Memory CD4+ T Cells in Immunity and Autoimmune Diseases

CD4+ T helper (Th) cells play central roles in immunity in health and disease. While much is known about the effector function of Th cells in combating pathogens and promoting autoimmune diseases, the roles and biology of memory CD4+ Th cells are complex and less well understood. In human autoimmune diseases such as multiple sclerosis (MS), there is a critical need to better understand the function and biology of memory T cells. In this review article we summarize current concepts in the field of CD4+ T cell memory, including natural history, developmental pathways, subsets, and functions. Furthermore, we discuss advancements in the field of the newly-described CD4+ tissue-resident memory T cells and of CD4+ memory T cells in autoimmune diseases, two major areas of important unresolved questions in need of answering to advance new vaccine design and development of novel treatments for CD4+ T cell-mediated autoimmune diseases

Myeloid cells as potential targets for immunotherapy in pediatric gliomas

Pediatric high-grade glioma (pHGG) including pediatric glioblastoma (pGBM) are highly aggressive pediatric central nervous system (CNS) malignancies. pGBM comprises approximately 3% of all pediatric CNS malignancies and has a 5-year survival rate of approximately 20%. Surgical resection and chemoradiation are often the standard of care for pGBM and pHGG, however, even with these interventions, survival for children diagnosed with pGBM and pHGG remains poor. Due to shortcomings associated with the standard of care, many efforts have been made to create novel immunotherapeutic approaches targeted to these malignancies. These efforts include the use of vaccines, cell-based therapies, and immune-checkpoint inhibitors. However, it is believed that in many pediatric glioma patients an immunosuppressive tumor microenvironment (TME) possess barriers that limit the efficacy of immune-based therapies. One of these barriers includes the presence of immunosuppressive myeloid cells. In this review we will discuss the various types of myeloid cells present in the glioma TME, including macrophages and microglia, myeloid-derived suppressor cells, and dendritic cells, as well as the specific mechanisms these cells can employ to enable immunosuppression. Finally, we will highlight therapeutic strategies targeted to these cells that are aimed at impeding myeloid-cell derived immunosuppression

Memory CD4+ T Cells in Immunity and Autoimmune Diseases

CD4+ T helper (Th) cells play central roles in immunity in health and disease. While much is known about the effector function of Th cells in combating pathogens and promoting autoimmune diseases, the roles and biology of memory CD4+ Th cells are complex and less well understood. In human autoimmune diseases such as multiple sclerosis (MS), there is a critical need to better understand the function and biology of memory T cells. In this review article we summarize current concepts in the field of CD4+ T cell memory, including natural history, developmental pathways, subsets, and functions. Furthermore, we discuss advancements in the field of the newly-described CD4+ tissue-resident memory T cells and of CD4+ memory T cells in autoimmune diseases, two major areas of important unresolved questions in need of answering to advance new vaccine design and development of novel treatments for CD4+ T cell-mediated autoimmune diseases

Immunoregulation via Cell Density and Quorum Sensing-like Mechanisms: An Underexplored Emerging Field with Potential Translational Implications

Quorum sensing (QS) was historically described as a mechanism by which bacteria detect and optimize their population density via gene regulation based on dynamic environmental cues. Recently, it was proposed that QS or similar mechanisms may have broader applications across different species and cell types. Indeed, emerging evidence shows that the mammalian immune system can also elicit coordinated responses on a population level to regulate cell density and function, thus suggesting that QS-like mechanisms may also be a beneficial trait of the immune system. In this review, we explore and discuss potential QS-like mechanisms deployed by the immune system to coordinate cellular-level responses, such as T cell responses mediated via the common gamma chain (γc) receptor cytokines and the aryl hydrocarbon receptors (AhRs). We present evidence regarding a novel role of QS as a multifunctional mechanism coordinating CD4+ and CD8+ T cell behavior during steady state and in response to infection, inflammatory diseases, and cancer. Successful clinical therapies such as adoptive cell transfer for cancer treatment may be re-evaluated to harness the effects of the QS mechanism(s) and enhance treatment responsiveness. Moreover, we discuss how signaling threshold perturbations through QS-like mediators may result in disturbances of the complex crosstalk between immune cell populations, undesired T cell responses, and induction of autoimmune pathology. Finally, we discuss the potential therapeutic role of modulating immune-system-related QS as a promising avenue to treat human diseases

