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A20 is a dual‐function ubiquitin‐editing enzyme that maintains immune homeostasis by restraining inflammation. Although A20 serves a similar negative feedback function for T‐cell receptor (TCR) signaling, the molecular mechanisms utilized and their ultimate impact on human T‐cell function remain unclear. TCR engagement triggers the assembly of the CARD11‐BCL10‐MALT1 (CBM) protein complex, a signaling platform that governs the activation of downstream transcription factors including NF‐κB and c‐Jun/AP‐1. Utilizing WT and A20 knockout Jurkat T cells, we found that A20 is required to negatively regulate NF‐κB and JNK. Utilizing a novel set of A20 mutants in NF‐κB and AP‐1‐driven reporter systems, we discovered the ZnF7 domain is crucial for negative regulatory capacity, while deubiquitinase activity is dispensable. Successful inactivation of A20 in human primary effector T cells congruently conferred sustained NF‐κB and JNK signaling, including enhanced upregulation of activation markers, and increased secretion of several cytokines including IL‐9. Finally, loss of A20 in primary human T cells resulted in decreased sensitivity to restimulation‐induced cell death and increased sensitivity to cytokine withdrawal‐induced death. These findings demonstrate the importance of A20 in maintaining T‐cell homeostasis via negative regulation of both NF‐κB and JNK signaling. [ABSTRACT FROM AUTHOR]

Regulatory B cells (Bregs) are a functionally distinct B‐cell subset involved in the maintenance of homeostasis and inhibition of inflammation. Studies, from the last two decades, have increased our understanding of cellular and molecular mechanisms involved in their generation, function, and to a certain extent phenotype. Current research endeavours to unravel the causes and consequences of Breg defects in disease, with increasing evidence highlighting the relevance of Bregs in promoting tumorigenic responses. Here we provide historical and emerging findings of the significance of Bregs in autoimmunity and transplantation, and how these insights have translated into the cancer field. [ABSTRACT FROM AUTHOR]

Summary Eltrombopag (ELT) is a thrombopoietin‐receptor agonist that stimulates platelet (PLT) production in patients with primary immune thrombocytopenia (ITP). One potential mechanism of ELT is modulating the inflammatory response by increasing PLTs binding to leucocytes. This study examined the effect of ELT on leucocyte–PLTs complexes in 38 ITP patients. Patients, predominantly females with a mean age of 59 years, underwent treatments like corticosteroids, intravenous immunoglobulin and splenectomy. Compared to healthy donors, ITP patients exhibited lower percentages of lymphocyte with bound PLTs, but similar monocyte‐ or neutrophil with bound PLTs. ELT treatment increased PLTs counts and all types of leucocyte with bound PLTs. Network analysis showed dynamic changes in leucocyte with bound PLTs relationships due to ELT. Machine learning indicated that higher percentages of monocytes with bound PLTs were linked to a better clinical response to ELT. A possible mechanism was an increased IL‐10 production in monocytes with bound PLTs from responder patients. This study provides insights into the immunological changes in ITP patients undergoing ELT and suggests potential predictive biomarkers for treatment response and disease monitoring. [ABSTRACT FROM AUTHOR]

Despite a substantial progress in the development of strategies against cancer, cancer still remains a major global health issue due to a high recurrence rate, and severe side effects, leading basic medical scientists and clinical specialists toward more efficient diagnostics, prognostics, and therapeutics. Therefore, there is an imperative need for a comprehensive understanding on the cellular immunopathophysiology involved in the tumor microenvironment. In addition, results from a wide range of studies depicted that an aberration in the cellular mechanisms and immunopathophysiological interactions like Circulating Tumor Cells (CTCs) plays an indispensable role in the metastasis and tumor progression, revolutionizing cancer management by offering non-invasive detection methods and a real-time monitoring of tumor dynamics. Moreover, CTCs can clarify the tumor heterogeneity and the evolution of resistance mechanisms, aiding in the early detection of tumors and informing personalized treatment strategies. An increase in CTCs count can be associated with a worsened cancer prognosis, providing promising biomarkers for tumor phenotyping, tumor spreading or relapse, and monitoring the treatment response in patients with cancer. Hence, this systematic review aims to highlight the diagnostic, prognostic, and therapeutic potentials of CTCs, necessitating further investigations and an interdisciplinary collaboration among basic medical scientists and oncologists to address the current gaps in the strategies of cancer management, precisely improving patient-care and optimized clinical outcomes.

