Search

Intermittent fasting (IF) refers to periodic fasting routines, that caloric intake is minimized not by meal portion size reduction but by intermittently eliminating ingestion of one or several consecutive meals. IF can instigate comprehensive and multifaceted alterations in energy metabolism, these metabolic channels may aboundingly function as primordial mechanisms that interface with the immune system, instigating intricate immune transformations. This review delivers a comprehensive understanding of IF, paying particular attention to its influence on the immune system, thus seeking to bridge these two research domains. We explore how IF effects lipid metabolism, hormonal levels, circadian rhythm, autophagy, oxidative stress, gut microbiota, and intestinal barrier integrity, and conjecture about the mechanisms orchestrating the intersect between these factors and the immune system. Moreover, the review includes research findings on the implications of IF on the immune system and patients burdened with autoimmune diseases. [ABSTRACT FROM AUTHOR]

What infants eat early in life may shape the immune system and have long‐standing consequences on the health of the host during later life. In the early months post‐birth, breast milk serves as the exclusive and optimal nourishment for infants, facilitating crucial molecular exchanges between mother and infant. Recent advances have uncovered that some maternal factors influence breastfed infant outcomes, including the risk of food allergy (FA). To date, accumulated data show that breastfed infants have a lower risk of FA. However, the issue remains disputed, some reported preventive allergy effects, while others did not confirm such effects, or if identified, protective effects were limited to early childhood. The disputed outcomes may be attributed to the maternal status, as it determines the compounds of the breast milk that breastfed infants are exposed to. In this review, we first detail the compounds in breast milk and their roles in infant FA. Then, we present maternal factors resulting in alterations in breast milk compounds, such as maternal health status, maternal diet intake, and maternal food allergen intake, which subsequently impact FA in breastfed infants. Finally, we analyze how these compounds in breast milk alleviated the infant FA by mother‐to‐infant transmission. Altogether, the mechanisms are primarily linked to the synergetic and direct effects of compounds in breast milk, via promoting the colonization of gut microbiota and the development of the immune system in infants. [ABSTRACT FROM AUTHOR]

Gliotoxin (GT), a secondary metabolite and virulence factor of the fungal pathogen Aspergillus fumigatus, suppresses innate immunity and supports the suppression of host immune responses. Recently, we revealed that GT blocks the formation of the chemotactic lipid mediator leukotriene (LT)B4 in activated human neutrophils and monocytes, and in rodents in vivo, by directly inhibiting LTA4 hydrolase. Here, we elucidated the impact of GT on LTB4 biosynthesis and the entire lipid mediator networks in human M1‐ and M2‐like monocyte‐derived macrophages (MDMs) and in human tissue‐resident alveolar macrophages. In activated M1‐MDMs with high capacities to generate LTs, the formation of LTB4 was effectively suppressed by GT, connected to attenuated macrophage phagocytic activity as well as human neutrophil movement and migration. In resting macrophages, especially in M1‐MDMs, GT elicited strong formation of prostaglandins, while bacterial exotoxins from Staphylococcus aureus evoked a broad spectrum of lipid mediator biosynthesis in both MDM phenotypes. We conclude that GT impairs functions of activated innate immune cells through selective suppression of LTB4 biosynthesis, while GT may also prime the immune system by provoking prostaglandin formation in macrophages. [ABSTRACT FROM AUTHOR]

The innate immune response is under selection pressures from changing environments and pathogens. While sequence evolution can be studied by comparing rates of amino acid mutations within and between species, how a gene's birth and death contribute to the evolution of immunity is less known. Short open reading frames, once regarded as untranslated or transcriptional noise, can often produce micropeptides of <100 amino acids with a wide array of biological functions. Some micropeptide sequences are well conserved, whereas others have no evolutionary conservation, potentially representing new functional compounds that arise from species‐specific adaptations. To date, few reports have described the discovery of novel micropeptides of the innate immune system. The diversity of immune‐related micropeptides is a blind spot for gene and functional annotation. Immune‐related micropeptides represent a potential reservoir of untapped compounds for understanding and treating disease. This review consolidates what is currently known about the evolution and function of innate immune‐related micropeptides to facilitate their investigation. [ABSTRACT FROM AUTHOR]

Cancer immunotherapy has revolutionized the treatment landscape by harnessing the power of the immune system to combat malignancies. Two of the most promising players in this field are cluster of differentiation 24 (CD24) and sialic acid‐binding Ig‐like lectin 10 (Siglec‐10), and both of them play pivotal roles in modulating immune responses. CD24, a cell surface glycoprotein, emerges as a convincing fundamental signal transducer for therapeutic intervention, given its significant implication in the processes related to tumour progression and immunogenic evasion. Additionally, the immunomodulatory functions of Siglec‐10, a prominent member within the Siglec family of immune receptors, have recently become a crucial point of interest, particularly in the context of the tumour microenvironment. Hence, the intricate interplay of both CD24 and Siglec‐10 assumes a critical role in fostering tumour growth, facilitating metastasis and also orchestrating immune evasion. Recent studies have found multiple evidences supporting the therapeutic potential of targeting CD24 in cancer treatment. Siglec‐10, on the other hand, exhibits immunosuppressive properties that contribute to immune tolerance within the tumour microenvironment. Therefore, we delve into the complex mechanisms through which Siglec‐10 modulates immune responses and facilitates immune escape in cancer. Siglec‐10 also acts as a viable target for cancer immunotherapy and presents novel avenues for the development of therapeutic interventions. Furthermore, we examine the synergy between CD24 and Siglec‐10 in shaping the immunosuppressive tumour microenvironment and discuss the implications for combination therapies. Therefore, understanding the roles of CD24 and Siglec‐10 in cancer immunotherapy opens exciting possibilities for the development of novel therapeutics. [ABSTRACT FROM AUTHOR]

