Pseudomonas aeruginosa in chronic lung disease: untangling the dysregulated host immune response.

Pseudomonas aeruginosa is a highly adaptable opportunistic pathogen capable of exploiting barriers and immune defects to cause chronic lung infections in conditions such as cystic fibrosis. In these contexts, host immune responses are ineffective at clearing persistent bacterial infection, instead driving a cycle of inflammatory lung damage. This review outlines key components of the host immune response to chronic P. aeruginosa infection within the lung, beginning with initial pathogen recognition, followed by a robust yet maladaptive innate immune response, and an ineffective adaptive immune response that propagates lung damage while permitting bacterial persistence. Untangling the interplay between host immunity and chronic P. aeruginosa infection will allow for the development and refinement of strategies to modulate immune-associated lung damage and potentiate the immune system to combat chronic infection more effectively.

The Role of the Transcriptional Coactivator BOB.1/OBF.1 in Adaptive Immunity.

BOB.1/OBF.1 is a transcriptional coactivator involved in octamer-dependent transcription. Thereby, BOB.1/OBF.1 is involved in the transcriptional regulation of genes important for lymphocyte physiology. BOB.1/OBF.1-deficient mice reveal multiple B- and T-cell developmental defects. The most prominent defect of these mice is the complete absence of germinal centers (GCs) resulting in severely impaired T-cell-dependent immune responses. In humans, BOB.1/OBF.1 is associated with several autoimmune and inflammatory diseases but also linked to liquid and solid tumors. Although its role for B-cell development is relatively well understood, its exact role for the GC reaction and T-cell biology has long been unclear. Here, the contribution of BOB.1/OBF.1 for B-cell maturation is summarized, and recent findings regarding its function in GC B- as well as in various T-cell populations are discussed. Finally, a detailed perspective on how BOB.1/OBF.1 contributes to different pathologies is provided.

Different species of Chiroptera: Immune cells and molecules.

The distinct composition and immune response characteristics of bats' innate and adaptive immune systems, which enable them to serve as host of numerous serious zoonotic viruses without falling ill, differ substantially from those of other mammals, it have garnered significant attention. In this article, we offer a systematic review of the names, attributes, and functions of innate and adaptive immune cells & molecules across different bat species. This includes descriptions of the differences shown by research between 71 bat species in 10 families, as well as comparisons between bats and other mammals. Studies of the immune cells & molecules of different bat species are necessary to understand the unique antiviral immunity of bats. By providing comprehensive information on these unique immune responses, it is hoped that new insights will be provided for the study of co-evolutionary dynamics between viruses and the bat immune system, as well as human antiviral immunity.

Life-history stage influences immune investment and oxidative stress in response to environmental heterogeneity in Antarctic fur seals.

Immune defenses are crucial for survival but costly to develop and maintain. Increased immune investment is therefore hypothesized to trade-off with other life-history traits. Here, we examined innate and adaptive immune responses to environmental heterogeneity in wild Antarctic fur seals. In a fully crossed, repeated measures design, we sampled 100 pups and their mothers from colonies of contrasting density during seasons of contrasting food availability. Biometric and cortisol data as well as blood for the analysis of 13 immune and oxidative status markers were collected at two key life-history stages. We show that immune responses of pups are more responsive than adults to variation in food availability, but not population density, and are modulated by cortisol and condition. Immune investment is associated with different oxidative status markers in pups and mothers. Our results suggest that early life stages show greater sensitivity to extrinsic and intrinsic effectors, and that immunity may be a strong target for natural selection even in low-pathogen environments such as Antarctica.

Human determinants of age-dependent patterns of death from infection.

Regardless of microbial virulence (i.e., the global infection-fatality ratio), age generally drives the prevalence of death from infection in unvaccinated humans. Four mortality patterns are recognized: the common U- and L-shaped curves of endemic infections and the unique W- and J-shaped curves of pandemic infections. We suggest that these patterns result from different sets of human genetic and immunological determinants. In this model, it is the interplay between (1) monogenic genotypes affecting immunity to primary infection that preferentially manifest early in life and related genotypes or their phenocopies, including auto-antibodies, which manifest later in life and (2) the occurrence and persistence of adaptive, acquired immunity to primary or cross-reactive infections, which shapes the age-dependent pattern of human deaths from infection.

Immune mechanisms in fibrotic interstitial lung disease.