Highly pathogenic viruses from family Phenuiviridae, which are mainly transmitted by arthropods, have intermittently sparked epidemics worldwide. In particular, tick-borne bandaviruses, such as severe fever with thrombocytopenia syndrome virus (SFTSV), continue to spread in mountainous areas, resulting in an average mortality rate as high as 10.5%, highlighting the urgency and importance of vaccine development. Here, an mRNA vaccine developed based on the full-length SFTSV glycoprotein, containing both the receptor-binding domain and the fusion domain, was shown to confer complete protection against SFTSV at a very low dose by triggering a type 1 helper T cell-biased cellular immune response in rodents. Moreover, the vaccine candidate elicited long-term immunity and protection against SFTSV for at least 5 months. Notably, it provided complete cross-protection against other bandaviruses, such as the Heartland virus and Guertu virus, in lethal challenge models. Further research revealed that the conserved epitopes among bandaviruses within the full-length SFTSV glycoprotein may facilitate broad-spectrum protection mediated by the cellular immune response. Collectively, these findings demonstrate that the full-length SFTSV glycoprotein mRNA vaccine is a promising vaccine candidate for SFTSV and other bandaviruses, and provide guidance for the development of broad-spectrum vaccines from conserved antigens and epitopes. IMPORTANCE Tick-borne bandaviruses, such as SFTSV and Heartland virus, sporadically trigger outbreaks in addition to influenza viruses and coronaviruses, yet there are no specific vaccines or therapeutics against them. mRNA vaccine technology has advantages in terms of enabling in situ expression and triggering cellular immunity, thus offering new solutions for vaccine development against intractable viruses, such as bandaviruses. In this study, we developed a novel vaccine candidate for SFTSV by employing mRNA vaccination technology and using a full-length glycoprotein as an antigen target. This candidate vaccine confers complete and durable protection against SFTSV at a notably low dose while also providing cross-protection against Heartland virus and Guertu virus. This study highlights the prospective value of fulllength SFTSV-glycoprotein-based mRNA vaccines and suggests a potential strategy for broad-spectrum bandavirus vaccines. [ABSTRACT FROM AUTHOR]

Summary: Autologous patient‐derived adoptive T‐cell therapies have revolutionized the management of relapsed multiple myeloma (MM). However, the current manufacturing and quality control processes result in lengthy vein‐to‐vein time, making bridging therapy necessary for most patients. Yet the decision and choice of optimal bridging therapy are complex in the heavily pretreated relapsed MM patient. In this perspective piece, the authors provide their approach and considerations while selecting an optimal bridging regimen before autologous chimeric antigen receptor T‐cell therapy. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a common inflammatory skin disorder. Mast cells play an important role in AD because they regulate allergic reactions and inflammatory responses. However, whether and how the modulation of mast cell activity affects AD has not been determined. In this study, we aimed to determine the effects and mechanisms of 3‐O‐cyclohexanecarbonyl‐11‐keto‐β‐boswellic acid (CKBA). This natural compound derivative alleviates skin inflammation by inhibiting mast cell activation and maintaining skin barrier homeostasis in AD. CKBA markedly reduced serum IgE levels and alleviated skin inflammation in calcipotriol (MC903)‐induced AD mouse model. CKBA also restrained mast cell degranulation both in vitro and in vivo. RNA‐seq analysis revealed that CKBA downregulated the extracellular signal‐regulated kinase (ERK) signaling in BM‐derived mast cells activated by anti‐2,4‐dinitrophenol/2,4‐dinitrophenol‐human serum albumin. We proved that CKBA suppressed mast cell activation via ERK signaling using the ERK activator (t‐butyl hydroquinone) and inhibitor (selumetinib; AZD6244) in AD. Thus, CKBA suppressed mast cell activation in AD via the ERK signaling pathway and could be a therapeutic candidate drug for AD. [ABSTRACT FROM AUTHOR]