Circadian rhythms are a ubiquitous feature in nearly all living organisms, representing oscillatory patterns with a 24‐h cycle that are widespread across various physiological processes. Circadian rhythms regulate a multitude of physiological systems, including the immune system. At the molecular level, most immune cells autonomously express clock‐regulating genes, which play critical roles in regulating immune cell functions. These functions encompass migration, phagocytic activity, immune cell metabolism (such as mitochondrial structural function and metabolism), signalling pathway activation, inflammatory responses, innate immune recognition, and adaptive immune processes (including vaccine responses and pathogen clearance). The endogenous circadian clock orchestrates multifaceted rhythmicity within the immune system, optimizing immune surveillance and responsiveness; this bears significant implications for maintaining immune homeostasis and resilience against diseases. This work provides an overview of circadian rhythm regulation within the immune system. [ABSTRACT FROM AUTHOR]

The coronavirus disease 2019 (COVID-19) pandemic has created unprecedented challenges worldwide. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19 and has a complex interaction with the immune system, including growing evidence of sex-specific differences in the immune response. Sex-disaggregated analyses of epidemiological data indicate that males experience more severe symptoms and suffer higher mortality from COVID-19 than females. Many behavioural risk factors and biological factors may contribute to the different immune response. This review examines the immune response to SARS-CoV-2 infection in the context of sex, with emphasis on potential biological mechanisms explaining differences in clinical outcomes. Understanding sex differences in the pathophysiology of SARS-CoV-2 infection will help promote the development of specific strategies to manage the disease.

It is widely understood that cancer is a significant cause of morbidity and mortality worldwide. Despite numerous available treatments, prognosis for many remains poor, thus, the development of novel therapies remains essential. Given the incredible success of many immunotherapies in this field, the important contribution of the immune system to the control, and elimination, of malignancy is clear. While many immunotherapies target higher‐order pathways, for example, through promoting T‐cell activation via immune checkpoint blockade, the potential to target specific immunological pathways is largely not well researched. Precisely understanding how immunity can be tailored to respond to specific challenges is an exciting idea with great potential, and may trigger the development of new therapies for cancer. Inborn Errors of Immunity (IEI) are a group of rare congenital disorders caused by gene mutations that result in immune dysregulation. This heterogeneous group, spanning widespread, multisystem immunopathology to specific immune cell defects, primarily manifest in immunodeficiency symptoms. Thus, these patients are particularly susceptible to life‐threatening infection, autoimmunity and malignancy, making IEI an especially complex group of diseases. While precise mechanisms of IEI‐induced malignancy have not yet been fully elucidated, analysis of these conditions can highlight the importance of particular genes, and downstream immune responses, in carcinogenesis and may help inform mechanisms which can be utilised in novel immunotherapies. In this review, we examine the links between IEIs and cancer, establishing potential connections between immune dysfunction and malignancy and suggesting roles for specific immunological mechanisms involved in preventing carcinogenesis, thus, guiding essential future research focused on cancer immunotherapy and providing valuable insight into the workings of the immune system in both health and disease. [ABSTRACT FROM AUTHOR]

The complement system, an arm of the innate immune system plays a critical role in both health and disease. The complement system is highly complex with dual possibilities, helping or hurting the host, depending on the location and local microenvironment. The traditionally known functions of complement include surveillance, pathogen recognition, immune complex trafficking, processing and pathogen elimination. The noncanonical functions of the complement system include their roles in development, differentiation, local homeostasis and other cellular functions. Complement proteins are present in both, the plasma and on the membranes. Complement activation occurs both extra‐ and intracellularly, which leads to considerable pleiotropy in their activity. In order to design more desirable and effective therapies, it is important to understand the different functions of complement, and its location‐based and tissue‐specific responses. This manuscript will provide a brief overview into the complex nature of the complement cascade, outlining some of their complement‐independent functions, their effects at different locale, and their implication in disease settings. [ABSTRACT FROM AUTHOR]

Effective delivery of luminal antigens to the underlying immune system is the initial step in generating antigen‐specific responses in the gut. However, a large body of information regarding the immune response activation process remains unknown. Recently, goblet cells (GCs) have been reported to form goblet cell‐associated antigen passages (GAPs). Luminal antigens can be transported inside GAPs and reach subepithelial immune cells to induce antigen‐specific immune responses, contributing largely to gut homeostasis and the prevention of some intestinal diseases like allergic enteritis and bacterial translocation. In this article, we summarized recent observations on the formation of intestinal GAPs and their roles in mucosal immunity. We hope that this review can offer a fresh perspective and valuable insights for clinicians and researchers interested in studying the intestinal immune system. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID‐19) is a respiratory tract infection caused by the new severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). An adequate T cell response is essential not only for fighting disease but also for the creation of immune memory. Thus, the present study aims to evaluate the T cells of patients with moderate, severe and critical COVID‐19 not only at the time of illness but also 2 months after diagnosis to observe whether changes in this compartment persist. In this study, 166 COVID‐19 patients were stratified into moderate/severe and critical disease categories. The maturation and activation of T cells were evaluated through flow cytometry. In addition, Treg cells were analysed. Until 15 days after diagnosis, patients presented a reduction in absolute and relative T lymphocyte counts. After 2 months, in moderate/severe patients, the counts returned to a similar level as that of the control group. In convalescent patients who had a critical illness, absolute T lymphocyte values increased considerably. Patients with active disease did not show differentiation of T cells. Nonetheless, after 2 months, patients with critical COVID‐19 showed a significant increase in CD4+ EMRA (CD45RA+ effector memory) T lymphocytes. Furthermore, COVID‐19 patients showed delayed T cell activation and reduced CD8+ suppressor T cells even 2 months after diagnosis. A reduction in CD4+ Treg cells was also observed, and their numbers returned to a similar level as that of healthy controls in convalescent patients. The results demonstrate that COVID‐19 patients have a delayed activation and differentiation of T cells. In addition, these patients have a great reduction of T cells with a suppressor phenotype. [ABSTRACT FROM AUTHOR]