Fibrotic interstitial lung diseases (fILDs) have poor survival rates and lack effective therapies. Despite evidence for immune mechanisms in lung fibrosis, immunotherapies have been unsuccessful for major types of fILD. Here, we review immunological mechanisms in lung fibrosis that have the potential to impact clinical practice. We first examine innate immunity, which is broadly involved across fILD subtypes. We illustrate how innate immunity in fILD involves a complex interplay of multiple cell subpopulations and molecular pathways. We then review the growing evidence for adaptive immunity in lung fibrosis to provoke a re-examination of its role in clinical fILD. We close with future directions to address key knowledge gaps in fILD pathobiology: (1) longitudinal studies emphasizing early-stage clinical disease, (2) immune mechanisms of acute exacerbations, and (3) next-generation immunophenotyping integrating spatial, genetic, and single-cell approaches. Advances in these areas are essential for the future of precision medicine and immunotherapy in fILD.

Hypoimmunogenic human iPSCs expressing HLA-G, PD-L1, and PD-L2 evade innate and adaptive immunity.

BACKGROUND: The human induced pluripotent stem cells (hiPSCs) can generate all the cells composing the human body, theoretically. Therefore, hiPSCs are thought to be a candidate source of stem cells for regenerative medicine. The major challenge of allogeneic hiPSC-derived cell products is their immunogenicity. The hypoimmunogenic cell strategy is allogenic cell therapy without using immune suppressants. Advances in gene engineering technology now permit the generation of hypoimmunogenic cells to avoid allogeneic immune rejection. In this study, we generated a hypoimmunogenic hiPSC (HyPSC) clone that had diminished expression of human leukocyte antigen (HLA) class Ia and class II and expressed immune checkpoint molecules and a safety switch. METHODS: First, we generated HLA class Ia and class II double knockout (HLA class Ia/II DKO) hiPSCs. Then, a HyPSC clone was generated by introducing exogenous ß-2-microglobulin (B2M), HLA-G, PD-L1, and PD-L2 genes, and the Rapamycin-activated Caspase 9 (RapaCasp9)-based suicide gene as a safety switch into the HLA class Ia/II DKO hiPSCs. The characteristics and immunogenicity of the HyPSCs and their derivatives were analyzed. RESULTS: We found that the expression of HLA-G on the cell surface can be enhanced by introducing the exogenous HLA-G gene along with B2M gene into HLA class Ia/II DKO hiPSCs. The HyPSCs retained a normal karyotype and had the characteristics of pluripotent stem cells. Moreover, the HyPSCs could differentiate into cells of all three germ layer lineages including CD45+ hematopoietic progenitor cells (HPCs), functional endothelial cells, and hepatocytes. The HyPSCs-derived HPCs exhibited the ability to evade innate and adaptive immunity. Further, we demonstrated that RapaCasp9 could be used as a safety switch in vitro and in vivo. CONCLUSION: The HLA class Ia/II DKO hiPSCs armed with HLA-G, PD-L1, PD-L2, and RapaCasp9 molecules are a potential source of stem cells for allogeneic transplantation.

[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.

IL-27 expression regulation and its effects on adaptive immunity against viruses.

IL-27, a member of the IL-6/IL-12 cytokine superfamily, is primarily secreted by antigen presenting cells, specifically by dendric cells, macrophages and B cells. IL-27 has antiviral activities and modulates both innate and adaptive immune responses against viruses. The role of IL-27 in the setting of viral infections is not well defined and both pro-inflammatory and anti-inflammatory functions have been described. Here, we discuss the latest advancements in the role of IL-27 in several viral infection models of human disease. We highlight important aspects of IL-27 expression regulation, the critical cell sources at different stages of the infection and their impact in cell mediated immunity. Lastly, we discuss the need to better define the antiviral and modulatory (pro-inflammatory vs anti-inflammatory) properties of IL-27 in the context of human chronic viral infections.

Cross-talk between ILC2 and Gata3high Tregs locally constrains adaptive type 2 immunity.

Regulatory T cells (Tregs) control adaptive immunity and restrain type 2 inflammation in allergic disease. Interleukin-33 promotes the expansion of tissue-resident Tregs and group 2 innate lymphoid cells (ILC2s); however, how Tregs locally coordinate their function within the inflammatory niche is not understood. Here, we show that ILC2s are critical orchestrators of Treg function. Using spatial, cellular, and molecular profiling of the type 2 inflamed niche, we found that ILC2s and Tregs engage in a direct (OX40L-OX40) and chemotaxis-dependent (CCL1-CCR8) cellular dialogue that enforces the local accumulation of Gata3high Tregs, which are transcriptionally and functionally adapted to the type 2 environment. Genetic interruption of ILC2-Treg communication resulted in uncontrolled type 2 lung inflammation after allergen exposure. Mechanistically, we found that Gata3high Tregs can modulate the local bioavailability of the costimulatory molecule OX40L, which subsequently controlled effector memory T helper 2 cell numbers. Hence, ILC2-Treg interactions represent a critical feedback mechanism to control adaptive type 2 immunity.

