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1.
Proc Natl Acad Sci U S A ; 121(23): e2309674121, 2024 Jun 04.
Article in English | MEDLINE | ID: mdl-38722806

ABSTRACT

The identification of immunogenic peptides has become essential in an increasing number of fields in immunology, ranging from tumor immunotherapy to vaccine development. The nature of the adaptive immune response is shaped by the similarity between foreign and self-protein sequences, a concept extensively applied in numerous studies. Can we precisely define the degree of similarity to self? Furthermore, do we accurately define immune self? In the current work, we aim to unravel the conceptual and mechanistic vagueness hindering the assessment of self-similarity. Accordingly, we demonstrate the remarkably low consistency among commonly employed measures and highlight potential avenues for future research.


Subject(s)
Peptides , Humans , Peptides/immunology , Peptides/chemistry , Adaptive Immunity/immunology , Immunotherapy/methods , Autoantigens/immunology , Animals
2.
Nat Commun ; 15(1): 4080, 2024 May 14.
Article in English | MEDLINE | ID: mdl-38744812

ABSTRACT

While preventing vertical HIV transmission has been very successful, HIV-exposed uninfected infants (iHEU) experience an elevated risk to infections compared to HIV-unexposed and uninfected infants (iHUU). Here we present a longitudinal multimodal analysis of infant immune ontogeny that highlights the impact of HIV/ARV exposure. Using mass cytometry, we show alterations in T cell memory differentiation between iHEU and iHUU being significant from week 15 of life. The altered memory T cell differentiation in iHEU was preceded by lower TCR Vß clonotypic diversity and linked to TCR clonal depletion within the naïve T cell compartment. Compared to iHUU, iHEU had elevated CD56loCD16loPerforin+CD38+CD45RA+FcεRIγ+ NK cells at 1 month postpartum and whose abundance pre-vaccination were predictive of vaccine-induced pertussis and rotavirus antibody responses post 3 months of life. Collectively, HIV/ARV exposure disrupted the trajectory of innate and adaptive immunity from birth which may underlie relative vulnerability to infections in iHEU.


Subject(s)
HIV Infections , Immunologic Memory , Infectious Disease Transmission, Vertical , Humans , HIV Infections/immunology , HIV Infections/virology , Infant , Female , Infant, Newborn , Memory T Cells/immunology , Male , Killer Cells, Natural/immunology , Receptors, Antigen, T-Cell/immunology , Receptors, Antigen, T-Cell/metabolism , Adaptive Immunity/immunology , Cell Differentiation/immunology , Longitudinal Studies
3.
Arch Oral Biol ; 164: 106005, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38781743

ABSTRACT

OBJECTIVES: This study aims to investigate the effects of type 17 immune response on the proliferation of oral epithelial cells in periodontitis. DESIGN: A time-dependent ligature induced periodontitis mouse model was utilized to explore gingival hyperplasia and the infiltration of interleukin 17A (IL-17A) positive cells. Immunohistochemistry and flow cytometry were employed to determine the localization and expression of IL-17A in the ligature induced periodontitis model. A pre-existing single-cell RNA sequencing dataset, comparing individuals affected by periodontitis with healthy counterparts, was reanalyzed to evaluate IL-17A expression levels. We examined proliferation markers, including proliferating cell nuclear antigen (PCNA), signal transducer and activator of transcription (STAT3), Yes-associated protein (YAP), and c-JUN, in the gingival and tongue epithelium of the periodontitis model. An anti-IL-17A agent was administered daily to observe proliferative changes in the oral mucosa within the periodontitis model. Cell number quantification, immunofluorescence, and western blot analyses were performed to assess the proliferative responses of human normal oral keratinocytes to IL-17A treatment in vitro. RESULTS: The ligature induced periodontitis model exhibited a marked infiltration of IL-17A-positive cells, alongside significant increase in thickness of the gingival and tongue epithelium. IL-17A triggers the proliferation of human normal oral keratinocytes, accompanied by upregulation of PCNA, STAT3, YAP, and c-JUN. The administration of an anti-IL-17A agent attenuated the proliferation in oral mucosa. CONCLUSIONS: These findings indicate that type 17 immune response, in response to periodontitis, facilitates the proliferation of oral epithelial cells, thus highlighting its crucial role in maintaining the oral epithelial barrier.


