Current Opinion in Immunology
ISSN / EISSN : 0952-7915 / 1879-0372
Published by: Elsevier BV (10.1016)
Total articles ≅ 4,298
Latest articles in this journal
Current Opinion in Immunology, Volume 72, pp 331-339; https://doi.org/10.1016/j.coi.2021.08.004
The binary view of inborn errors of immunity classified as either autoinflammatory conditions or primary immunodeficiency in the strict sense, that is, increased susceptibility to infection is challenged by the description of recent inborn errors of immunity (IEI) triggers leading to activation and disruption of cell death pathways, play a major part in the pathophysiology of infection and autoinflammation. In addition, molecules with a double role in the extracellular versus intracellular milieu add to the complexity. In all, in-depth study of human inborn errors of immunity will continue to instruct us on fundamental immunology and lead to novel therapeutic targets and approaches that can be used in other monogenic and polygenic/complex immune disorders.
Current Opinion in Immunology, Volume 72, pp 324-330; https://doi.org/10.1016/j.coi.2021.09.001
The skin represents the largest area for direct contact between microbes and host immunocytes and is a site for constant communication between the host and this diverse and essential microbial community. Coagulase-negative staphylococci are an abundant bacterial genus on the human skin and are regulated through various mechanisms that include the epidermal barrier environment and innate and adaptive immune systems within the epidermis and dermis. In turn, some species and strains of these bacteria produce beneficial products that augment host immunity by exerting specifically targeted antimicrobial, anti-inflammatory, or anti-neoplastic activity while also promoting broad innate and adaptive immune responses. The use of selected skin commensals as a therapeutic has shown promise in recent human clinical trials. This emerging concept of bacteriotherapy is defining mechanisms of action and validating the dependence on the microbiome for maintenance of immune homeostasis.
Current Opinion in Immunology, Volume 72, pp 298-308; https://doi.org/10.1016/j.coi.2021.07.010
Although IL-2 was first recognized as growth factor for T cells, it is now also appreciated to be a key regulator of T cells through its effects on regulatory T cells (Treg). The IL-2 receptor (IL-2R) subunits’ different (i) ligand affinities, (ii) dimerization or trimerization relationships with other cytokine subunits, (iii) expression across multiple cell types, and (iv) downstream signaling effects, largely dictate cellular tolerance and antimicrobial processes. Defects in IL-2Rγ result in profound and almost universally fatal immune deficiency, unless treated with hematopoietic stem cell transplantation (HSCT). Defects in IL-2Rα and IL-2Rβ result in more limited infection susceptibility, particularly to herpesviruses. However, the most prominent clinical symptomatology for IL-2Rα and IL-2Rβ defects include multi-organ autoimmunity and inflammation, consistent with the critical role of IL-2 in establishing and maintaining immune tolerance. Here, we review how we have arrived at our current understanding of the complex roles of IL-2/2R in host defense and tolerance focusing on the insights gained from human clinical immunology.
Current Opinion in Immunology, Volume 72, pp 318-323; https://doi.org/10.1016/j.coi.2021.08.001
Chronic mucocutaneous candidiasis (CMC) is one of the earliest and most frequent clinical manifestations of autosomal recessive autoimmune polyendocrine syndrome type 1 (APS-1), a monogenic inborn error of immunity caused by deleterious variants of the autoimmune regulator (AIRE) gene. APS-1 patients suffer from various autoimmune diseases, due to the defective thymic deletion of autoreactive T cells, and the development of a large range of autoantibodies (auto-Abs) against various tissue antigens, and some cytokines. The mechanisms underlying CMC remained elusive for many years, until the description in 2010 of high serum titers of neutralizing auto-Abs against IL-17A, IL-17F, and/or IL-22, which are present in almost all APS-1 patients. Excessively high mucosal concentrations of IFN-γ were recently proposed as an alternative mechanism for CMC in APS-1.
Current Opinion in Immunology, Volume 74, pp 1-8; https://doi.org/10.1016/j.coi.2021.07.006
T cell receptor (TCR) sequencing has emerged as a powerful new technology in analysis of the host–tumour interaction. The advances in NextGen sequencing technologies, coupled with powerful novel bioinformatic tools, allow quantitative and reproducible characterisation of repertoires from tumour and blood samples from an increasing number of patients with a variety of solid cancers. In this review, we consider how global metrics such as T cell clonality and diversity can be extracted from these repertoires and used to give insight into the mechanism of action of immune checkpoint blockade. Furthermore, we explore how the analysis of TCR overlap between repertories can help define spatial and temporal heterogeneity of the anti-tumoural immune response. Finally, we review how analysis of TCR sequence and structure, either of individual TCRs or from sets of related TCRs can be used to annotate the antigenic specificity, with important implications for the development of personalised adoptive cellular immunotherapies.
