[Research advances in the development and function of macrophages and classical dendritic cells during resting and infection].

Macrophages (MACs) and classical dendritic cells (cDCs) represent the front line of immune defense, playing crucial roles in both innate and adaptive immunity due to their remarkable tissue specificity and precise adaptation to environmental cues. MACs contribute to maintaining tissue homeostasis and immune surveillance, while cDCs function as the most efficient antigen-presenting cells, playing a critical role in immune responses. These two cell types share similarities and interconnections. Both MACs and cDCs are capable of recognizing pathogens and tissue damage, secreting cytokines to activate other innate immune cells, and initiating or modulating adaptive immunity through interactions with T cells. In this review, we provide a comprehensive analysis of the research advances in the development and functions of MACs and cDCs during resting and infection processes, elucidate their interrelationships and interactions within the immune system, and offer a theoretical basis for in-depth studies of diseases.

Mitochondrial Reactive Oxygen Species in Infection and Immunity.

Reactive oxygen species (ROS) contain at least one oxygen atom and one or more unpaired electrons and include singlet oxygen, superoxide anion radical, hydroxyl radical, hydroperoxyl radical, and free nitrogen radicals. Intracellular ROS can be formed as a consequence of several factors, including ultra-violet (UV) radiation, electron leakage during aerobic respiration, inflammatory responses mediated by macrophages, and other external stimuli or stress. The enhanced production of ROS is termed oxidative stress and this leads to cellular damage, such as protein carbonylation, lipid peroxidation, deoxyribonucleic acid (DNA) damage, and base modifications. This damage may manifest in various pathological states, including ageing, cancer, neurological diseases, and metabolic disorders like diabetes. On the other hand, the optimum levels of ROS have been implicated in the regulation of many important physiological processes. For example, the ROS generated in the mitochondria (mitochondrial ROS or mt-ROS), as a byproduct of the electron transport chain (ETC), participate in a plethora of physiological functions, which include ageing, cell growth, cell proliferation, and immune response and regulation. In this current review, we will focus on the mechanisms by which mt-ROS regulate different pathways of host immune responses in the context of infection by bacteria, protozoan parasites, viruses, and fungi. We will also discuss how these pathogens, in turn, modulate mt-ROS to evade host immunity. We will conclude by briefly giving an overview of the potential therapeutic approaches involving mt-ROS in infectious diseases.

The global role of G6PD in infection and immunity.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzymopathy in humans. G6PD is an essential enzyme in the pentose phosphate pathway (PPP), generating NADPH needed for cellular biosynthesis and reactive oxygen species (ROS) homeostasis, the latter especially key in red blood cells (RBCs). Beyond the RBC, there is emerging evidence that G6PD exerts an immunologic role by virtue of its functions in leukocyte oxidative metabolism and anabolic synthesis necessary for immune effector function. We review these here, and consider the global immunometabolic role of G6PD activity and G6PD deficiency in modulating inflammation and immunopathology.

Microalgae-made human vaccines and therapeutics: A decade of advances.

Microalgal emergence is a promising platform with two-decade historical background for producing vaccines and biopharmaceuticals. During that period, microalgal-based vaccines have reported successful production for various diseases. Thus, species selection is important for genetic transformation and delivery methods that have been developed. Although many vaccine prototypes have been produced for infectious and non-infectious diseases, fewer studies have reached immunological and immunoprotective evaluations. Microalgae-made vaccines for Staphylococcus aureus, malaria, influenza, human papilloma, and Zika viruses have been explored in their capacity to induce humoral or cellular immune responses and protective efficacies against experimental challenges. Therefore, specific pathogen antigens and immune system role are important and addressed in controlling these infections. Regarding non-communicable diseases, these vaccines have been investigated for breast cancer; microalgal-produced therapeutic molecules and microalgal-made interferon-α have been explored for hypertension and potential applications in treating viral infections and cancer, respectively. Thus, conducting immunological trials is emphasized, discussing the promising results observed in terms of immunogenicity, desired immune response for controlling affections, and challenges for achieving the desired protection levels. The potential advantages and hurdles associated with this innovative approach are highlighted, underlining the relevance of assessing immune responses in preclinical and clinical trials to validate the efficacy of these biopharmaceuticals. The promising future of this healthcare technology is also envisaged.