Subject(s)
Adaptive Immunity , Cell Proliferation , Epithelial Cells , Interleukin-17 , Periodontitis , Periodontitis/immunology , Epithelial Cells/cytology , Epithelial Cells/immunology , Cell Proliferation/genetics , Animals , Mice , Disease Models, Animal , Interleukin-17/genetics , Interleukin-17/immunology , Protein Transport/immunology , Keratinocytes/cytology , Keratinocytes/immunology , Humans , Cell Line , Alveolar Bone Loss/immunology , Adaptive Immunity/immunology
4.
Adv Protein Chem Struct Biol ; 140: 381-417, 2024.
Article in English | MEDLINE | ID: mdl-38762276

ABSTRACT

Cardiovascular disease (CVD) and cancer are major contributors to global morbidity and mortality. This book chapter delves into the intricate relationship between the immune system and the pathogenesis of both cardiovascular and cancer diseases, exploring the roles of innate and adaptive immunities, immune regulation, and immunotherapy in these complex conditions. The innate immune system acts as the first line of defense against tissue damage and infection, with a significant impact on the initiation and progression of CVD and cancer. Endothelial dysfunction, a hallmark in CVD, shares commonalities with the tumor microenvironment in cancer, emphasizing the parallel involvement of the immune system in both conditions. The adaptive immune system, particularly T cells, contributes to prolonged inflammation in both CVD and cancer. Regulatory T cells and the intricate balance between different T cell subtypes influence disease progression, wound healing, and the outcomes of ischemic injury and cancer immunosurveillance. Dysregulation of immune homeostasis can lead to chronic inflammation, contributing to the development and progression of both CVD and cancer. Thus, immunotherapy emerged as a promising avenue for preventing and managing these diseases, with strategies targeting immune cell modulation, cytokine manipulation, immune checkpoint blockade, and tolerance induction. The impact of gut microbiota on CVD and cancer too is explored in this chapter, highlighting the role of gut leakiness, microbial metabolites, and the potential for microbiome-based interventions in cardiovascular and cancer immunotherapies. In conclusion, immunomodulatory strategies and immunotherapy hold promise in reshaping the landscape of cardiovascular and cancer health. Additionally, harnessing the gut microbiota for immune modulation presents a novel approach to prevent and manage these complex diseases, emphasizing the importance of personalized and precision medicine in healthcare. Ongoing research and clinical trials are expected to further elucidate the complex immunological underpinnings of CVD and cancer thereby refining these innovative approaches.


Subject(s)
Cardiovascular Diseases , Neoplasms , Humans , Neoplasms/immunology , Neoplasms/therapy , Cardiovascular Diseases/immunology , Immunotherapy , Immunity, Innate/immunology , Gastrointestinal Microbiome/immunology , Animals , Adaptive Immunity/immunology
5.
Immunity ; 57(5): 957-972, 2024 May 14.
Article in English | MEDLINE | ID: mdl-38749398

ABSTRACT

Platelets prevent blood loss during vascular injury and contribute to thrombus formation in cardiovascular disease. Beyond these classical roles, platelets are critical for the host immune response. They guard the vasculature against pathogens via specialized receptors, intracellular signaling cascades, and effector functions. Platelets also skew inflammatory responses by instructing innate immune cells, support adaptive immunosurveillance, and influence antibody production and T cell polarization. Concomitantly, platelets contribute to tissue reconstitution and maintain vascular function after inflammatory challenges. However, dysregulated activation of these multitalented cells exacerbates immunopathology with ensuing microvascular clotting, excessive inflammation, and elevated risk of macrovascular thrombosis. This dichotomy underscores the critical importance of precisely defining and potentially modulating platelet function in immunity.