Current Opinion in Immunology, Volume 73, pp 25-33; https://doi.org/10.1016/j.coi.2021.07.013
The ability of the innate and adaptive immune systems to communicate with each other is central to protective immune responses and maintenance of host health. Myeloid cells of the innate immune system are able to sense microbial ligands, perturbations in cellular homeostasis, and virulence factors, thereby allowing them to relay distinct pathogen-specific information to naïve T cells in the form of pathogen-derived peptides and a unique cytokine milieu. Once primed, effector T helper cells produce lineage-defining cytokines to help combat the original pathogen, and a subset of these cells persist as memory or effector-memory populations. These memory T cells then play a dual role in host protection by not only responding rapidly to reinfection, but by also directly instructing myeloid cells to express licensing cytokines. This means there is a bi-directional flow of information first from the innate to the adaptive immune system, and then from the adaptive back to innate immune system. Here, we focus on how signals, first from pathogens and then from primed effector and memory T cells, are integrated by myeloid cells and its consequences for protective immunity or systemic inflammation.
Current Opinion in Immunology, Volume 72, pp 309-317; https://doi.org/10.1016/j.coi.2021.07.004
Viral encephalitis is a major neglected medical problem. Host defense mechanisms against viral infection of the central nervous system (CNS) have long remained unclear. The few previous studies of CNS-specific immunity to viruses in mice in vivo and humans in vitro have focused on the contributions of circulating leukocytes, resident microglial cells and astrocytes, with neurons long considered passive victims of viral infection requiring protection from extrinsic antiviral mechanisms. The last decade has witnessed the gradual emergence of the notion that neurons also combat viruses through cell-intrinsic mechanisms. Forward genetic approaches in humans have shown that monogenic inborn errors of TLR3, IFN-α/β, or snoRNA31 immunity confer susceptibility to herpes simplex virus 1 (HSV-1) infection of the forebrain, whereas inborn errors of DBR1 underlie brainstem infections due to various viruses, including HSV-1. The study of human pluripotent stem cell (hPSC)-derived CNS-resident cells has unraveled known (i.e. TLR3-dependent IFN-α/β immunity) and new (i.e. snoRNA31-dependent or DBR1-dependent immunity) cell-intrinsic antiviral mechanisms operating in neurons. Reverse genetic approaches in mice have confirmed that some known antiviral mechanisms also operate in mouse neurons (e.g. TLR3 and IFN-α/β immunity). The search for human inborn errors of immunity (IEIs) underlying various forms of viral encephalitis, coupled with mouse models in vivo, and hPSC-based culture models of CNS and peripheral nervous system cells and organoids in vitro, should shed further light on the cell-specific and tissue-specific mechanisms of host defense against viruses in the human brain.
Current Opinion in Immunology, Volume 72, pp 286-297; https://doi.org/10.1016/j.coi.2021.07.011
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is caused by mutations in the Autoimmune Regulator (AIRE) gene, which impair the thymic negative selection of self-reactive T-cells and underlie the development of autoimmunity that targets multiple endocrine and non-endocrine tissues. Beyond autoimmunity, APECED features heightened susceptibility to certain specific infections, which is mediated by anti-cytokine autoantibodies and/or T-cell driven autoimmune tissue injury. These include the ‘signature’ APECED infection chronic mucocutaneous candidiasis (CMC), but also life-threatening coronavirus disease 2019 (COVID-19) pneumonia, bronchiectasis-associated bacterial pneumonia, and sepsis by encapsulated bacteria. Here we discuss the expanding understanding of the immunological mechanisms that contribute to infection susceptibility in this prototypic syndrome of impaired central tolerance, which provide the foundation for devising improved diagnostic and therapeutic strategies for affected patients.
Current Opinion in Immunology, Volume 73, pp 16-24; https://doi.org/10.1016/j.coi.2021.07.007
Monocytes are innate immune cells that develop in the bone marrow and are continually released into circulation, where they are poised to enter tissues in response to homeostatic or inflammatory cues. Monocytes are highly plastic cells that can differentiate in tissues into a variety of monocyte-derived cells to replace resident tissue macrophages, promote inflammatory responses, or resolution of inflammation. As such, monocytes can support tissue homeostasis as well as productive and pathogenic immune responses. Recent work shows previously unappreciated heterogeneity in monocyte development and differentiation in the steady state and during infectious, autoimmune, and inflammatory diseases. Monocyte-derived cells can differentiate via signals from cytokines, pattern recognition receptors or other factors, which can influence development in the bone marrow or in tissues. An improved understanding of these monocyte-derived cells and the signals that drive their differentiation in distinct inflammatory settings could allow for targeting these pathways in pathological inflammation.
Current Opinion in Immunology, Volume 71, pp 132-137; https://doi.org/10.1016/j.coi.2021.06.018
The TNF superfamily member a proliferation inducing ligand (APRIL, TNFSF13) plays a late role in humoral immunity at the level of antibody-producing plasmocytes. The recent characterization of the first immunodeficient patient with an inactivating mutation in the APRIL gene provided the last piece of functional data lacking in the human system. Based on this function, APRIL has been considered as a valuable target to dampen unwanted antibody production. After reviewing the late data acquired on the physiological function of APRIL in humoral immunity, we will here review the state of the art regarding APRIL targeting in autoimmune diseases.