Accumulation of senescent cells (SNCs) with a senescence‐associated secretory phenotype (SASP) has been implicated as a major source of chronic sterile inflammation leading to many age‐related pathologies. Herein, we provide evidence that a bifunctional immunotherapeutic, HCW9218, with capabilities of neutralizing TGF‐β and stimulating immune cells, can be safely administered systemically to reduce SNCs and alleviate SASP in mice. In the diabetic db/db mouse model, subcutaneous administration of HCW9218 reduced senescent islet β cells and SASP resulting in improved glucose tolerance, insulin resistance, and aging index. In naturally aged mice, subcutaneous administration of HCW9218 durably reduced the level of SNCs and SASP, leading to lower expression of pro‐inflammatory genes in peripheral organs. HCW9218 treatment also reverted the pattern of key regulatory circadian gene expression in aged mice to levels observed in young mice and impacted genes associated with metabolism and fibrosis in the liver. Single‐nucleus RNA Sequencing analysis further revealed that HCW9218 treatment differentially changed the transcriptomic landscape of hepatocyte subtypes involving metabolic, signaling, cell‐cycle, and senescence‐associated pathways in naturally aged mice. Long‐term survival studies also showed that HCW9218 treatment improved physical performance without compromising the health span of naturally aged mice. Thus, HCW9218 represents a novel immunotherapeutic approach and a clinically promising new class of senotherapeutic agents targeting cellular senescence‐associated diseases. [ABSTRACT FROM AUTHOR]

Tumor is one of the intractable diseases causing human death at present.Although the prognosis of tumor patients has been improved to a certain extent through various modern treatment methods,multidrug resistance is still the main problem leading to poor tumor treatment effect.Nanomaterials are one of the research hotspots in recent years.They have many advantages,such as EPR(enhanced permeability and retention) effects,controllable modification and targeting,and have attracted more and more attention in the breakthrough of tumor drug resistance.Nano drug delivery system plays an important role in tumor therapy and can be a new way to reverse tumor drug resistance.The mechanism of multidrug resistance and the application of nanotechnology in drug resistance were reviewed.It is pointed out that further research should be carried out in the following aspects: 1) Combining with the mechanism of tumor drug resistance,reasonably control drug concentration to overcome drug resistance;2) Further explore the biosafety of nanodrug delivery system,optimize the nanodrug delivery system,avoid or reduce possible toxic and side reactions,and provide a more comprehensive theoretical basis for reversing tumor drug resistance;3) Improve the efficiency of reversing tumor drug resistance of nanodrug delivery system by combining immunology,photo dynamics,acoustic dynamics and other methods.

One of the mechanisms of cellular dysfunction during the chronization of immune-system-mediated inflammatory diseases is a change in the profile of expression and co-expression of receptors on cells. The aim of this study was to compare patterns of redistribution of TNF receptors (TNFRs) among patients with different durations of rheumatoid arthritis (RA) or asthma. Subgroup analysis was performed on RA (n = 41) and asthma (n = 22) patients with disease duration<10 years and >10 years and on 30 comparable healthy individuals. The co-expression profile of TNFR1 and TNFR2 was assessed in T cells, B cells, monocytes, regulatory T cells, T-helper subsets, and cytotoxic T-lymphocyte subsets. Percentages of cells with different co-expression combinations and receptor density per cell were estimated. Longer disease duration was significantly associated with a redistribution of receptors in immunocompetent cell subsets with an increase in the expression of TNFR1 in asthma but did not correlate with significant unidirectional changes in receptor expression in RA. In asthma, a higher proportion of cells with a certain type of TNF receptor (as compared with the healthy group) was correlated with a simultaneous greater density of this receptor type. In RA, an inverse correlation was observed (compensatory lower receptor density). Mechanisms of long-term changes in the expression of TNF receptors differ significantly between the diseases of autoimmune and allergic etiology. The formation of irreversible morphostructural alterations was strongly correlated with changes in the expression of TNFR1 in asthma and with changes in the expression of TNFR2 in RA. [ABSTRACT FROM AUTHOR]

Type 1 diabetes (T1D) is an autoimmune disease resulting in the destruction of the insulin-producing pancreatic beta cells. Disease progression occurs along a trajectory from genetic risk, the development of islet autoantibodies, and autoreactive T cells ultimately progressing to clinical disease. Natural history studies and mechanistic studies linked to clinical trials have provided insight into the role of the immune system in disease pathogenesis. Here, we review our current understanding of the underlying etiology of T1D, focusing on the immune cell types that have been implicated in progression from pre-symptomatic T1D to clinical diagnosis and established disease. This knowledge has been foundational for the development of immunotherapies aimed at the prevention and treatment of T1D. This review summarizes the current understanding of the underlying immunopathology of T1D, focusing on the immune cell types implicated in progression from pre-symptomatic T1D to clinical diagnosis and established disease. It also highlights how this knowledge is driving the development of immunotherapies aimed at the prevention and treatment of T1D. [ABSTRACT FROM AUTHOR]