Oncogenic Merkel cell polyomavirus (MCPyV) provokes a widespread and asymptomatic infection in humans. Herein, sera from healthy children and young adults (HC, n = 344) aged 0–20 years old were evaluated for anti‐MCPyV immunoglobulin G (IgG) and IgM antibodies employing a recently developed immunoassay. Serum MCPyV IgG data from healthy subjects (HS, n = 510) and elderlies (ES, n = 226), aged 21–65/66–100 years old, from our previous studies, were included. The anti‐MCPyV IgG and IgM rates in HC sera were 40.7% and 29.7%, respectively. A lower prevalence of anti‐MCPyV IgGs was found in HC aged 0–5 years old (13%) compared to 6–10 (52.3%), 11–15 (60.5%) and 16–20 years old (61.6%) cohorts. Age‐stratified HCs exhibited similar anti‐MCPyV IgM rates (27.9%–32.9%). Serological profiles indicated that anti‐MCPyV IgGs and IgMs had low optical densities (ODs) during the first years of life, while IgM ODs appeared to decrease throughout young adulthood. A lower anti‐MCPyV IgGs rate was found in HC (40.7%) than HS (61.8%) and ES (63.7%). Upon the 5‐years range age‐stratification, a lower anti‐MCPyV IgGs rate was found in the younger HC cohort aged 0–5 years old compared to the remaining older HC/HS/ES cohorts (52.3%–72%). The younger HC cohort exhibited the lowest anti‐MCPyV IgG ODs than the older cohorts. Low anti‐MCPyV IgMs rates and ODs were found in the 21–25 (17.5%) and 26–30 (7.7%) years old cohorts. Our data indicate that, upon an early‐in‐life seroconversion, the seropositivity for oncogenic MCPyV peaks in late childhood/young adulthood and remains at high prevalence and relatively stable throughout life. [ABSTRACT FROM AUTHOR]

The cyclic GMP–AMP synthase–stimulator of interferon genes (cGAS–STING) pathway is an essential component of the innate immune system and is central to the identification of abnormal DNA leakage caused by ionising radiation (IR) damage. Cell‐intrinsic cGAS–STING initiation has been revealed to have tremendous potential for facilitating interferon synthesis and T‐cell priming. Targeting the cGAS–STING axis has been proposed as a strategy to improve radiosensitivity or enhance immunosurveillance. However, due to the complex biology of the irradiated tumour microenvironment and the extensive involvement of the cGAS–STING pathway in various physiological and pathological processes, many defects in this strategy limit the therapeutic effect. Here, we outline the molecular mechanisms by which IR activates the cGAS–STING pathway and analyse the dichotomous roles of the cGAS–STING pathway in modulating cancer immunity after radiotherapy (RT). Then, based on the crosstalk between the cGAS–STING pathway and other signalling events induced by IR, such as necroptosis, autophagy and other cellular effects, we discuss the immunomodulatory actions of the broad cGAS–STING signalling network in RT and their potential therapeutic applications. Finally, recent advances in combination therapeutic strategies targeting cGAS–STING in RT are explored. [ABSTRACT FROM AUTHOR]

Microglia, the resident immune cells in the retina and nervous system, make irreplaceable contributions to the maintenance of normal homeostasis and immune surveillance of these systems. Recently, great progress has been made in determining the origin, distribution, features and functions of retinal microglia and in identifying their roles in retinal diseases. In the retinal microenvironment, microglia constantly monitor changes in their surroundings and maintain balanced functions by communicating with other retinal cells. When disturbed, activated microglia may kill degenerated neurons and photoreceptors through phagocytosis and exacerbate retinal injury by producing multiple proinflammatory mediators. Numerous animal studies and in situ analyses of human tissue have shown that retinal microglia are involved in multiple retinal diseases. The functions and mechanisms of activated microglia in retinal disorders are gradually being elucidated. Increasing evidence points towards the dual roles of microglia in the retina and they are regulated by many factors. How to inhibit the detrimental effects of microglia and promote beneficial effects are worth studying. This review focuses primarily on the features and functions of microglia and how they participate in retinal diseases based on existing research findings. We also discuss current opinions about microglial transdifferentiation. [ABSTRACT FROM AUTHOR]

T‐cell exhaustion has been extensively researched, compared with B‐cell exhaustion and NK‐cell exhaustion, which have received considerably less attention; and there is less of a consensus on the precise definitions of NK‐cell and B‐cell exhaustion. NK‐cell exhaustion, B‐cell exhaustion and T‐cell exhaustion are examples of lymphocyte exhaustion, and they have several differences and similarities. Lymphocyte exhaustion is also frequently confused with anergy, cellular senescence and suppression, because these conditions can have significant overlapping similarities with exhaustion. An additional source of confusion is due to the fact that lymphocyte exhaustion is not a binary state, but instead has a spectrum of severity induced by different levels and duration of continuous antigenic stimulation. Concurrent multiple types of lymphocyte exhaustion are possible, and this situation is herein called poly‐lymphocyte exhaustion. Poly‐lymphocyte exhaustion for the same cancer or pathogen would be especially dangerous. As there are significant advantages for a pathogen by inducing poly‐lymphocyte exhaustion in an immune system, there are pathogens with an evolved capability to induce poly‐lymphocyte exhaustion. These pathogens may include certain manipulative viruses, bacteria, fungi and protozoan parasites. [ABSTRACT FROM AUTHOR]