Subject(s)
Blood Platelets , Immunity, Innate , Blood Platelets/immunology , Humans , Animals , Immunity, Innate/immunology , Inflammation/immunology , Adaptive Immunity/immunology , Thrombosis/immunology , Signal Transduction/immunology , T-Lymphocytes/immunology
6.
Mol Neurodegener ; 19(1): 38, 2024 Apr 24.
Article in English | MEDLINE | ID: mdl-38658964

ABSTRACT

BACKGROUND: Alzheimer's disease (AD) is the most frequent cause of dementia. Recent evidence suggests the involvement of peripheral immune cells in the disease, but the underlying mechanisms remain unclear. METHODS: We comprehensively mapped peripheral immune changes in AD patients with mild cognitive impairment (MCI) or dementia compared to controls, using cytometry by time-of-flight (CyTOF). RESULTS: We found an adaptive immune signature in AD, and specifically highlight the accumulation of PD1+ CD57+ CD8+ T effector memory cells re-expressing CD45RA in the MCI stage of AD. In addition, several innate and adaptive immune cell subsets correlated to cerebrospinal fluid (CSF) biomarkers of AD neuropathology and measures for cognitive decline. Intriguingly, subsets of memory T and B cells were negatively associated with CSF biomarkers for tau pathology, neurodegeneration and neuroinflammation in AD patients. Lastly, we established the influence of the APOE ε4 allele on peripheral immunity. CONCLUSIONS: Our findings illustrate significant peripheral immune alterations associated with both early and late clinical stages of AD, emphasizing the necessity for further investigation into how these changes influence underlying brain pathology.


Subject(s)
Adaptive Immunity , Alzheimer Disease , Cognitive Dysfunction , Disease Progression , Humans , Alzheimer Disease/immunology , Alzheimer Disease/cerebrospinal fluid , Aged , Male , Cognitive Dysfunction/immunology , Female , Adaptive Immunity/immunology , Biomarkers/cerebrospinal fluid , Aged, 80 and over , Middle Aged
7.
PLoS Pathog ; 20(4): e1012119, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38626206

ABSTRACT

Laboratory model organisms have provided a window into how the immune system functions. An increasing body of evidence, however, suggests that the immune responses of naive laboratory animals may differ substantially to those of their wild counterparts. Past exposure, environmental challenges and physiological condition may all impact on immune responsiveness. Chronic infections of soil-transmitted helminths, which we define as establishment of adult, fecund worms, impose significant health burdens on humans, livestock and wildlife, with limited treatment success. In laboratory mice, Th1 versus Th2 immune polarisation is the major determinant of helminth infection outcome. Here we compared antigen-specific immune responses to the soil-transmitted whipworm Trichuris muris between controlled laboratory and wild free-ranging populations of house mice (Mus musculus domesticus). Wild mice harbouring chronic, low-level infections produced lower levels of cytokines in response to Trichuris antigen than laboratory-housed C57BL/6 mice. Wild mouse effector/memory CD4+ T cell phenotype reflected the antigen-specific cytokine response across the Th1/Th2 spectrum. Increasing egg shedding was associated with body condition loss. However, local Trichuris-specific Th1/Th2 balance was positively associated with worm burden only in older wild mice. Thus, although the fundamental relationships between the CD4+ T helper cell response and resistance to T. muris infection are similar in both laboratory and wild M. m. domesticus, there are quantitative differences and age-specific effects that are analogous to human immune responses. These context-dependent immune responses demonstrate the fundamental importance of understanding the differences between model and natural systems for translating mechanistic models to 'real world' immune function.


Subject(s)
Adaptive Immunity , Mice, Inbred C57BL , Trichuriasis , Trichuris , Animals , Trichuris/immunology , Trichuriasis/immunology , Trichuriasis/parasitology , Mice , Adaptive Immunity/immunology , Disease Models, Animal , Female , Animals, Wild/immunology , Animals, Wild/parasitology , Th2 Cells/immunology , Cytokines/immunology , Cytokines/metabolism , Antigens, Helminth/immunology , Male
8.
Hum Immunol ; 85(3): 110795, 2024 May.
Article in English | MEDLINE | ID: mdl-38582657

