Crossroads Of Immunity Research Articles

ATP-dependent transporters: emerging players at the crossroads of immunity and metabolism.

Nearly 50 ATP-binding cassette (ABC) transporters are encoded by mammalian genomes. These transporters are characterized by conserved nucleotide-binding and hydrolysis (i.e., ATPase) domains, and power directional transport of diverse substrate classes - ions, small molecule metabolites, xenobiotics, hydrophobic drugs, and even polypeptides - into or out of cells or subcellular organelles. Although immunological functions of ABC transporters are only beginning to be unraveled, emerging literature suggests these proteins have under-appreciated roles in the development and function of T lymphocytes, including many of the key effector, memory and regulatory subsets that arise during responses to infection, inflammation or cancers. One transporter in particular, MDR1 (Multidrug resistance-1; encoded by the ABCB1 locus in humans), has taken center stage as a novel player in immune regulation. Although MDR1 remains widely viewed as a simple drug efflux pump in tumor cells, recent evidence suggests that this transporter fills key endogenous roles in enforcing metabolic fitness of activated CD4 and CD8 T cells. Here, we summarize current understanding of the physiological functions of ABC transporters in immune regulation, with a focus on the anti-oxidant functions of MDR1 that may shape both the magnitude and repertoires of antigen-specific effector and memory T cell compartments. While much remains to be learned about the functions of ABC transporters in immunobiology, it is already clear that they represent fertile new ground, both for the definition of novel immunometabolic pathways, and for the discovery of new drug targets that could be leveraged to optimize immune responses to vaccines and cancer immunotherapies.

Neurodevelopmental disorder and immunodeficiency

Background: Neurodevelopment is closely entwined with immune maturation and function during embryogenesis. While haematopoietic-derived microglia have recognized roles in a number of neurodevelopmental processes, the contribution of molecules classically involved in the immune system (including complement, toll-like receptors, and cytokines) are also emerging. To date, approximately 11% of genes known to cause primary immunodeficiency also confer varying degrees of neurological abnormalities. These can range from intellectual disability, cognitive and behavioural disorders, through to seizures, spasticity, and motor development delay. However, very rarely are sensory processing defects associated with aberrations of the immune system. Aims: To define the clinical presentation and immune phenotype of a novel syndrome encompassing immunodeficiency, neurodevelopmental abnormalities, and altered pain sensitivity in two siblings. Methods: Comprehensive retrospective review of the patient’s charts were performed, in accordance with local research ethics board approval. Results: We describe two teenage sisters who presented with recurrent sinopulmonary infections, lymphopenia affecting both B and T cells, developmental delay, learning and processing disorder, seizures, and reduced sensitivity to pain. Other features include bronchogenic cyst, microscopic hematuria, oral ulcers, papular urticaria, and keratosis pilaris. Conclusion: An underlying defect in genes known to cause primary immunodeficiency was not identified, suggesting the role of an as-yet undefined molecule at the crossroads of immunity, neurodevelopment, and sensory processing. Statement of novelty: We report on two patients, siblings, with a novel phenotype of combined immunodeficiency, neurodevelopmental delay, and reduced sensitivity to painful stimuli.

IGFBP-6: At the Crossroads of Immunity, Tissue Repair and Fibrosis.

Insulin-like growth factors binding protein-6 (IGFBP-6) is involved in a relevant number of cellular activities and represents an important factor in the immune response, particularly in human dendritic cells (DCs). Over the past several years, significant insights into the IGF-independent effects of IGFBP-6 were discovered, such as the induction of chemotaxis, capacity to increase oxidative burst and neutrophils degranulation, ability to induce metabolic changes in DCs, and, more recently, the regulation of the Sonic Hedgehog (SHH) signaling pathway during fibrosis. IGFBP-6 has been implicated in different human diseases, and it plays a rather controversial role in the biology of tumors. Notably, well established relationships between immunity, stroma activity, and fibrosis are prognostic and predictive of response to cancer immunotherapy. This review aims at describing the current understanding of mechanisms that link IGFBP-6 and fibrosis development and at highlighting the multiple roles of IGFBP-6 to provide an insight into evolutionarily conserved mechanisms that can be relevant for inflammation, tumor immunity, and immunological diseases.

Role of lymph node stroma and microenvironment in T cell tolerance.