Annexin‐A1 has a well‐defined anti‐inflammatory role in the innate immune system, but its function in adaptive immunity remains controversial. This glucocorticoid‐induced protein has been implicated in a range of inflammatory conditions and cancers, as well as being found to be overexpressed on the T cells of patients with autoimmune disease. Moreover, the formyl peptide family of receptors, through which annexin‐A1 primarily signals, has also been implicated in these diseases. In contrast, treatment with recombinant annexin‐A1 peptides resulted in suppression of inflammatory processes in murine models of inflammation. This review will focus on what is currently known about annexin‐A1 in health and disease and discuss the potential of this protein as a biomarker and therapeutic target. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID‐19) is a respiratory infection caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) and marked by an intense inflammatory response and immune dysregulation in the most severe cases. In order to better clarify the relationship between peripheral immune system changes and the severity of COVID‐19, this study aimed to evaluate the frequencies and absolute numbers of peripheral subsets of neutrophils, monocytes, and dendritic cells (DCs), in addition to quantifying the levels of inflammatory mediators. One hundred fifty‐seven COVID‐19 patients were stratified into mild, moderate, severe, and critical disease categories. The cellular components and circulating cytokines were assessed by flow cytometry. Nitric oxide (NOx) and myeloperoxidase (MPO) levels were measured by colourimetric tests. COVID‐19 patients presented neutrophilia, with signs of emergency myelopoiesis. Alterations in the monocytic component were observed in patients with moderate to critical illness, with an increase in classical monocytes and a reduction in nonclassical monocytes, in addition to a reduction in the expression of HLA‐DR in all subtypes of monocytes, indicating immunosuppression. DCs, especially plasmacytoid DCs, also showed a large reduction in moderate to critical patients. COVID‐19 patients showed an increase in MPO, interleukin (IL)‐12, IL‐6, IL‐10, and IL‐8, accompanied by a reduction in IL‐17A and NOx. IL‐10 levels ≥14 pg/ml were strongly related to the worst outcome, with a sensitivity of 78·3% and a specificity of 79·1%. The results of this study indicate the presence of systemic effects induced by COVID‐19, which appear to be related to the pathophysiology of the disease, highlighting the potential of IL‐10 as a possible prognostic biomarker for COVID‐19. [ABSTRACT FROM AUTHOR]

The immune system plays fundamental roles in the mammary gland, shaping developmental processes and controlling inflammation during infection and cancer.Here, we reveal unanticipated heterogeneity in the myeloid cell compartment duringdevelopment of virgin, pregnant, lactating and involuting mouse mammary glands,and in milk. We investigate the functional consequences of individual and compoundchemokine receptor deficiency on cell recruitment. Diverse myeloid cell recruitmentwas also shown in models of sterile inflammation and bacterial infection.Strikingly, we have shown that inflammation and infection can alter the abundanceof terminal end buds, a key developmental structure, within the pubertal mammarygland. This previously unknown effect of inflammatory burden during puberty couldhave important implications for understanding pubertal development. [ABSTRACT FROM AUTHOR]

Often referred to as the bridge between innate and adaptive immunity, dendritic cells (DCs) are professional antigen‐presenting cells (APCs) that constitute a unique, yet complex cell system. Among other APCs, DCs display the unique property of inducing protective immune responses against invading microbes, or cancer cells, while safeguarding the proper homeostatic equilibrium of the immune system and maintaining self‐tolerance. Unsurprisingly, DCs play a role in many diseases such as autoimmunity, allergy, infectious disease and cancer. This makes them attractive but challenging targets for therapeutics. Since their initial discovery, research and understanding of DC biology have flourished. We now recognize the presence of multiple subsets of DCs distributed across tissues. Recent studies of phenotype and gene expression at the single cell level have identified heterogeneity even within the same DC type, supporting the idea that DCs have evolved to greatly expand the flexibility of the immune system to react appropriately to a wide range of threats. This review is meant to serve as a quick and robust guide to understand the basic divisions of DC subsets and their role in the immune system. Between mice and humans, there are some differences in how these subsets are identified and function, and we will point out specific distinctions as necessary. Throughout the text, we are using both fundamental and therapeutic lens to describe overlaps and distinctions and what this could mean for future research and therapies. [ABSTRACT FROM AUTHOR]

The IL‐7/IL‐7R pathway plays a vital role in the immune system, especially in the inflammatory response. Monocytes/macrophages (osteoclast precursors) have been recently recognized as important participants in the osteoclastogenesis of rheumatoid arthritis (RA) patients. Here, we aimed to investigate the therapeutic potential of IL‐7/IL‐7R pathway in RA and to determine whether it could restrain osteoclastogenic functions and therefore ameliorate RA. Firstly, collagen‐induced arthritis (CIA) mice were administered with IL‐7Rα‐target antibodies to assess their therapeutic effect on arthritis. We found that blockade of the IL‐7/IL‐7R pathway protected CIA mice from bone destruction in addition to inducing inflammatory remission, by altering the RANKL/RANK/OPG ratio and consequently decreasing osteoclast formation. To explore the effect and mechanism of this pathway, bone marrow cells were induced to osteoclasts and treated with IL‐7, a STAT5 inhibitor or supernatants from T cells. The results showed that the IL‐7/IL‐7R pathway played a direct inhibitory role in osteoclast differentiation via STAT5 signalling pathway in a RANKL‐induced manner. We applied flow cytometry to analyse the effect of IL‐7 on T‐cell RANKL expression and found that IL‐7/IL‐7R pathway had an indirect role in the osteoclast differentiation process by enhancing the RANKL expression on T cells. In conclusion, the IL‐7/IL‐7R pathway exhibited a dual effect on osteoclastogenesis of CIA mice by interacting with osteoimmunology processes and could be a novel therapeutic target for autoimmune diseases such as RA. [ABSTRACT FROM AUTHOR]

