA-4 predominantly functions in a cell-extrinsic manner, suggesting that CTLA-4 expressed on one cell can modify the behaviour of another cell. This was followed by the demonstration that CTLA-4 is highly expressed in regulatory T cells and can contribute to their suppressive activity. In line with a cell-extrinsic function, increasing evidence indicates that CTLA-4-positive cells can modify the phenotype of antigen presenting cells (APC), thereby regulating the priming of naive T cells. Notably, CTLA-4 is able to downregulate expression of costimulatory ligands on APC via a process of trans-endocytosis. The identification of patients with mutations in the ctla4 gene has provided an opportunity to study the contribution of CTLA-4 to Treg function and immune regulation in the human immune system. Finally, it has become apparent that CTLA-4 also plays a role in controlling humoral immunity, via the regulation of CD28-driven follicular helper T cell differentiation. At the recent German Society for Immunology congress, I discussed some of the contributions of my own lab to the unfolding of the CTLA-4 story, in the context of the work of others in the field. Despite the enormous clinical potential associated with modulation of the CTLA-4 pathway, including the use of soluble CTLA-4 molecules in autoimmune settings and blocking antibodies in cancer, it is clear there is still much to learn about this important pathway

CD4 T cell differentiation in type 1 diabetes

Susceptibility to type 1 diabetes is associated strongly with human leucocyte antigen (HLA) genes, implicating T cells in disease pathogenesis. In humans, CD8 T cells predominantly infiltrate the islets, yet their activation and propagation probably requires CD4 T cell help. CD4 T cells can select from several differentiation fates following activation, and this choice has profound consequences for their subsequent cytokine production and migratory potential. In turn, these features dictate which other immune cell types T cells interact with and influence, thereby determining downstream effector functions. Obtaining an accurate picture of the type of CD4 T cell differentiation associated with a particular immune-mediated disease therefore constitutes an important clue when planning intervention strategies. Early models of T cell differentiation focused on the dichotomy between T helper type 1 (Th1) and Th2 responses, with type 1 diabetes (T1D) being viewed mainly as a Th1-mediated pathology. However, several additional fate choices have emerged in recent years, including Th17 cells and follicular helper T cells. Here we revisit the issue of T cell differentiation in autoimmune diabetes, highlighting new evidence from both mouse models and patient samples. We assess the strengths and the weaknesses of the Th1 paradigm, review the data on interleukin (IL)-17 production in type 1 diabetes and discuss emerging evidence for the roles of IL-21 and follicular helper T cells in this disease setting. A better understanding of the phenotype of CD4 T cells in T1D will undoubtedly inform biomarker development, improve patient stratification and potentially reveal new targets for therapeutic intervention

The effect of westerlies on East African rainfall and the associated role of tropical cyclones and the Madden–Julian Oscillation

Variability of rainfall in East Africa has major impacts on lives and livelihoods. From floods to droughts, this variability is important on short daily time‐scales to longer decadal time‐scales, as is apparent from the devastating effects of droughts in East Africa over recent decades. Past studies have highlighted the Congo airmass in enhancing East African rainfall. Our detailed analysis of the feature shows that days with a westerly moisture flow, bringing the Congo airmass, enhance rainfall by up to 100% above the daily mean, depending on the time of year. Conversely, there is a suppression of rainfall on days with a strong easterly flow. Days with a westerly moisture flux are in a minority in all seasons but we show that long rains with more westerly days are wetter, and that during the most‐recent decade which has had more frequent droughts (associated with the “Eastern African climate paradox”), there has been few days with such westerlies. We also investigate the influence of the Madden–Julian Oscillation (MJO) and tropical cyclones, and their interaction with the westerly flow. We show that days of westerly moisture flux are more likely during phases 3 and 4 of the MJO and when there are one or more tropical cyclones present. In addition, tropical cyclones are more likely to form during these phases of the MJO, and more likely to be coincident with westerlies when forming to the east of Madagascar. Overall, our analysis brings together many different processes that have been discussed in the literature but not yet considered in complete combination. The results demonstrate the importance of the Congo airmass on daily to climate time‐scales, and in doing so offers useful angles of investigation for future studies into prediction of East African rainfall

IL-21 Promotes CD4 T Cell Responses by Phosphatidylinositol 3-Kinase-Dependent Upregulation of CD86 on B Cells.

The cytokine IL-21 is a potent immune modulator with diverse mechanisms of action on multiple cell types. IL-21 is in clinical use to promote tumor rejection and is an emerging target for neutralization in the setting of autoimmunity. Despite its clinical potential, the biological actions of IL-21 are not yet fully understood and the full range of effects of this pleiotropic cytokine are still being uncovered. In this study, we identify a novel role for IL-21 as an inducer of the costimulatory ligand CD86 on B lymphocytes. CD86 provides critical signals through T cell-expressed CD28 that promote T cell activation in response to Ag engagement. Expression levels of CD86 are tightly regulated in vivo, being actively decreased by regulatory T cells and increased in response to pathogen-derived signals. In this study, we demonstrate that IL-21 can trigger potent and sustained CD86 upregulation through a STAT3 and PI3K-dependent mechanism. We show that elevated CD86 expression has functional consequences for the magnitude of CD4 T cell responses both in vitro and in vivo. These data pinpoint CD86 upregulation as an additional mechanism by which IL-21 can elicit immunomodulatory effects

Design thinking for mHealth application co-design to support heart failure self-management

Heart failure is a prevalent, progressive chronic disease costing in excess of $1billion per year in Australia alone. Disease self-management has positive implications for the patient and decreases healthcare usage. However, adherence to recommended guidelines is challenging and existing literature reports sub-optimal adherence. mHealth applications in chronic disease education have the potential to facilitate patient enablement for disease self-management. To the best of our knowledge no heart failure self-management application is available for safe use by our patients. In this paper, we present the process established to co-design a mHealth application in support of heart-failure self-management. For this development, an interdisciplinary team systematically proceeds through the phases of Stanford University's Design Thinking process; empathise, define, ideate, prototype and test with a user-centred philosophy. Using this clinician-led heart failure app research as a case study, we describe a sequence of procedures to engage with local patients, carers, software developers, eHealth experts and clinical colleagues to foster rigorously developed and locally relevant patient-facing mHealth solutions. Importantly, patients are engaged in each stage with ethnographic interviews, a series of workshops and multiple re-design iterations

Partnering in Digital Health Design: Engaging the Multidisciplinary Team in a Needs Analysis

Using participatory co-design methods and in partnership with consumers we have developed a mHealth application to support heart failure self-management. In the first phase of the research we conducted a needs analysis with clinicians. The objectives were to define the features to perceivably support self-management and the clinical requirements in preparation for its implementation as an adjunct to existing multidisciplinary care. Interviews were conducted using the 'Rose, Thorn, Bud' technique from Design Thinking together with a brainstorming session with post-it notes. Six sixty-minute interviews and one email exchange with seven clinicians produced 154 data points in total; 97 relating to self-management support and 57 to clinical relevance. Analysis of these data points resulted in design implications articulated in a design brief for use in subsequent co-design workshops. Our discussion focuses on a critique of the technique, which appears to be useful for this stakeholder group although concerns of adequately representing complexity emerged. This method was considered inadequately comprehensive for use in the needs analysis with patients and family. The authors encourage further research evaluating in-hospital processes for co-designed health technologies