Serum Neuroinflammatory Disease-Induced Central Nervous System Proteins Predict Clinical Onset of Experimental Autoimmune Encephalomyelitis

There is an urgent need in multiple sclerosis (MS) patients to develop biomarkers and laboratory tests to improve early diagnosis, predict clinical relapses, and optimize treatment responses. In healthy individuals, the transport of proteins across the blood–brain barrier (BBB) is tightly regulated, whereas, in MS, central nervous system (CNS) inflammation results in damage to neuronal tissues, disruption of BBB integrity, and potential release of neuroinflammatory disease-induced CNS proteins (NDICPs) into CSF and serum. Therefore, changes in serum NDICP abundance could serve as biomarkers of MS. Here, we sought to determine if changes in serum NDICPs are detectable prior to clinical onset of experimental autoimmune encephalomyelitis (EAE) and, therefore, enable prediction of disease onset. Importantly, we show in longitudinal serum specimens from individual mice with EAE that pre-onset expression waves of synapsin-2, glutamine synthetase, enolase-2, and synaptotagmin-1 enable the prediction of clinical disease with high sensitivity and specificity. Moreover, we observed differences in serum NDICPs between active and passive immunization in EAE, suggesting hitherto not appreciated differences for disease induction mechanisms. Our studies provide the first evidence for enabling the prediction of clinical disease using serum NDICPs. The results provide proof-of-concept for the development of high-confidence serum NDICP expression waves and protein biomarker candidates for MS

Formation of Protocell-like Vesicles in a Thermal Diffusion Column

Formation of Protocell-like Vesicles in a Thermal Diffusion Colum

Formation of Protocell-like Vesicles in a Thermal Diffusion Column

Formation of Protocell-like Vesicles in a Thermal Diffusion Colum

The Evolution of Board-Certified Emergency Physicians and Staffing of Emergency Departments in Israel

Introduction: Emergency medicine (EM) was recognized as a specialty in Israel in 1999. Fifty-nine of the 234 (25%) attending physicians working in emergency departments (ED) nationwide in 2002 were board-certified emergency physicians (EP). A 2012 study revealed that 123/270 (45%) of ED attendings were EPs, and that there were 71 EM residents. The EPs primarily worked midweek morning shifts, leaving the EDs mostly staffed by other specialties. Our objective in this study was to re-evaluate the EP workforce in Israeli EDs and their employment status and satisfaction 10 years after the last study, which was conducted in 2012. Methods: We performed a three-part, prospective cross-sectional study: 1) a survey, sent to all EDs in Israel, to assess the numbers, level of training, and specialties of physicians working in EDs; 2) an anonymous questionnaire, sent to EPs in Israel, to assess their demographics, training, employment, and work satisfaction; and 3) interviews of a convenience sample of EPs analyzed by a thematic approach. Results: There were 266 board-certified EPs, 141 (53%) of whom were employed in EDs full-time or part-time. Sixty-two non-EPs also worked in EDs. The EPs were present in the EDs primarily during weekday morning shifts. There were 273 EM residents nationwide. A total of 101 questionnaires were completed and revealed that EPs working part-time in the ED worked fewer hours, received higher salaries, and had more years of experience compared to EPs working full time or not working in the ED. Satisfaction correlated only with working part time. Meaningful work, diversity, and rewarding relationships with patients and colleagues were major positive reasons for working in the ED. Feeling undervalued, carrying a heavy caseload, and having complicated relationships with other hospital departments were reasons against working in the ED. Conclusion: Our study findings showed an increase in the number of trained and in-training EPs, and a decrease in the percentage of board-certified EPs who persevere in the EDs. Emergency medicine in Israel is at a crossroads: more physicians are choosing EM than a decade ago, but retention of board-certified EPs is a major concern, as it is worldwide. We recommend taking measures to maintain trained and experienced EPs working in the ED by allowing part-time ED positions, introducing dedicated academic time, and diversifying EP roles, functioning, and work routine

Additional file 1 of Early response index: a statistic to discover potential early stage disease biomarkers

Proteins detected by different methods in different days.xlsx — This file lists all the significant features detected by various methods at different timepoints on EAE dataset. (XLSX 34.1 kb