Innate and adaptive immune response of Rainbow trout (Oncorhynchus mykiss) naturally infected with Yersinia ruckeri.

Rainbow trout is an important fish species for Peruvian artisanal aquaculture, comprising over 60 % of the total aquaculture production. However, their industry has been highly affected by several bacterial agents such as Yersinia ruckeri. This pathogen is the causative agent of Enteric Redmouth Disease, and causes high mortality in fingerlings and chronic infection in adult rainbow trout. To date, the immune response of rainbow trout against Y. ruckeri has been well studied in laboratory-controlled infection studies (i.e. intraperitoneal infection, bath immersion), however, the immune response during natural infection has not been explored. To address this, in this study, 35 clinically healthy O. mykiss without evidence of lesions or changes in behavior and 32 rainbow trout naturally infected by Y. ruckeri, were collected from semi-intensive fish farms located in the Central Highlands of Peru. To evaluate the effect on the immune response, RT-qPCR, western blotting, and ELISA were conducted using head kidney, spleen, and skin tissues to evaluate the relative gene expression and protein levels. Our results show a significant increase in the expression of the pro-inflammatory cytokines il1b, tnfa, and il6, as well as ifng in all three tissues, as well as increases in IL-1ß and IFN-γ protein levels. The endogenous pathway of antigen presentation showed to play a key role in defense against Y. ruckeri, due to the upregulation of mhc-I, tapasin, and b2m transcripts, and the significant increase of Tapasin protein levels in infected rainbow trout. None of the genes associated with the exogenous pathway of antigen presentation showed a significant increase in infected fish, suggesting that this pathway is not involved in the response against this intracellular pathogen. Finally, the transcripts of immunoglobulins IgM and IgT did not show a modulation, nor were the protein levels evaluated in this study.

The TAK1/JNK axis participates in adaptive immunity by promoting lymphocyte activation in Nile tilapia.

The transforming growth factor beta-activated kinase 1 (TAK1)/c-Jun N-terminal kinase (JNK) axis is an essential MAPK upstream mediator and regulates immune signaling pathways. However, whether the TAK1/JNK axis harnesses the strength in regulation of signal transduction in early vertebrate adaptive immunity is unclear. In this study, by modeling on Nile tilapia (Oreochromis niloticus), we investigated the potential regulatory function of TAK1/JNK axis on lymphocyte-mediated adaptive immune response. Both OnTAK1 and OnJNK exhibited highly conserved sequences and structures relative to their counterparts in other vertebrates. Their mRNA was widely expressed in the immune-associated tissues, while phosphorylation levels in splenic lymphocytes were significantly enhanced on the 4th day post-infection by Edwardsiella piscicida. In addition, OnTAK1 and OnJNK were significantly up-regulated in transcriptional level after activation of lymphocytes in vitro by phorbol 12-myristate 13-acetate plus ionomycin (P + I) or PHA, accompanied by a predominant increase in phosphorylation level. More importantly, inhibition of OnTAK1 activity by specific inhibitor NG25 led to a significant decrease in the phosphorylation level of OnJNK. Furthermore, blocking the activity of OnJNK with specific inhibitor SP600125 resulted in a marked reduction in the expression of T-cell activation markers including IFN-γ, CD122, IL-2, and CD44 during PHA-induced T-cell activation. In summary, these findings indicated that the conserved TAK1/JNK axis in Nile tilapia was involved in adaptive immune responses by regulating the activation of lymphocytes. This study enriched the current knowledge of adaptive immunity in teleost and provided a new perspective for understanding the regulatory mechanism of fish immunity.

Bacteroides uniformis CECT 7771 requires adaptive immunity to improve glucose tolerance but not to prevent body weight gain in diet-induced obese mice.