Summary: Dysfunction of the immune system underlies a plethora of human diseases, requiring the development of immunomodulatory therapeutic intervention. To date, most strategies employed have been focusing on the modification of T lymphocytes, and although remarkable improvement has been obtained, results often fall short of the intended outcome. Recent cutting‐edge technologies have highlighted macrophages as potential targets for disease control. Macrophages play central roles in development, homeostasis and host defence, and their dysfunction and dysregulation have been implicated in the onset and pathogenesis of multiple disorders including cancer, neurodegeneration, autoimmunity and metabolic diseases. Recent advancements have led to a greater understanding of macrophage origin, diversity and function, in both health and disease. Over the last few years, a variety of strategies targeting macrophages have been developed and these open new therapeutic opportunities. Here, we review the progress in macrophage reprogramming in various disorders and discuss the potential implications and challenges for macrophage‐targeted approaches in human disease. [ABSTRACT FROM AUTHOR]

Summary: Within each individual, the adaptive immune system generates a repertoire of cells expressing receptors capable of recognizing diverse potential pathogens. The theoretical diversity of the T‐cell receptor (TCR) repertoire exceeds the actual size of the T‐cell population in an individual by several orders of magnitude – making the observation of identical TCRs in different individuals extremely improbable if all receptors were equally likely. Despite this disparity between the theoretical and the realized diversity of the repertoire, these 'public' receptor sequences have been identified in autoimmune, cancer and pathogen interaction contexts. Biased generation processes explain the presence of public TCRs in the naive repertoire, but do not adequately explain the different abundances of these public TCRs. We investigate and characterize the distribution of genomic TCR‐β sequences of naive CD8+ T cells from three genetically identical mice, comparing non‐productive (non‐functional sequences) and productive sequences. We find public TCR‐β sequences at higher abundances compared with unshared sequences in the productive, but not in the non‐productive, repertoire. We show that neutral processes such as recombination biases, codon degeneracy and generation probability do not fully account for these differences, and conclude that thymic or peripheral selection plays an important role in increasing the abundances of public TCR‐β sequences. [ABSTRACT FROM AUTHOR]

Summary: The presentation of antigenic peptides by major histocompatibility complex (MHC) class I and class II molecules is crucial for activation of the adaptive immune system. The nucleotide‐binding domain and leucine‐rich repeat receptor family members CIITA and NLRC5 function as the major transcriptional activators of MHC class II and class I gene expression, respectively. Since the identification of NLRC5 as the master regulator of MHC class I and class‐I‐related genes, there have been major advances in understanding the function of NLRC5 in infectious diseases and cancer. Here, we discuss the biological significance and mechanism of NLRC5‐dependent MHC class I expression. [ABSTRACT FROM AUTHOR]

Summary: In the face of ineffective vaccines, increasing antibiotic resistance and the decline in new antibacterial drugs in the pipeline, tuberculosis (TB) still remains pandemic. Exposure to Mycobacterium tuberculosis (Mtb), which causes TB, results in either direct elimination of the pathogen, most likely by the innate immune system, or infection and containment that requires both innate and adaptive immunity to form the granuloma. Host defence strategies against infectious diseases are comprised of both host resistance, which is the ability of the host to prevent invasion or to eliminate the pathogen, and disease tolerance, which is defined by limiting the collateral tissue damage. In this review, we aim to examine the metabolic demands of the immune cells involved in both host resistance and disease tolerance, chiefly the macrophage and T‐lymphocyte. We will further discuss how baseline metabolic heterogeneity and inflammation‐driven metabolic reprogramming during infection are linked to their key immune functions containing mycobacterial growth and instructing protective immunity. Targeting key players in immune cellular metabolism may provide a novel opportunity for treatments at different stages of TB disease. [ABSTRACT FROM AUTHOR]

Summary: Neurodegeneration is characterized by gradual onset and limited availability of specific biomarkers. Apart from various aetiologies such as infection, trauma, genetic mutation, the interaction between the immune system and CNS is widely associated with neuronal damage in neurodegenerative diseases. The immune system plays a distinct role in disease progression and cellular homeostasis. It induces cellular and humoral responses, and enables tissue repair, cellular healing and clearance of cellular detritus. Aberrant and chronic activation of the immune system can damage healthy neurons. The pro‐inflammatory mediators secreted by chief innate immune components, the complement system, microglia and inflammasome can augment cytotoxicity. Furthermore, these inflammatory mediators accelerate microglial activation resulting in progressive neuronal loss. Various animal studies have been carried out to unravel the complex pathology and ascertain biomarkers for these harmful diseases, but have had limited success. The present review will provide a thorough understanding of microglial activation, complement system and inflammasome generation, which lead the healthy brain towards neurodegeneration. In addition to this, possible targets of immune components to confer a strategic treatment regime for the alleviation of neuronal damage are also summarized. [ABSTRACT FROM AUTHOR]

Summary: Circadian rhythms influence daily molecular oscillations in gene/protein expression and aspects of biology and physiology, including behaviour, body temperature and sleep–wake cycles. These circadian rhythms have been associated with a number of metabolic, immune and microbial changes that correlate with health and susceptibility to disease, including infection. While light is the main inducer of circadian rhythms, other factors, including the microbiota, can have important effects on peripheral rhythms. The microbiota have been of significant interest to many investigators over the past decade, with the development of molecular techniques to identify large numbers of species and their function. These studies have shown microbial associations with disease susceptibility, and some of these have demonstrated that alterations in microbiota cause disease. Microbial circadian oscillations impact host metabolism and immunity directly and indirectly. Interestingly, microbial oscillations also regulate host circadian rhythms, and the host circadian rhythms in turn modulate microbial composition. Thus, it is of considerable interest and importance to understand the crosstalk between circadian rhythms and microbiota and especially the microbial influences on the host. In this review, we aim to discuss the role of circadian microbial oscillations and how they influence host immunity. In addition, we discuss how host circadian rhythms can also modulate microbial rhythms. We also discuss potential connections between microbes and circadian rhythms and how these may be used therapeutically to maximize clinical success. [ABSTRACT FROM AUTHOR]