ABSTRACT

The coronavirus disease 2019 (COVID-19) has merged as a global health threat since its outbreak in December 2019. Despite widespread recognition, there has been a paucity of studies focusing on the T cell receptor (TCR) bias in adaptive immunity induced by SARS-CoV-2. This research conducted a comparative analysis of the TCR immune repertoire to identify notable αß TCR bias sequences associated with the SARS-CoV-2 virus antigen. The present study encompassed 73 symptomatic COVID-19 patients, categorized as moderate/mild or severe/critical, along with 9 healthy controls. Our findings revealed specific TCR chains prominently utilized by moderate and severe patients, identified as TRAV30-J34-TRBV3-1-J2-7 and TRAV12-3-J6-TRBV28-J1-1, respectively. Additionally, our research explored critical TCR preferences in the bronchoalveolar lavage fluid (BALF) of COVID-19 patients at various disease stages. Indeed, monitoring the dynamics of immune repertoire changes in COVID-19 patients could serve as a crucial biomarker for predicting disease progression and recovery. Furthermore, the study explored TCR bias in both peripheral blood mononuclear cells (PBMCs) and BALF. The most common αß VJ pair observed in BALF was TRAV12-3-J18-TRBV7-6-J2-7. In addition, a comparative analysis with the VDJdb database indicated that the HLA-A*02:01 allele exhibited the widest distribution and highest frequency in COVID-19 patients across different periods. This comprehensive examination provided a global characterization of the TCR immune repertoire in COVID-19 patients, contributing significantly to our understanding of TCR bias induced by SARS-CoV-2.


Subject(s)
COVID-19 , Receptors, Antigen, T-Cell, alpha-beta , SARS-CoV-2 , Humans , COVID-19/immunology , SARS-CoV-2/immunology , Male , Female , Middle Aged , Receptors, Antigen, T-Cell, alpha-beta/genetics , Receptors, Antigen, T-Cell, alpha-beta/immunology , Receptors, Antigen, T-Cell, alpha-beta/metabolism , Adult , Bronchoalveolar Lavage Fluid/immunology , Aged , Receptors, Antigen, T-Cell/immunology , Receptors, Antigen, T-Cell/genetics , Receptors, Antigen, T-Cell/metabolism , Adaptive Immunity/immunology , Severity of Illness Index
9.
Cell Immunol ; 399-400: 104824, 2024.
Article in English | MEDLINE | ID: mdl-38615612

ABSTRACT

Infection of the respiratory tract with respiratory syncytial virus (RSV) is common and occurs repeatedly throughout life with most severe disease occurring at the extremes of age: in young infants and the elderly. Effective anti-viral therapeutics are not available and therefore prevention has been the primary strategy for reducing the disease burden. Our current understanding of respiratory mucosal cell biology and the immune response within the respiratory tract is inadequate to prevent infection caused by a pathogen like RSV that does not disseminate outside of this environment. Gaps in our understanding of the activation of innate and adaptive immunity in response to RSV and the role of age upon infection also limit improvements in the design of therapeutics and vaccines for young infants. However, advancements in structural biology have improved our ability to characterize antibodies against viral proteins and in 2023 the first vaccines for those over 60 years and pregnant women became available, potentially reducing the burden of disease. This review will examine our current understanding of the critical facets of anti-RSV immune responses in infants and young children as well as highlight areas where more research is needed.


Subject(s)
Adaptive Immunity , Immunity, Innate , Respiratory Syncytial Virus Infections , Humans , Respiratory Syncytial Virus Infections/immunology , Respiratory Syncytial Virus Infections/prevention & control , Adaptive Immunity/immunology , Immunity, Innate/immunology , Infant , Respiratory Syncytial Virus Vaccines/immunology , Respiratory Syncytial Virus, Human/immunology , Child, Preschool , Antibodies, Viral/immunology , Female , Respiratory Syncytial Viruses/immunology
10.
J Math Biol ; 88(6): 75, 2024 Apr 30.
Article in English | MEDLINE | ID: mdl-38689137

ABSTRACT

The aim of this paper is to develop and investigate a novel mathematical model of the dynamical behaviors of chronic hepatitis B virus infection. The model includes exposed infected hepatocytes, intracellular HBV DNA-containing capsids, uses a general incidence function for viral infection covering a variety of special cases available in the literature, and describes the interaction of cytotoxic T lymphocytes that kill the infected hepatocytes and the magnitude of B-cells that send antibody immune defense to neutralize free virions. Further, one time delay is incorporated to account for actual capsids production. The other time delays are used to account for maturation of capsids and free viruses. We start with the analysis of the proposed model by establishing the local and global existence, uniqueness, non-negativity and boundedness of solutions. After defined the threshold parameters, we discuss the stability properties of all possible steady state constants by using the crafty Lyapunov functionals, the LaSalle's invariance principle and linearization methods. The impacts of the three time delays on the HBV infection transmission are discussed through local and global sensitivity analysis of the basic reproduction number and of the classes of infected states. Finally, an application is provided and numerical simulations are performed to illustrate and interpret the theoretical results obtained. It is suggested that, a good strategy to eradicate or to control HBV infection within a host should concentrate on any drugs that may prolong the values of the three delays.