The time-dependent changes in serum immunoglobulin after kidney transplantation and its association with infection.

Introduction: Kidney transplant recipients often experience significant alterations in their immune system, which can lead to increased susceptibility to infections. This study aimed to analyze time-dependent changes in serum immunoglobulin and complement levels and determine the risk factors associated with infection. Methods: A retrospective analysis of serum samples from 192 kidney transplant recipients who received transplantations between August 2016 and December 2019 was conducted. The serum samples were obtained at preoperative baseline (T0), postoperative 2 weeks (T1), 3 months (T2), and 1 year (T3). The levels of serum C3, C4, IgG, IgA, and IgM were measured to evaluate immune status over time. Results: The analysis revealed significant decreases in IgG and IgA levels at T1. This period was associated with the highest occurrence of hypogammaglobulinemia (HGG) and hypocomplementemia (HCC), as well as an increased incidence of severe infection requiring hospitalization and graft-related viral infections. Using a time-dependent Cox proportional hazards model adjusted for time-varying confounders, HGG was significantly associated with an increased risk of infection requiring hospitalization (HR, 1.895; 95% CI: 1.871-1.920, P-value<0.001) and graft-related viral infection (HR, 1.152; 95% CI: 1.144-1.160, P-value<0.001). Discussion: The findings suggest that monitoring serum immunoglobulin levels post-transplant provides valuable insights into the degree of immunosuppression. Hypogammaglobulinemia during the early post-transplant period emerges as a critical risk factor for infection, indicating that serum immunoglobulins could serve as feasible biomarkers for assessing infection risk in kidney transplant recipients.

Emerging concepts in alcohol, infection & immunity: A summary of the 2023 alcohol and immunology research interest group (AIRIG) meeting.

On December 8th 2023, the annual Alcohol and Immunology Research Interest Group (AIRIG) meeting was held at the University of Colorado Anschutz Medical Campus in Aurora, Colorado. The 2023 meeting focused broadly on how acute and chronic alcohol exposure leads to immune dysregulation, and how this contributes to damage in multiple tissues and organs. These include impaired lung immunity, intestinal dysfunction, autoimmunity, the gut-Central Nervous System (CNS) axis, and end-organ damage. In addition, diverse areas of alcohol research covered multiple pathways behind alcohol-induced cellular dysfunction, including inflammasome activation, changes in miRNA expression, mitochondrial metabolism, gene regulation, and transcriptomics. Finally, the work presented at this meeting highlighted novel biomarkers and therapeutic interventions for patients suffering from alcohol-induced organ damage.

Tryptophan catabolism via the kynurenine pathway regulates infection and inflammation: from mechanisms to biomarkers and therapies.

BACKGROUND: L-Tryptophan (L-Trp), an essential amino acid, is the only amino acid whose level is regulated specifically by immune signals. Most proportions of Trp are catabolized via the kynurenine (Kyn) pathway (KP) which has evolved to align the food availability and environmental stimulation with the host pathophysiology and behavior. Especially, the KP plays an indispensable role in balancing the immune activation and tolerance in response to pathogens. SCOPE OF REVIEW: In this review, we elucidate the underlying immunological regulatory network of Trp and its KP-dependent catabolites in the pathophysiological conditions by participating in multiple signaling pathways. Furthermore, the KP-based regulatory roles, biomarkers, and therapeutic strategies in pathologically immune disorders are summarized covering from acute to chronic infection and inflammation. MAJOR CONCLUSIONS: The immunosuppressive effects dominate the functions of KP induced-Trp depletion and KP-produced metabolites during infection and inflammation. However, the extending minor branches from the KP are not confined to the immune tolerance, instead they go forward to various functions according to the specific condition. Nevertheless, persistent efforts should be made before the clinical use of KP-based strategies to monitor and cure infectious and inflammatory diseases.