Summary: T cells must display diversity regarding both the cell state and T‐cell receptor (TCR) repertoire to provide effective immunity against pathogens; however, the generation and evolution of cellular T‐cell heterogeneity in the adaptive immune system remains unclear. In the present study, a combination of multiplex PCR and immune repertoire sequencing (IR‐seq) was used for a standardized analysis of the TCR β‐chain repertoire of CD4+ naive, CD4+ memory, CD8+ naive and CD8+ memory T cells. We showed that the T‐cell subsets could be distinguished from each another with regard to the TCR β‐chain (TCR‐β) diversity, CDR3 length distribution and TRBV usage, which could be observed both in the preselection and in the post‐selection repertoire. Moreover, the Dβ‐Jβ and Vβ‐Dβ combination patterns at the initial recombination step, template‐independent insertion of nucleotides and inter‐subset overlap were consistent between the pre‐ and post‐selection repertoires, with a remarkably positive correlation. Taken together, these results support differentiation of the CD4+ and CD8+ T‐cell subsets prior to thymic selection, and these differences survived both positive and negative selection. In conclusion, these findings provide deeper insight into the generation and evolution of TCR repertoire generation. [ABSTRACT FROM AUTHOR]

Summary: Immunoglobulins emerging from B lymphocytes and capable of recognizing almost all kinds of antigens owing to the extreme diversity of their antigen‐binding portions, known as variable (V) regions, play an important role in immune responses. The exons encoding the V regions are known as V (variable), D (diversity), or J (joining) genes. V, D, J segments exist as multiple copy arrays on the chromosome. The recombination of the V(D)J gene is the key mechanism to produce antibody diversity. The recombinational process, including randomly choosing a pair of V, D, J segments, introducing double‐strand breaks adjacent to each segment, deleting (or inverting in some cases) the intervening DNA and ligating the segments together, is defined as V(D)J recombination, which contributes to surprising immunoglobulin diversity in vertebrate immune systems. To enhance both the ability of immunoglobulins to recognize and bind to foreign antigens and the effector capacities of the expressed antibodies, naive B cells will undergo class switching recombination (CSR) and somatic hypermutation (SHM). However, the genetics mechanisms of V(D)J recombination, CSR and SHM are not clear. In this review, we summarize the major progress in mechanism studies of immunoglobulin V(D)J gene recombination and CSR as well as SHM, and their regulatory mechanisms. [ABSTRACT FROM AUTHOR]

Summary: Transforming growth factor β (TGF‐β) is a multifunctional cytokine that regulates cell growth, differentiation, adhesion, migration and death dependent on cell type, developmental stage, or tissue conditions. Various cell types secrete TGF‐β, but always as an inactive complex. Hence, for TGF‐β to function, this latent complex must somehow be activated. Work in recent years has highlighted a critical role for members of the αv integrin family, including αvβ1, αvβ3, αvβ5, αvβ6 and αvβ8 that are involved in TGF‐β activation in various contexts, particularly at barrier sites such as the gut, lung and skin. The integrins facilitating this context‐ and location‐specific regulation can be dysregulated in certain diseases, so are potential therapeutic targets in a number of disorders. In this review, we discuss the role of TGF‐β at these barrier sites with a focus on how integrin‐mediated TGF‐β activation regulates tissue and immune homeostasis, and how this is altered in disease. [ABSTRACT FROM AUTHOR]

Summary: Mucosal surfaces are key interfaces between the host and its environment, but also constitute ports of entry for numerous pathogens. The gut and lung mucosae act as points of nutrient and gas exchange, respectively, but the physiological purpose of the female reproductive tract (FRT) is to allow implantation and development of the fetus. Our understanding of immune responses in the FRT has traditionally lagged behind our grasp of the situation at other mucosal sites, but recently reproductive immunologists have begun to make rapid progress in this challenging area. Here, we review current knowledge of immune responses in the human FRT and their heterogeneity within and between compartments. In the commensal‐rich vagina, the immune system must allow the growth of beneficial microbes, whereas the key challenge in the uterus is allowing the growth of the semi‐allogeneic fetus. In both compartments, these objectives must be balanced with the need to eliminate pathogens. Our developing understanding of immune responses in the FRT will help us develop interventions to prevent the spread of sexually transmitted diseases and to improve outcomes of pregnancy for mothers and babies. [ABSTRACT FROM AUTHOR]

Summary: Annexins are well‐known Ca2+ phospholipid‐binding proteins, which have a wide variety of cellular functions. The role of annexin A1 (AnxA1) in the innate immune system has focused mainly on the anti‐inflammatory and proresolving properties through its binding to the formyl‐peptide receptor 2 (FPR2)/ALX receptor. However, studies suggesting an intracellular role of AnxA1 are emerging. In this study, we aimed to understand the role of AnxA1 for interleukin (IL)‐1β release in response to activators of the nucleotide‐binding domain leucine‐rich repeat (NLR) and pyrin domain containing receptor 3 (NLRP3) inflammasome. Using AnxA1 knockout mice, we observed that AnxA1 is required for IL‐1β release in vivo and in vitro. These effects were due to reduction of transcriptional levels of IL‐1β, NLRP3 and caspase‐1, a step called NLRP3 priming. Moreover, we demonstrate that AnxA1 co‐localize and directly bind to NLRP3, suggesting the role of AnxA1 in inflammasome activation is independent of its anti‐inflammatory role via FPR2. Therefore, AnxA1 regulates NLRP3 inflammasome priming and activation in a FPR2‐independent manner. [ABSTRACT FROM AUTHOR]