Introduction : Although CD20 is classically a B cell marker, in the last three decades, dim expression has been noted on a subset of T cells as well that has been independently verified by a number of groups. Our understanding of these cells and their function is not well established. Methods: A thorough review of original articles on CD20+T cells was undertaken of Pubmed by using combination of phrases including "CD20+", "CD20-positive" and "T cells". Articles in English were considered, and there was no time restriction. Results: CD20+T cells express the standard T cell markers and, in comparison to CD20¯ T cells, appear to express greater inflammatory cytokines and markers of effector function. Although the ontogeny of these cells is still being established, the current theory is that CD20 may be acquired by trogocytosis from B cells. CD20+T cells may be found in healthy controls and in a wide range of pathologies including autoimmune diseases, haematological and non-haematological malignancies and human immunodeficiency virus (HIV) infections. One of the best studied diseases where these cells are found is multiple sclerosis (MS) where a number of therapeutic interventions, including anti-CD20 depletion, have been shown to effectively deplete these cells. Conclusion: This review summarises the latest understanding of CD20+T cells, their presence in various diseases, their putative function and how they may be an ongoing target of CD20-depleting agents. Unfortunately, our understanding of these cells is still at its infancy and ongoing study in a wider range of pathologies is required. [ABSTRACT FROM AUTHOR]

T cells are important to the immune system as they remove foreign pathogens such as bacteria, cancer cells, viruses, and parasites. T cells can change their DNA by undergoing a process called V(D)J recombination. There are two types of T cells: gamma-delta (γδ) and alpha-beta (αβ). Gamma-delta T cells have been eliciting interest in the past few years as they have an important role in autoimmune diseases, various infections, and cancer. I hypothesized that there are many more gammadelta T cell subtypes that haven’t been characterized yet. Certain subsets of gamma-delta T cells can only be found in the liver as they perform specific functions in liver diseases. Their effect on liver diseases depends on the subset and cytokines produced so characterizing them now can be beneficial in developing vaccines in the future. These new subtypes could have an important role in tumor detection and regression. Cluster 1 had T follicular helper cells, cluster 2 had regulatory T cells, cluster 3 had effector memory cells, cluster 4 had activated tissue memory cells, and cluster 7 had T helper 2-like cells. [ABSTRACT FROM AUTHOR]

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Luminal A breast cancer is the most common subtype of the most common cancer in women. Current treatments using surgery and chemotherapy have greatly improved patient outcomes in recent decades but are still far from perfect. mRNA vaccines, which instruct the body to create specific proteins, hold the best promise going forward as a "cure" for luminal A breast cancer. Immunological therapies are emerging in solving problems that chemotherapy, surgery and targeted therapies cannot. The ultimate goal of immunotherapy would be to help the immune system recognize and destroy tumor cells as well as make antigens. In this paper, mRNA's potential for addressing the heterogenous nature of tumors, envisioning how it might be made to effectively elicit an immune response are explored; in particular, how it can be modified quickly to change which mutated genes it targets. This paper also discusses the limitations of this emerging technology and the difficulties of evaluating its efficacy when it has yet to enter clinical trials. Finally, this paper concludes by offering thoughts on how its development might be accelerated, predictions on effective targets, and likely dates for such a vaccine to debut as a real-world treatment. [ABSTRACT FROM AUTHOR]

• Aging is related to oxidative stress and inflammation. • Resveratrol, through Nrf2, appears to act in the increase of IL-10. • The Nrf2 cell signaling pathway is the main pathway responsible for the biological effects of resveratrol in aging. During aging, in addition to increased oxidative stress, inflammation also occurs. A chronic and low-grade inflammation - called "inflammaging" - develops, which contributes to the etiology of diseases related to aging. Resveratrol (Resv.) is a polyphenol well known for its biologically active properties, such as antioxidant and anti-inflammatory properties. This balance can be regulated by Nrf2 - a transcription factor that regulates cellular defense against oxidative agents through the expression or inhibition of certain genes. The objective was to evaluate the effect of Nrf2 on the production of cytokines in leukocytes of different ages treated with resveratrol (5µm). The subjects were divided into three groups: 20–39, 40–59 and 60–80 years old. After separation of the leukocytes, a 24-hour treatment was carried out with and without ML385 inhibitor with the treatments: Control, Resv, Peroxide and Peroxide+Resv. 150 µM peroxide was set to develop an oxidative environment. Cytokines were measured by ELISA (* p < 0.05). In general, there was an increase in TNF and IL-6 in cells stimulated with peroxide compared to controls. A decrease in these two cytokines was also observed in cells treated with resveratrol, both at basal levels and in an oxidizing environment (with peroxide). The polyphenol was able to increase IL-10 only in the youngest age groups. The same profile was observed comparing the same groups when the Nrf2 pathway was inhibited with ML385. It is concluded that resveratrol may have a better effect on preventing oxidation and inflammation present in aging, especially through the antioxidant and anti-inflammatory Nrf2 pathway. [ABSTRACT FROM AUTHOR]