BACKGROUND: The metabolic disturbances of obesity can be mitigated by strategies modulating the gut microbiota. In this study, we sought to identify whether innate or adaptive immunity mediates the beneficial metabolic effects of the human intestinal bacterium Bacteroides uniformis CECT 7771 in obesity. METHODS: We evaluated the effects of orally administered B. uniformis on energy homeostasis, intestinal immunity, hormone levels, and gut microbiota in wild-type and Rag1-deficient mice with diet-induced obesity. We also assessed whether B. uniformis needed to be viable to exert its beneficial effects in obesity and to directly induce immunoregulatory effects. RESULTS: The administration of B. uniformis to obese mice improved glucose tolerance and insulin secretion, restored the caloric intake suppression after an oral glucose challenge, and reduced hyperglycemia. The pre- and post-prandial glucose-related benefits were associated with restoration of the anti-inflammatory tone mediated by type 2 macrophages and regulatory T cells (Tregs) in the lamina propria of the small intestine. Contrastingly, B. uniformis administration failed to improve glucose tolerance in obese Rag1-/- mice, but prevented the increased body weight gain and adiposity. Overall, the beneficial effects seemed to be independent of enteroendocrine effects and of major changes in gut microbiota composition. B. uniformis directly induced Tregs generation from naïve CD4+ T cells in vitro and was not required to be viable to improve glucose homeostasis but its viability was necessary to prevent body weight gain in diet-induced obese wild-type mice. CONCLUSIONS: Here we demonstrate that B. uniformis modulates the energy homeostasis in diet-induced obese mice through different mechanisms. The bacterium improves oral glucose tolerance by adaptive immunity-dependent mechanisms that do not require cell viability and prevents body weight gain by adaptive immunity-independent mechanisms which require cell viability. Video Abstract.

Exploring T Cell Receptor Repertoires in Myocardial Diseases.

Mounting experimental and clinical evidence has revealed that adaptive immune mechanisms targeting myocardial antigens are triggered by different forms of cardiac injury and impact disease progression. B and T lymphocytes recognize specific antigens via unique adaptive immune receptors generated through a somatic rearrangement process that generates a potential repertoire of 1019 unique receptors. While the adaptive immune receptor repertoire diversity provides the basis for immunologic specificity, making sense of it can be a challenging task. In the present review, we discuss key aspects underlying the generation of TCRs (T cell receptors) and emerging tools for their study in the context of myocardial diseases. Moreover, we outline how exploring TCR repertoires could lead to a deeper understanding of myocardial pathophysiological principles and potentially serve as diagnostic tools.

Circadian Rhythms in Anticancer Immunity: Mechanisms and Treatment Opportunities.

Circadian rhythms of approximately 24 h have emerged as important modulators of the immune system. These oscillations are important for mounting short-term, innate immune responses, but surprisingly also long-term, adaptive immune responses. Recent data indicate that they play a central role in antitumor immunity, in both mice and humans. In this review, we discuss the evolving literature on circadian antitumor immune responses and the underlying mechanisms that control them. We further provide an overview of circadian treatment regimens-chrono-immunotherapies-that harness time-of-day differences in immunity for optimal efficacy. Our aim is to provide an overview for researchers and clinicians alike, for a better understanding of the circadian immune system and how to best harness it for chronotherapeutic interventions. This knowledge is important for a better understanding of immune responses per se and could revolutionize the way we approach the treatment of cancer and a range of other diseases, ultimately improving clinical practice.

Characterization of the Hepatic Transcriptome for Divergent Immune-Responding Sheep Following Natural Exposure to Gastrointestinal Nematodes.

Infections with gastrointestinal nematodes (GINs) reduce the economic efficiency of sheep operations and compromise animal welfare. Understanding the host's response to GIN infection can help producers identify animals that are naturally resistant to infection. The objective of this study was to characterize the hepatic transcriptome of sheep that had been naturally exposed to GIN parasites. The hepatic transcriptome was studied using RNA-Sequencing technology in animals characterized as high (n = 5) or medium (n = 6) based on their innate immune acute-phase (AP) response phenotype compared with uninfected controls (n = 4), and with biased antibody-mediated (AbMR, n = 5) or cell-mediated (CMR, n = 5) adaptive immune responsiveness compared to uninfected controls (n = 3). Following the assessment of sheep selected for innate responses, 0, 136, and 167 genes were differentially expressed (DE) between high- and medium-responding animals, high-responding and uninfected control animals, and medium-responding and uninfected control animals, respectively (false discovery rate (FDR) < 0.05, and fold change |FC| > 2). When adaptive immune responses were assessed, 0, 53, and 57 genes were DE between antibody- and cell-biased animals, antibody-biased and uninfected control animals, and cell-biased and uninfected control animals, respectively (FDR < 0.05, |FC| > 2). Functional analyses identified enriched gene ontology (GO) terms and metabolic pathways related to the innate immune response and energy metabolism. Six functional candidate genes were identified for further functional and validation studies to better understand the underlying biological mechanisms of host responses to GINs. These, in turn, can potentially help improve decision making and management practices to increase the overall host immune response to GIN infection.