The ability to induce functional reprogramming of regulatory T (Treg) cells in the tumor microenvironment is an extremely important therapeutic opportunity. However, when discussing such an approach, the opposing effect that the activation of the Treg cell compartments may have in inducing the immune inflammatory response and its link with the efficacy of immunotherapy should be considered. In fact, Treg reprogramming has a dual effect: immediate, with mechanisms that activate immunosurveillance, and late, mediated by the macrophage activation that yields an inflammatory status that is deleterious for the antineoplastic efficiency of the immune system response. Persistence of the inflammatory response is associated with specific changes of oxidative and glycolytic metabolic pathways that interfere with conventional T‐cell activation and function and may be one of the reasons for the failure of immunotherapy in advanced cancer patients. Therefore, in addition to modulating Treg cell action, the combined use of drugs able to block chronic inflammation mediated mainly by macrophages, to counteract the oxidative stress, and to positively regulate the metabolic derangements, could improve the effectiveness of modern immunotherapy. In conclusion, reprogramming of Treg cells may be an appropriate strategy for treating early stages of neoplastic diseases, whereas other immunosuppressive mechanisms should be the target of a combined immunotherapy approach in more advanced phases of cancer. [ABSTRACT FROM AUTHOR]

Summary: Chloroquines are 4‐aminoquinoline‐based drugs mainly used to treat malaria. At pharmacological concentrations, they have significant effects on tissue homeostasis, targeting diverse signaling pathways in mammalian cells. A key target pathway is autophagy, which regulates macromolecule turnover in the cell. In addition to affecting cellular metabolism and bioenergetic flow equilibrium, autophagy plays a pivotal role at the interface between inflammation and cancer progression. Chloroquines consequently have critical effects in tissue metabolic activity and importantly, in key functions of the immune system. In this article, we will review the work addressing the role of chloroquines in the homeostasis of mammalian tissue, and the potential strengths and weaknesses concerning their use in cancer therapy. [ABSTRACT FROM AUTHOR]

Summary: Host−microbiota interaction plays fundamental roles in the homeostasis of mucosal immunity. Dysbiosis of intestinal microbiota has been demonstrated to participate in various immune responses and many multifactorial diseases. Study of intestinal microbiota has moved beyond the consequences of dysbiosis to the causal microbiota associated with diseases. However, studies of pulmonary microbiota and its dysbiosis are still in their infancy. Improvement of culture‐dependent and ‐independent techniques has facilitated our understanding of lung microbiota that not only exists in healthy lung tissue but also exerts great impact on immune responses under both physiological and pathological conditions. In this review, we summarize recent progresses of lung microbiota dysbiosis and its impact on the local immune system that determines the balance of tolerance and inflammation. We discuss the causal roles of pulmonary dysbiosis under disease settings, and propose that the interaction between lung microbiota and host is critical for establishing the immune homeostasis in lung. [ABSTRACT FROM AUTHOR]

Summary: The intricate host–microbial interaction and the overwhelming complexity of the mucosal immune system in the adult host raise the question of how this system is initially established. Here, we propose the implementation of the concept of the 'postnatal window of opportunity' into the model of a 'layered immunity' to explain how the newborn's mucosal immune system matures and how host–microbial immune homeostasis is established after birth. We outline the concept of a timed succession of non‐redundant phases during postnatal immune development and discuss the possible influence of external factors and conditions. [ABSTRACT FROM AUTHOR]

Summary: Recent advances in high‐throughput molecular profiling technologies and multiplexed imaging platforms have revolutionized our ability to characterize the tumor immune microenvironment. As a result, studies of tumor‐associated immune cells increasingly involve complex data sets that require sophisticated methods of computational analysis. In this review, we present an overview of key assays and related bioinformatics tools for analyzing the tumor‐associated immune system in bulk tissues and at the single‐cell level. In parallel, we describe how data science strategies and novel technologies have advanced tumor immunology and opened the door for new opportunities to exploit host immunity to improve cancer clinical outcomes. [ABSTRACT FROM AUTHOR]

Summary: Formation of supramolecular assemblies appears to be a general mechanism in immune signalling pathways. These supramolecular assemblies appear to form through a nucleated polymerization mechanism. This review examines selected immune signalling pathways that involve supramolecular assemblies, describes the concepts of protein polymerization, and discusses how those concepts of protein polymerization implicate new elegant ways for signal amplification, setting threshold and noise reduction in these pathways. Formation of supramolecular assemblies appears to be a general mechanism in immune signalling pathways. This review examines selected immune signalling pathways that involve supramolecular assemblies, describes the concepts of protein polymerization, and discusses how those concepts may implicate new molecular mechanisms in signal transduction. [ABSTRACT FROM AUTHOR]

Summary: Interleukin‐17 (IL‐17) is a pro‐inflammatory cytokine and is involved in the development of many diseases. Recent studies have revealed that IL‐17‐producing γδ T cells (γδ17 cells) in addition to IL‐17‐producing CD4+ T cells [T helper type 17 (Th17) cells] are often the main producers of IL‐17 in mouse models of inflammatory diseases. γδ T cells are functionally committed during intra‐thymic differentiation. γδ thymocytes capable of producing IL‐17, which express the transcription factor retinoic‐acid‐receptor‐related orphan receptor γt and the signature cytokine receptor IL‐23R, leave the thymus, and produce IL‐17 rapidly by the stimulation with IL‐1β and IL‐23 in the periphery. Therefore, γδ17 cells play important roles in the early phase of host defence against pathogens and in inflammatory diseases. γδ T cells that can produce IL‐17 are also increased in the skin of patients with psoriasis and in peripheral blood of patients with ankylosing sclerosis. Indeed, the therapy targeting IL‐17 has been approved or is in clinical trials, and proved to be very efficient to treat psoriasis, psoriatic arthritis and ankylosing sclerosis. In this review, we discuss recent knowledge about the pathophysiological function of γδ17 cells in infection and inflammatory diseases and therapeutic advances targeting IL‐17. One of the main producers of the pro‐inflammatory cytokine interleukin‐17 (IL‐17) is γδ T (γδ17) cells. γδ17 cells play important roles in host defence against pathogens and in inflammatory diseases. In this review, we discuss recent knowledge about the pathophysiological function of γδ17 cells and therapeutic advances targeting IL‐17. [ABSTRACT FROM AUTHOR]