(1) Background: Pemphigus is a blistering autoimmune disease of the skin and/or mucous membranes, characterised by the presence of specific autoantibodies directed against structural proteins of the human skin. Recent reports indicate that new haematological parameters, termed Extended Inflammation Parameters (EIP), can be used to assess the activation of immune cells during active inflammation. These include parameters assessing both neutrophil activation (NEUT-RI, NEUT-GI) and the number of activated lymphocytes (RE-LYMP). The aim of this study was to investigate the relationship between changes in NEUT-RI, NEUT-GI and RE-LYMP and the disease activity in patients with pemphigus. (2) Results: The study involved 32 patients with diagnosed different types of pemphigus. Neutrophil activation parameters (NEUT-RI and NEUT-GI) and lymphocytes (RE-LYMP) were significantly higher in these patients compared to the parameters in healthy participants (respectively p = 0.0127, p = 0.0011 and p = 0.0033). The increased quantity of activated lymphocytes (RE-LYMP) also correlated significantly with the extent of skin and/or mucosal lesions in patients assessed by the PDAI scale (p < 0.02). (3) Conclusions: The NEUT-RI, NEUT-GI and RE-LYMP parameters proved to be appropriate markers of inflammation severity in pemphigus, also in relation to local lesions, which was not possible with the inflammation markers (CRP, ESR) used so far on a routine basis. [ABSTRACT FROM AUTHOR]

One of the earliest hallmarks of immune aging is thymus involution, which not only reduces the number of newly generated and exported T cells, but also alters the composition and organization of the thymus microenvironment. Thymic T‐cell export continues into adulthood, yet the impact of thymus involution on the quality of newly generated T‐cell clones is not well established. Notably, the number and proportion of medullary thymic epithelial cells (mTECs) and expression of tissue‐restricted antigens (TRAs) decline with age, suggesting the involuting thymus may not promote efficient central tolerance. Here, we demonstrate that the middle‐aged thymic environment does not support rapid motility of medullary thymocytes, potentially diminishing their ability to scan antigen presenting cells (APCs) that display the diverse self‐antigens that induce central tolerance. Consistent with this possibility, thymic slice assays reveal that the middle‐aged thymic environment does not support efficient negative selection or regulatory T‐cell (Treg) induction of thymocytes responsive to either TRAs or ubiquitous self‐antigens. This decline in central tolerance is not universal, but instead impacts lower‐avidity self‐antigens that are either less abundant or bind to TCRs with moderate affinities. Additionally, the decline in thymic tolerance by middle age is accompanied by both a reduction in mTECs and hematopoietic APC subsets that cooperate to drive central tolerance. Thus, age‐associated changes in the thymic environment result in impaired central tolerance against moderate‐avidity self‐antigens, potentially resulting in export of increasingly autoreactive naive T cells, with a deficit of Treg counterparts by middle age. [ABSTRACT FROM AUTHOR]

Background: The co-expression patterns of type 1 and 2 tumor necrosis factor (TNF)-α membrane receptors (TNFR1/TNFR2) are associated with the presence, stage, and activity of allergic diseases. The aim of this study was to assess the expression levels and dynamics of TNFRs on immune cells and to assess associations between their expression and severity of bronchial asthma (BA). Methods: Patients with severe (n = 8), moderate (n = 10), and mild (n = 4) BA were enrolled. As a comparison group, data from 46 healthy volunteers (HV) were accessed. Co-expression of TNFR1/2 was evaluated as a percentage of cells and the number of receptors of each type per cell. Multivariate logistic regression analysis was used to identify diagnostic biomarkers of BA. Results: More than 90% of the monocytes in patients with mild BA were TNFR1+TNFR2+ but had significantly lower TNFR1 expression density compared with HV (7.82- to 14.08-fold, depending on disease severity). Lower percentages of the TNFR+ B-lymphocytes were observed in combination with significantly lower receptors density in BA compared with HV (2.59- to 11.64-fold for TNFR1 and 1.72- to 3.4-fold for TNFR2, depending on disease severity). The final multivariate model for predicting the presence of BA included the percentage of double-positive CD5+ B-lymphocytes and average number of TNFR1 molecules expressed on cytotoxic naive T-lymphocytes and T-helper cells (R2 = 0.87). Conclusions: The co-expression patterns of TNFRs on immune cells in BA differed significantly compared with HV. The expression differences were associated with disease severity. TNFR1 expression changes were key parameters that discriminated patients with BA from those with HV. [ABSTRACT FROM AUTHOR]