Subject(s)
Adaptive Immunity , Capsid , Computer Simulation , Hepatitis B virus , Hepatitis B, Chronic , Hepatocytes , Mathematical Concepts , Hepatocytes/immunology , Hepatocytes/virology , Hepatitis B virus/immunology , Humans , Capsid/immunology , Adaptive Immunity/immunology , Hepatitis B, Chronic/immunology , Hepatitis B, Chronic/virology , Hepatitis B, Chronic/transmission , Models, Immunological , T-Lymphocytes, Cytotoxic/immunology , Basic Reproduction Number/statistics & numerical data , B-Lymphocytes/immunology , DNA, Viral/immunology , Models, Biological
11.
Nature ; 628(8006): 162-170, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38538791

ABSTRACT

Ageing of the immune system is characterized by decreased lymphopoiesis and adaptive immunity, and increased inflammation and myeloid pathologies1,2. Age-related changes in populations of self-renewing haematopoietic stem cells (HSCs) are thought to underlie these phenomena3. During youth, HSCs with balanced output of lymphoid and myeloid cells (bal-HSCs) predominate over HSCs with myeloid-biased output (my-HSCs), thereby promoting the lymphopoiesis required for initiating adaptive immune responses, while limiting the production of myeloid cells, which can be pro-inflammatory4. Ageing is associated with increased proportions of my-HSCs, resulting in decreased lymphopoiesis and increased myelopoiesis3,5,6. Transfer of bal-HSCs results in abundant lymphoid and myeloid cells, a stable phenotype that is retained after secondary transfer; my-HSCs also retain their patterns of production after secondary transfer5. The origin and potential interconversion of these two subsets is still unclear. If they are separate subsets postnatally, it might be possible to reverse the ageing phenotype by eliminating my-HSCs in aged mice. Here we demonstrate that antibody-mediated depletion of my-HSCs in aged mice restores characteristic features of a more youthful immune system, including increasing common lymphocyte progenitors, naive T cells and B cells, while decreasing age-related markers of immune decline. Depletion of my-HSCs in aged mice improves primary and secondary adaptive immune responses to viral infection. These findings may have relevance to the understanding and intervention of diseases exacerbated or caused by dominance of the haematopoietic system by my-HSCs.


Subject(s)
Adaptive Immunity , Aging , Cell Lineage , Hematopoietic Stem Cells , Lymphocytes , Myeloid Cells , Rejuvenation , Animals , Female , Male , Mice , Adaptive Immunity/immunology , Aging/immunology , B-Lymphocytes/cytology , B-Lymphocytes/immunology , Hematopoietic Stem Cells/cytology , Hematopoietic Stem Cells/immunology , Inflammation/immunology , Inflammation/pathology , Lymphocytes/cytology , Lymphocytes/immunology , Lymphopoiesis , Myeloid Cells/cytology , Myeloid Cells/immunology , Myelopoiesis , Phenotype , T-Lymphocytes/cytology , T-Lymphocytes/immunology , Viruses/immunology
12.
Eur J Immunol ; 54(5): e2350392, 2024 May.
Article in English | MEDLINE | ID: mdl-38361213

ABSTRACT

Extracellular vesicles (EVs) are nanosized particles released by nearly every cell type across all kingdoms of life. As a result, EVs are ubiquitously present in various human body fluids. Composed of a lipid bilayer, EVs encapsulate proteins, nucleic acids, and metabolites, thus playing a crucial role in immunity, for example, by enabling intercellular communication. More recently, there has been increasing evidence that EVs can also act as key regulators of allergic immune responses. Their ability to facilitate cell-to-cell contact and to transport a variety of different biomolecules enables active modulation of both innate and adaptive immune processes associated with allergic reactions. A comprehensive understanding of the intricate mechanisms underlying the interactions among allergens, immune cells, and EVs is imperative to develop innovative strategies for controlling allergic responses. This review highlights the recent roles of host cell- and bacteria-derived EVs in allergic diseases, presenting experimental and clinical evidence that underscores their significance. Additionally, the therapeutic potential of EVs in allergy management is outlined, along with the challenges associated with targeted delivery and cargo stability for clinical use. Optimization of EV composition and targeting strategies holds promise for advancing translational applications and establishing EVs as biomarkers or safe therapeutics for assessing allergic reactions. For these reasons, EVs represent a promising avenue for advancing both our understanding and management of allergic immune processes.