Brain border-associated macrophages: common denominators in infection, aging, and Alzheimer's disease?

Mammalian brain border-associated macrophages (BAMs) are strategically positioned to support vital properties and processes: for example, the composition of the brain's perivascular extracellular matrix and cerebrospinal fluid flow via the glymphatic pathway. BAMs also effectively restrict the spread of infectious microbes into the brain. However, while fighting infections, BAMs sustain long-term transcriptomic changes and can be replaced by inflammatory monocytes, potentially leading to a gradual loss of their beneficial homeostatic functions. We hypothesize that by expediting the deterioration of BAMs, multiple infection episodes might be associated with accelerated brain aging and the putative development of neurodegenerative diseases. Our viewpoint is supported by recent studies suggesting that rejuvenating aged BAMs, and counterbalancing their detrimental inflammatory signatures during infections, might hold promise in treating aging-related neurological disorders, including Alzheimer's disease (AD).

The beneficial roles and mechanisms of estrogens in immune health and infection disease.

Multiple epidemiologic studies have revealed that gender is considered one of the important factors in the frequency and severity of certain infectious diseases, in which estrogens may play a vital role. There is growing evidence that estrogens as female sex hormone can modulate multiple biological functions outside of the reproductive system, such as in brain and cardiovascular system. However, it is largely unknown about the roles and mechanisms of estrogens/estrogen receptors in immune health and infection disease. Thence, by reading a lot of literature, we summarized the regulatory mechanisms of estrogens/estrogen receptors in immune cells and their roles in certain infectious diseases with gender differences. Therefore, estrogens may have therapeutic potentials to prevent and treat these infectious diseases, which needs further clinical investigation.

Association between serum IgG concentrations and the incidence of infections in patients with chronic lymphocytic leukemia and secondary immunodeficiency under treatment with Privigen.

OBJECTIVE: To investigate the association between serum immunoglobulin G (IgG) concentrations and the incidence of infections in patients with chronic lymphocytic leukemia (CLL) and secondary immunodeficiency receiving treatment with Privigen. MATERIALS AND METHODS: Data was analyzed from a non-interventional study conducted in 31 centers in Germany and 1 in Austria. Adult CLL patients with hypogammaglobulinemia and recurrent infections were allowed to enter the study upon signing informed consent, if a prior decision for treatment with Privigen had been made. All infections requiring an antimicrobial treatment were subject to analysis. Patients were stratified according to their mean post-baseline serum IgG trough levels in a group with lower IgG trough levels (≤ 5.0 g/L), and a group with higher IgG trough levels (> 5.0 g/L). RESULTS: Overall, 89 patients and 840 treatment cycles were analyzed. Up to 11 treatment cycles (average duration 29 days) were documented in each patient. In the group with higher IgG trough levels (> 5.0 g/L, N = 72), significantly fewer infections were observed than in the group with lower IgG trough levels (≤ 5.0 g/L, N = 17), including fewer severe and serious infections. The Privigen dosage was a major determinant of the post-baseline serum IgG levels. Overall tolerability of Privigen was assessed as very good or good in 91% of patients. CONCLUSION: This analysis confirms the association of serum IgG trough levels with the incidence of infections and highlights the importance of careful monitoring of IgG levels during treatment of secondary immunodeficiencies in CLL patients.

Insights from CTTACC: immune system reset by cellular therapies for chronic illness after trauma, infection, and burn.