Summary: The field of mucosal immunology has, for the last 10 years, been largely dominated by advances in our understanding of the commensal microbiota. Developments of novel experimental methodologies and analysis techniques have provided unparalleled insight into the profound impact the microbiota has on the development and function of the immune system. In this cross‐journal review series published in Immunology and Clinical and Experimental Immunology, we aim to summarize the current state of research concerning the interplay between the microbiota and mucosal immunity. In addition, the series examines how the increased understanding of the microbiota is changing the nature of immunological research, both in the laboratory and in the clinic. [ABSTRACT FROM AUTHOR]

Summary: The mucosal surface of the respiratory tract encounters microbes, such as fungal particles, with every inhaled breath. When pathogenic fungi breach the physical barrier and innate immune system within the lung to establish an infection, adaptive immunity is engaged, often in the form of helper CD4 T‐cell responses. Type 1 responses, characterized by interferon‐γ production from CD4 cells, promote clearance of Histoplasma capsulatum and Cryptococcus neoformans infection. Likewise, interleukin‐17A (IL‐17A) production from Th17 cells promotes immunity to Blastomyces dermatitidis and Coccidioides species infection by recruiting neutrophils. In contrast the development of T helper type 2 responses, characterized by IL‐5 production from T cells and eosinophil influx into the lungs, drives allergic bronchopulmonary aspergillosis and poor outcomes during C. neoformans infection. Experimental vaccines against several endemic mycoses, including Histoplasma capsulatum, Coccidioides, Cryptococcus and Blastomyces dermatitidis, induce protective T‐cell responses and foreshadow the development of vaccines against pulmonary fungal infections for use in humans. Additionally, recent work using antifungal T cells as immunotherapy to protect immune‐compromised patients from opportunist fungal infections also shows great promise. This review covers the role of T‐cell responses in driving protection and pathology in response to pulmonary fungal infections, and highlights promising therapeutic applications of antifungal T cells. [ABSTRACT FROM AUTHOR]

Summary: Ascertaining the dominant cell type driving an immunological disease is essential to understanding the causal pathology and, therefore, selecting or developing an effective treatment. Classifying immunological diseases in this way has led to successful treatment regimens for many monogenic diseases; however, when the dominant cell type is unclear and there is no obvious causal genetic mutation, then identifying the correct disease classification and appropriate therapy can be challenging. In this review we focus on pulmonary immunological diseases where an innate immune signature has been identified as a predominant aspect of the immunopathology. We describe the molecular pathology of ‘autoinflammatory diseases of the lung’ and propose that small molecule and biological therapies, including recombinant interleukin‐1 receptor antagonist, that target key innate immune pathways, are likely be beneficial in the control of pulmonary and systemic inflammation in these conditions. In addition, the successful use of macrolide antibiotics to treat lung infections in these conditions further confirms that the innate immune system is the key conductor of inflammation in these pulmonary diseases, as there is a strong body of evidence that macrolides are able to modulate the NLRP3 inflammasome and interleukin‐1β and interleukin‐18 secretion, both of which are central players in the innate immune response. Throughout this review we highlight the published evidence of autoinflammatory disease in chronic obstructive pulmonary disease, bronchiectasis, cystic fibrosis and rheumatoid lung disease and suggest that the fundamental pathology of these diseases places them towards the autoinflammatory pole of the immunological disease continuum. [ABSTRACT FROM AUTHOR]

Summary: The immune system evolved to protect organisms from invading pathogens. A network of pro‐ and anti‐inflammatory cell types equipped with special effector molecules guarantees efficient elimination of intruders like viruses and bacteria. However, imbalances can lead to an excessive response of effector cells incurring autoimmune or allergic diseases. An interplay of genetic and environmental factors contributes to autoimmune diseases and recent studies provided evidence for an impact of dietary habits on the immune status and related disorders. Western societies underwent a change in lifestyle associated with changes in food consumption. Salt (sodium chloride) is one component prevalent in processed food frequently consumed in western countries. Here we summarize recent advances in understanding the mechanisms behind the effects of sodium chloride on immune cells like regulatory T cells (Tregs) and T helper (TH) 17 cells and its implication as a risk factor for several diseases. [ABSTRACT FROM AUTHOR]

Commensal microbes and the host immune system have been co-evolved for mutual regulation. Microbes regulate the host immune system, in part, by producing metabolites. A mounting body of evidence indicates that diverse microbial metabolites profoundly regulate the immune system via host receptors and other target molecules. Immune cells express metabolite-specific receptors such as P2X7, GPR41, GPR43, GPR109A, aryl hydrocarbon receptor precursor (AhR), pregnane X receptor (PXR), farnesoid X receptor (FXR), TGR5 and other molecular targets. Microbial metabolites and their receptors form an extensive array of signals to respond to changes in nutrition, health and immunological status. As a consequence, microbial metabolite signals contribute to nutrient harvest from diet, and regulate host metabolism and the immune system. Importantly, microbial metabolites bidirectionally function to promote both tolerance and immunity to effectively fight infection without developing inflammatory diseases. In pathogenic conditions, adverse effects of microbial metabolites have been observed as well. Key immune-regulatory functions of the metabolites, generated from carbohydrates, proteins and bile acids, are reviewed in this article. [ABSTRACT FROM AUTHOR]