Subject(s)
Extracellular Vesicles , Hypersensitivity , Humans , Extracellular Vesicles/immunology , Hypersensitivity/immunology , Hypersensitivity/therapy , Animals , Cell Communication/immunology , Immunity, Innate/immunology , Allergens/immunology , Adaptive Immunity/immunology , Biomarkers
13.
Nat Rev Immunol ; 24(5): 358-374, 2024 May.
Article in English | MEDLINE | ID: mdl-38097778

ABSTRACT

Lymph nodes are secondary lymphoid organs in which immune responses of the adaptive immune system are initiated and regulated. Distributed throughout the body and embedded in the lymphatic system, local lymph nodes are continuously informed about the state of the organs owing to a constant drainage of lymph. The tissue-derived lymph carries products of cell metabolism, proteins, carbohydrates, lipids, pathogens and circulating immune cells. Notably, there is a growing body of evidence that individual lymph nodes differ from each other in their capacity to generate immune responses. Here, we review the structure and function of the lymphatic system and then focus on the factors that lead to functional heterogeneity among different lymph nodes. We will discuss how lymph node heterogeneity impacts on cellular and humoral immune responses and the implications for vaccination, tumour development and tumour control by immunotherapy.


Subject(s)
Lymph Nodes , Humans , Lymph Nodes/immunology , Animals , Neoplasms/immunology , Neoplasms/pathology , Immunotherapy/methods , Immunity, Humoral/immunology , Adaptive Immunity/immunology , Vaccination
14.
Int J Mol Sci ; 24(13)2023 Jul 01.
Article in English | MEDLINE | ID: mdl-37446157

ABSTRACT

Atherosclerotic cardiovascular disease is the most common cause of morbidity and death worldwide. Recent studies have demonstrated that this chronic inflammatory disease of the arterial wall can be controlled through the modulation of immune system activity. Many patients with cardiovascular disease remain at elevated risk of recurrent events despite receiving current, state-of-the-art preventive medical treatment. Much of this residual risk is attributed to inflammation. Therefore, finding new treatment strategies for this category of patients became of common interest. This review will discuss the experimental and clinical data supporting the possibility of developing immune-based therapies for lowering cardiovascular risk, explicitly focusing on vaccination strategies.


Subject(s)
Atherosclerosis , Immunomodulation , Humans , Atherosclerosis/immunology , Atherosclerosis/prevention & control , Atherosclerosis/therapy , Heart Disease Risk Factors , Inflammation , Vaccination/trends , Immunity, Innate/immunology , Adaptive Immunity/immunology , Immunity, Humoral/immunology , Autoantigens/immunology , Clinical Trials as Topic , Vaccines/immunology , Vaccines/therapeutic use
16.
Semin Immunol ; 65: 101707, 2023 01.
Article in English | MEDLINE | ID: mdl-36527759

ABSTRACT

Immuno-oncology has traditionally focused on the cellular arm of the adaptive immune response, while attributing tumor-promoting activity to humoral responses in tumor-bearing hosts. This view stems from mouse models that do not necessarily recapitulate the antibody response process consistently observed in most human cancers. In recent years, the field has reconsidered the coordinated action of T and B cell responses in the context of anti-tumor immunity, as in any other immune response. Thus, recent studies in human cancer identify B cell responses with better outcome, typically in association with superior T cell responses. An area of particular interest is tertiary lymphoid structures, where germinal centers produce isotype switched antibodies and B cells and T lymphocytes interact with other immune cell types. The presence of these lymphoid structures is associated with better immunotherapeutic responses and remain poorly understood. Here, we discuss recent discoveries on how coordination between humoral and cellular responses is required for effective immune pressure against malignant progression, providing a perspective on the role of tertiary lymphoid structures and interventions to elicit their formation in unresectable tumors.