BACKGROUND AIMS: In this paper, we present a review of several selected talks presented at the CTTACC conference (Cellular Therapies in Trauma and Critical Care) held in Scottsdale, AZ in May 2023. This conference review highlights the potential for cellular therapies to "reset" the dysregulated immune response and restore physiologic functions to normal. Improvements in medical care systems and technology have increasingly saved lives after major traumatic events. However, many of these patients have complicated post-traumatic sequelae, ranging from short-term multi-organ failure to chronic critical illness. METHODS/RESULTS: Patients with chronic critical illness have been found to have dysregulated immune responses. These abnormal and harmful immune responses persist for years after the initial insult and can potentially be mitigated by treatment with cellular therapies. CONCLUSIONS: The sessions emphasized the need for more research and clinical trials with cellular therapies for the treatment of a multitude of chronic illnesses: post-trauma, radiation injury, COVID-19, burns, traumatic brain injury (TBI) and other chronic infections.

The immunopathological landscape of human pre-TCRα deficiency: From rare to common variants.

We describe humans with rare biallelic loss-of-function PTCRA variants impairing pre-α T cell receptor (pre-TCRα) expression. Low circulating naive αß T cell counts at birth persisted over time, with normal memory αß and high γδ T cell counts. Their TCRα repertoire was biased, which suggests that noncanonical thymic differentiation pathways can rescue αß T cell development. Only a minority of these individuals were sick, with infection, lymphoproliferation, and/or autoimmunity. We also report that 1 in 4000 individuals from the Middle East and South Asia are homozygous for a common hypomorphic PTCRA variant. They had normal circulating naive αß T cell counts but high γδ T cell counts. Although residual pre-TCRα expression drove the differentiation of more αß T cells, autoimmune conditions were more frequent in these patients compared with the general population.

Smoking changes adaptive immunity with persistent effects.

Individuals differ widely in their immune responses, with age, sex and genetic factors having major roles in this inherent variability1-6. However, the variables that drive such differences in cytokine secretion-a crucial component of the host response to immune challenges-remain poorly defined. Here we investigated 136 variables and identified smoking, cytomegalovirus latent infection and body mass index as major contributors to variability in cytokine response, with effects of comparable magnitudes with age, sex and genetics. We find that smoking influences both innate and adaptive immune responses. Notably, its effect on innate responses is quickly lost after smoking cessation and is specifically associated with plasma levels of CEACAM6, whereas its effect on adaptive responses persists long after individuals quit smoking and is associated with epigenetic memory. This is supported by the association of the past smoking effect on cytokine responses with DNA methylation at specific signal trans-activators and regulators of metabolism. Our findings identify three novel variables associated with cytokine secretion variability and reveal roles for smoking in the short- and long-term regulation of immune responses. These results have potential clinical implications for the risk of developing infections, cancers or autoimmune diseases.

The function of γδ T cells in humoral immune responses.

PURPOSE: The purpose of this review is to discuss the role of γδ T cells played in humoral immune responses. BACKGROUND: The γδ T cell receptor (γδ TCR) recognizes antigens, including haptens and proteins, in an MHC-independent manner. The recognition of these antigens by γδ TCRs crosses antigen recognition by the B cell receptors (BCRs), suggesting that γδ T cells may be involved in the process of antigen recognition and activation of B cells. However, the role of γδ T cells in humoral immune responses is still less clear. METHODS: The kinds of literature about the γδ T cell-B cell interaction were searched on PubMed with search terms, such as γδ T cells, antibody, B cell responses, antigen recognition, and infection. RESULTS: Accumulating evidence indicates that γδ T cells, independent of αß T cells, participate in multiple steps of humoral immunity, including B cell maturation, activation and differentiation, antibody production and class switching. Mechanically, γδ T cells affect B cell function by directly interacting with B cells, secreting cytokines, or modulating αß T cells. CONCLUSION: In this review, we summarize current knowledge on how γδ T cells take part in the humoral immune response, which may assist future vaccine design.

Analysis of the Toll and Spaetzle Genes Involved in Toll Pathway-Dependent Antimicrobial Gene Induction in the Red Flour Beetle, Tribolium castaneum (Coleoptera; Tenebrionidae).