Knowledge on Human Papillomavirus Infections, Cancer Biology, Immune Interactions, Vaccination Coverage and Common Treatments: A Comprehensive Review.

Human papillomavirus (HPV) is a circular, double-stranded DNA virus and recognized as the most prevalent sexually transmitted infectious agent worldwide. The HPV life cycle encompasses three primary stages. First, the virus infiltrates the basal cells of the stratified epidermis. Second, there is a low-level expression of viral genes and preservation of the viral genome in the basal layer. Lastly, productive replication of HPV occurs in differentiated cells. An effective immune response, involving various immune cells, including innate immunity, keratinocytes, dendritic cells, and natural killer T cells, is instrumental in clearing HPV infection and thwarting the development of HPV-associated tumors. Vaccines have demonstrated their efficacy in preventing genital warts, high-grade precancerous lesions, and cancers in females. In males, the vaccines can also aid in preventing genital warts, anal precancerous lesions, and cancer. This comprehensive review aims to provide a thorough and detailed exploration of HPV infections, delving into its genetic characteristics, life cycle, pathogenesis, and the role of high-risk and low-risk HPV strains. In addition, this review seeks to elucidate the intricate immune interactions that govern HPV infections, spanning from innate immunity to adaptive immune responses, as well as examining the evasion mechanisms used by the virus. Furthermore, the article discusses the current landscape of HPV vaccines and common treatments, contributing to a holistic understanding of HPV and its associated diseases.

Animal models of immune-mediated demyelinating polyneuropathies.

Immune-mediated demyelinating polyneuropathies (IMDPs) are rare disorders in which dysregulated adaptive immune responses cause peripheral nerve demyelinating inflammation and axonal injury in susceptible individuals. Despite significant advances in understanding IMDP pathogenesis guided by patient data and representative mammalian models, specific therapies are lacking. Significant knowledge gaps in IMDP pathogenesis still exist, e.g. precise antigen(s) and mechanisms that initially trigger immune system activation and identification of large population disease susceptibility factors. The initial directional cues for antigen-specific effector or autoreactive leukocyte trafficking into peripheral nerves are also unknown. An overview of current animal models, with emphasis on the experimental autoimmune neuritis and spontaneous autoimmune peripheral polyneuropathy models, is provided. Insights on the initial directional cues for peripheral nerve tissue specific autoimmunity using a novel Major Histocompatibility Complex class II conditional knockout mouse strain are also discussed, suggesting an essential research tool to study cell- and time-dependent adaptive immunity in autoimmune diseases.

A novel oral TLR7 agonist orchestrates immune response and synergizes with PD-L1 blockade via type I IFN pathway in lung cancer.

Despite the groundbreaking impact of immune checkpoint blockade (ICB), response rates in non-small cell lung cancer remain modest, particularly in immune-excluded or immune-desert microenvironments. Toll-like receptor 7 (TLR7) emerges as a latent target bridging innate and adaptive immunity, offering a promising avenue for combination therapies to augment ICB efficacy. Here, we explored the anti-tumor activity of the novel oral TLR7 agonist TQ-A3334 and its potential to enhance anti-programmed death ligand 1 (PD-L1) therapy through a combination strategy in a syngeneic murine lung cancer model. Oral administration of TQ-A3334 significantly alleviated tumor burden in C57BL/6J mice, modulated by type I interferon (IFN), and exhibited low toxicity. This therapy elicited activation of both innate and adaptive immune cells in tumor tissue, particularly increasing the abundance of CD8+ TILs through type I IFN pathway and subsequent CXCL10 expression. In vitro examinations validated that IFN-α-stimulated tumor cells exhibited increased secretion of CXCL10, conducive to the promoted trafficking of CD8+ T cells. Furthermore, combining TQ-A3334 with anti-PD-L1 treatment exceeded tumor control, with a further increase in CD8+ TIL frequency compared to monotherapy. These findings suggest that TQ-A3334 can mobilize innate immunity and promote T cell recruitment into the tumor microenvironment; a combination of TQ-A3334 and anti-PD-L1 antibodies can intensify the sensitivity of tumors to anti-PD-L1 therapy, which demonstrates significant potential for treating poorly immune-infiltrated lung cancer.