Subject(s)
B-Lymphocytes , Neoplasms , T-Lymphocytes , Tertiary Lymphoid Structures , Animals , Humans , Mice , Adaptive Immunity/immunology , B-Lymphocytes/immunology , Neoplasms/immunology , Neoplasms/therapy , T-Lymphocytes/immunology , Tertiary Lymphoid Structures/immunology
17.
Front Immunol ; 13: 965018, 2022.
Article in English | MEDLINE | ID: mdl-35967443

ABSTRACT

Chronic hepatitis B virus (HBV) infection remains to be a substantial global burden, especially for end-stage liver diseases. It is well accepted that HBV-specific T and B cells are essential for controlling HBV infection. Toll-like receptors (TLRs) represent one of the major first-line antiviral defenses through intracellular signaling pathways that induce antiviral inflammatory cytokines and interferons, thereby shaping adaptive immunity. However, HBV has evolved strategies to counter TLR responses by suppressing the expression of TLRs and blocking the downstream signaling pathways, thus limiting HBV-specific adaptive immunity and facilitating viral persistence. Recent studies have stated that stimulation of the TLR signaling pathway by different TLR agonists strengthens host innate immune responses and results in suppression of HBV replication. In this review, we will discuss how TLR-mediated responses shape HBV-specific adaptive immunity as demonstrated in different experimental models. This information may provide important insight for HBV functional cure based on TLR agonists as immunomodulators.


Subject(s)
Adaptive Immunity , Hepatitis B, Chronic , Hepatitis B , Immunity, Innate , Toll-Like Receptors , Adaptive Immunity/immunology , Antiviral Agents/therapeutic use , Hepatitis B virus , Hepatitis B, Chronic/immunology , Humans , Immunity, Innate/immunology , Toll-Like Receptors/immunology
18.
J Immunol ; 208(8): 2067-2076, 2022 04 15.
Article in English | MEDLINE | ID: mdl-35365564

ABSTRACT

The E3 ubiquitin ligase Riplet mediates retinoic acid-inducible gene-I polyubiquitination and is essential for viral-induced expression of type I IFNs in dendritic cells and macrophages. The function of Riplet in innate immunity has been well demonstrated; however, its role in adaptive immunity during the antitumor immune response is unclear. In this study, we examined the role of Riplet in the T cell-mediated antitumor immune response. Riplet was expressed in T cells and upregulated in CD8+ T cells in response to TCR-mediated stimulation. Furthermore, PR domain containing 1, eomesodermin, and killer cell lectin-like receptor G1 expression was increased in effector CD8+ T cells by Riplet knockout in vitro, which suggests that Riplet is involved in the effector function of CD8+ T cells. Our results indicated that Riplet deficiency augmented the antitumor response of MO4 (OVA-expressing melanoma)-bearing mice treated with OVA peptide-pulsed dendritic cells. Moreover, both CD4+ and CD8+ T cells played important roles in Riplet-mediated augmentation of the antitumor immune response. In tumor-draining lymph nodes, the Th1 response was promoted, and the induction of OVA-specific CD8+ T cells and IFN-γ production were enhanced by Riplet deficiency. Furthermore, the IFN-γ response and OVA-specific cytotoxicity of CD8+ T cells in tumor tissue were augmented by Riplet deficiency. The expression of Cxcl9fluorescence-minus-one and Cxcl10 mRNA was also enhanced in the tumor microenvironment by Riplet knockout, consistent with the augmented recruitment of CTLs. Overall, we clarified a function of Riplet in T cells, which is to suppress the antitumor immune response through modulating Th1 and CTLs.


Subject(s)
Adaptive Immunity , T-Lymphocytes , Ubiquitin-Protein Ligases , Adaptive Immunity/immunology , Animals , CD8-Positive T-Lymphocytes/immunology , Dendritic Cells , Immunity, Innate/immunology , Mice , Mice, Inbred C57BL , Mice, Knockout , T-Lymphocytes/immunology , T-Lymphocytes, Cytotoxic/immunology , Th1 Cells/immunology , Ubiquitin-Protein Ligases/biosynthesis , Ubiquitin-Protein Ligases/immunology
19.
PLoS One ; 17(2): e0264124, 2022.
Article in English | MEDLINE | ID: mdl-35202394