Insects rely only on their innate immune system to protect themselves from pathogens. Antimicrobial peptide (AMP) production is the main immune reaction in insects. In Drosophila melanogaster, the reaction is regulated mainly by the Toll and immune deficiency (IMD) pathways. Spaetzle proteins, activated by immune signals from upstream components, bind to Toll proteins, thus, activating the Toll pathway, which in turn, induces AMP genes. Previous studies have shown the difference in immune systems related to Toll and IMD pathways between D. melanogaster and Tribolium castaneum. In T. castaneum, nine Toll and seven spaetzle (spz) genes were identified. To extend our understanding of AMP production by T. castaneum, we conducted functional assays of Toll and spaetzle genes related to Toll-pathway-dependent AMP gene expression in T. castaneum under challenge with bacteria or budding yeast. The results revealed that Toll3 and Toll4 double-knockdown and spz7 knockdown strongly and moderately reduced the Toll-pathway-dependent expression of AMP genes, respectively. Moreover, Toll3 and Toll4 double-knockdown pupae more rapidly succumbed to entomopathogenic bacteria than the control pupae, but spz7 knockdown pupae did not. The results suggest that Toll3 and Toll4 play a large role in Toll-pathway-dependent immune reactions, whereas spz7 plays a small part.

Functional T cells are capable of supernumerary cell division and longevity.

Differentiated somatic mammalian cells putatively exhibit species-specific division limits that impede cancer but may constrain lifespans1-3. To provide immunity, transiently stimulated CD8+ T cells undergo unusually rapid bursts of numerous cell divisions, and then form quiescent long-lived memory cells that remain poised to reproliferate following subsequent immunological challenges. Here we addressed whether T cells are intrinsically constrained by chronological or cell-division limits. We activated mouse T cells in vivo using acute heterologous prime-boost-boost vaccinations4, transferred expanded cells to new mice, and then repeated this process iteratively. Over 10 years (greatly exceeding the mouse lifespan)5 and 51 successive immunizations, T cells remained competent to respond to vaccination. Cells required sufficient rest between stimulation events. Despite demonstrating the potential to expand the starting population at least 1040-fold, cells did not show loss of proliferation control and results were not due to contamination with young cells. Persistent stimulation by chronic infections or cancer can cause T cell proliferative senescence, functional exhaustion and death6. We found that although iterative acute stimulations also induced sustained expression and epigenetic remodelling of common exhaustion markers (including PD1, which is also known as PDCD1, and TOX) in the cells, they could still proliferate, execute antimicrobial functions and form quiescent memory cells. These observations provide a model to better understand memory cell differentiation, exhaustion, cancer and ageing, and show that functionally competent T cells can retain the potential for extraordinary population expansion and longevity well beyond their organismal lifespan.

Dual Immune Regulatory Roles of Interleukin-33 in Pathological Conditions.

Interleukin-33 (IL-33), a member of the IL-1 cytokine family and a multifunctional cytokine, plays critical roles in maintaining host homeostasis and in pathological conditions, such as allergy, infectious diseases, and cancer, by acting on multiple types of immune cells and promoting type 1 and 2 immune responses. IL-33 is rapidly released by immune and non-immune cells upon stimulation by stress, acting as an "alarmin" by binding to its receptor, suppression of tumorigenicity 2 (ST2), to trigger downstream signaling pathways and activate inflammatory and immune responses. It has been recognized that IL-33 displays dual-functioning immune regulatory effects in many diseases and has both pro- and anti-tumorigenic effects, likely depending on its primary target cells, IL-33/sST2 expression levels, cellular context, and the cytokine microenvironment. Herein, we summarize our current understanding of the biological functions of IL-33 and its roles in the pathogenesis of various conditions, including inflammatory and autoimmune diseases, infections, cancers, and cases of organ transplantation. We emphasize the nature of context-dependent dual immune regulatory functions of IL-33 in many cells and diseases and review systemic studies to understand the distinct roles of IL-33 in different cells, which is essential to the development of more effective diagnoses and therapeutic approaches for IL-33-related diseases.