Lymph nodes (LNs) are at the cross roads of immunity and tolerance. These tissues are compartmentalized into specialized niche areas by lymph node stromal cells (LN SCs). LN SCs shape the LN microenvironment and guide immunological cells into different zones through establishment of a CCL19 and CCL21 gradient. Following local immunological cues, LN SCs modulate activity to support immune cell priming, activation, and fate. This review will present our current understanding of LN SC subsets roles in regulating T cell tolerance. Three major types of LN SC subsets, namely fibroblastic reticular cells, lymphatic endothelial cells, and blood endothelial cells, are discussed. These subsets serve as scaffolds to support and regulate T cell homeostasis. They contribute to tolerance by presenting peripheral tissue antigens to both CD4 and CD8 T cells. The role of LN SCs in regulating T cell migration and tolerance induction is discussed. Looking forward, recent advances in bioengineered materials and approaches to leverage LN SCs to induce T cell tolerance are highlighted, as are current clinical practices that allow for manipulation of the LN microenvironment to induce tolerance. Increased understanding of LN architecture, how different LN SCs integrate immunological cues and shape immune responses, and approaches to induce T cell tolerance will help further combat autoimmune diseases and graft rejection.

Stroke in atrial fibrillation and improving the identification of ‘high‐risk’ patients: the crossroads of immunity and thrombosis

Stroke in atrial fibrillation and improving the identification of ‘high‐risk’ patients: the crossroads of immunity and thrombosis

Quo vadis, Pep? Plant elicitor peptides at the crossroads of immunity, stress, and development.

The first line of inducible plant defence, pattern-triggered immunity (PTI), is activated by the recognition of exogenous as well as endogenous elicitors. Exogenous elicitors, also called microbe-associated molecular patterns, signal the presence of microbes. In contrast, endogenous elicitors seem to be generated and recognized under more diverse circumstances, making the evaluation of their biological relevance much more complex. Plant elicitor peptides (Peps) are one class of such endogenous elicitors, which contribute to immunity against attack by bacteria, fungi, as well as herbivores. Recent studies indicate that the Pep-triggered signalling pathways also operate during the response to a more diverse set of stresses including starvation stress. In addition, in silico data point to an involvement in the regulation of plant development, and a study on Pep-mediated inhibition of root growth supports this indication. Importantly, Peps are neither limited to the model plant Arabidopsis nor to a specific plant family like the previously intensively studied systemin peptides. On the contrary, they are present and active in angiosperms all across the phylogenetic tree, including many important crop plants. Here we summarize the progress made in research on Peps from their discovery in 2006 until now. We discuss the two main models which describe their likely function in plant immunity, highlight the studies supporting additional roles of Pep-triggered signalling and identify urgent research tasks to further uncover their biological relevance.

Interferon regulatory factors: at the crossroads of immunity, metabolism, and disease

The interferon-regulatory factor (IRF) family comprises nine members in mammals. Although this transcription factor family was originally thought to function primarily in the immune system, contributing to both the innate immune response and the development of immune cells, recent advances have revealed that IRFs plays critical roles in other biological processes, such as metabolism. Accordingly, abnormalities in the expression and/or function of IRFs have increasingly been linked to disease. Herein, we provide an update on the recent progress regarding the regulation of immune responses and immune cell development associated with IRFs. Additionally, we discuss the relationships between IRFs and immunity, metabolism, and disease, with a particular focus on the role of IRFs as stress sensors. This article is part of a Special Issue entitled: Autophagy and protein quality control in cardiometabolic diseases.

Spondyloarthropathy: disease at the crossroads of immunity

Up until recently, the prevailing paradigm relating to spondyloarthropathy (SpA) pathogenesis was that they were human leukocyte antigen (HLA)-associated, T-cell-driven autoimmune diseases. This view is now being questioned. Careful studies of well-characterised cohorts of patients with SpA, including detailed analysis of involved tissue, together with clinical trials of targeted treatments, in particular anti-tumour necrosis factor (TNF) therapies, have contributed enormously to both interest in and understanding of disease pathogenesis. In this chapter, our current knowledge and understanding of the relative contributions of the components of the innate and adaptive arms of the immune response to SpA pathogenesis is reviewed. It is clear that both arms of the immune response are involved and inter-dependent in SpA. With continued emphasis on discovery research, including detailed analysis of novel therapeutic interventions, significant additional breakthroughs in SpA are likely to be forthcoming.