ABSTRACT

BACKGROUND: The vast majority of COVID-19 cases both symptomatic and asymptomatic develop immunity after COVID-19 contagion. Whether lasting differences exist between infection and vaccination boosted immunity is yet to be known. The aim of this study was to determine how long total anti-SARS-CoV2 antibodies due to past infection persist in peripheral blood and whether sex, age or haematological features can influence their lasting. MATERIAL AND METHODS: A series of 2421 donations either of SARS-CoV-2 convalescent plasma or whole blood from 1107 repeat donors from January 2020 to March 2021 was analysed. An automated chemiluminescence immunoassay for total antibodies recognizing the nucleocapsid protein of SARS-CoV-2 in human serum and plasma was performed. Sex, age, blood group, blood cell counts and percentages and immunoglobulin concentrations were extracted from electronic recordings. Blood donation is allowed after a minimum of one-month post symptom's relapse. Donors were 69.7% males and their average age was 46. The 250 donors who had later donations after a positive one underwent further analysis. Both qualitative (positivity) and quantitative (rise or decline of optical density regarding consecutive donations) outcomes were evaluated. RESULTS AND DISCUSSION: In 97.6% of donors with follow-up, anti-SARS-CoV-2 protein N total antibodies remained positive at the end of a follow-up period of 12.4 weeks median time (1-46, SD = 9.65) after the first positive determination. The blood group was not related to antibody waning. Lower lymphocyte counts and higher neutrophils would help predict future waning or decay of antibodies. Most recovered donors maintain their total anti-SARS-CoV-2 N protein antibodies for at least 16 weeks (at least one month must have been awaited from infection resolution to blood donation). The 10 individuals that could be followed up longer than 40 weeks (approximately 44 weeks after symptom's relapse) were all still positive.


Subject(s)
COVID-19/immunology , COVID-19/therapy , SARS-CoV-2/immunology , Adaptive Immunity/immunology , Adult , Aged , Aged, 80 and over , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , Blood Donors , COVID-19/blood , Female , Humans , Immunization, Passive , Immunoglobulin G/blood , Male , Middle Aged , Plasma , SARS-CoV-2/pathogenicity , COVID-19 Serotherapy
20.
Cells ; 11(4)2022 02 13.
Article in English | MEDLINE | ID: mdl-35203299

ABSTRACT

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is the pathogenic agent of Coronavirus-Induced Disease-2019 (COVID-19), a multi-organ syndrome which primarily targets the respiratory system. In this review, considering the large amount of data pointing out the role of the Aryl hydrocarbon Receptor (AhR) in the inflammatory response and in the modulation of innate and adaptive immunity, we describe some mechanisms that strongly suggest its involvement in the management of COVID-19's inflammatory framework. It regulates both the expression of Angiotensin Converting Enzyme-2 (ACE-2) and its stabilizing partner, the Broad neutral Amino acid Transporter 1 (B0AT1). It induces Indolamine 2,3 dioxygenase (IDO-1), the enzyme which, starting from Tryptophan (Trp), produces Kynurenine (Kyn, Beta-Anthraniloyl-L-Alanine). The accumulation of Kyn and the depletion of Trp arrest T cell growth and induce apoptosis, setting up an immune-tolerant condition, whereas AhR and interferon type I (IFN-I) build a mutual inhibitory loop that also involves NF-kB and limits the innate response. AhR/Kyn binding boosts the production of Interleukin-6 (IL-6), thus reinforcing the inflammatory state and counteracting the IDO-dependent immune tolerance in the later stage of COVID-19. Taken together, these data depict a framework where sufficient clues suggest the possible participation of AhR in the management of COVID-19 inflammation, thus indicating an additional therapeutic target for this disease.


Subject(s)
COVID-19/metabolism , Receptors, Aryl Hydrocarbon/metabolism , SARS-CoV-2/metabolism , Adaptive Immunity/immunology , Amino Acid Transport Systems, Neutral/metabolism , Angiotensin-Converting Enzyme 2/metabolism , Basic Helix-Loop-Helix Transcription Factors/metabolism , Basic Helix-Loop-Helix Transcription Factors/physiology , COVID-19/immunology , COVID-19/transmission , Humans , Immunity, Innate/immunology , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Inflammation/immunology , Kynurenine/metabolism , Receptors, Aryl Hydrocarbon/physiology , SARS-CoV-2/pathogenicity , Signal Transduction , Tryptophan/metabolism
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