Background and objective: The purpose of this study was to evaluate whether gingival fibroblasts (GFs) can be differently activated and polarized into distinct functional subtypes by T‐helper (Th) cytokines. Methods: Gingival fibroblasts were stimulated with interferon (IFN)‐γ, interleukin (IL)‐4, IL‐17, and transforming growth factor (TGF)‐β, representative cytokines of Th1, Th2, Th17, and regulatory T cells, respectively, and the gene expression profiles were analyzed by microarray. Differentially expressed genes (DEGs) in GFs stimulated by 4 cytokines were screened, and a gene ontology (GO) analysis of the DEGs was conducted. To confirm the reliability of the microarray results, the DEGs that showed the largest differences compared with non‐stimulated GFs were further analyzed by RT‐PCR. To evaluate the effect of polarization on GFs responses to lipopolysaccharide (LPS), GFs stimulated by 4 cytokines were further stimulated with Escherichia coli LPS and mRNA levels of several genes were analyzed using RT‐PCR. Results: Differentially expressed genes by 4 Th cytokines were enriched in different GO terms, and the patterns of gene expression on GFs were shown functionally different. GFs stimulated with IFN‐γ (GF(IFN‐γ)) up‐regulated the expression of chemokines (chemokine (C‐X‐C motif) ligand (CXCL)9, −10, −11, chemokine (C‐C motif) ligand (CCL)8), molecules involved in antigen presentation, complement component 3 (C3), and other immune response–related molecules, whereas they down‐regulated the expression of several types of collagen, extracellular matrix (ECM) components, and DNA replication and nuclear protein–related molecules. By contrast, GF(IL‐4) up‐regulated the expression of ECM components, cell adhesion molecules, and tissue development–related molecules and down‐regulated the expression of chemokines (CXCL10 and CXCL8) and adaptive immune response–related molecules. GF(IL‐17) up‐regulated the expression of chemokines and other molecules for neutrophil infiltration and activation, the pro‐inflammatory cytokine IL‐6, and C3. GF(TGF‐β) up‐regulated the expression of cell growth–related molecules, ECM components, several types of collagen, and cell adhesion molecules and down‐regulated the expression of molecules related to complement activation and bacterial recognition. GFs stimulated by 4 cytokines responded differently to LPS. Conclusion: These results show that Th cytokines can polarize GFs into cells with functionally distinct features: immune‐activating but tissue‐destructive GF(IFN‐γ), tissue‐reparative, and immune‐inhibiting GF(IL‐4), highly pro‐inflammatory GF(IL‐17), and potent tissue‐reparative GF(TGF‐β). [ABSTRACT FROM AUTHOR]

Background: We aimed to characterise the adaptive immune response to Mycobacterium abscessus complex (MABSC) and its cross-reactivity with Mycobacterium avium complex (MAC) and Mycobacterium bovis (Bacille Calmette-Guérin, BCG) in cystic fibrosis (CF) patients and non-CF controls in terms of lymphocyte proliferation and immunophenotyping, cytokine production and anti-MABSC IgG plasma levels. Methods: In this cross-sectional analysis, peripheral blood mononuclear cells (PBMC) from CF patients with MABSC (CF/MABSC, n=12), MAC infection history (CF/MAC, n=5), no NTM history (CF/NTM-, n=15), BCG-vaccinated (C/BCG+, n=9) and non-vaccinated controls (C/BCG-, n=8) were cultured for four days under stimulation with an in-house MABSC lysate and we used flow cytometry to assess lymphocyte proliferation (given by lymphoblast formation) and immunophenotypes. Cytokine production was assessed after overnight whole blood stimulation with the same lysate, and anti-MABSC IgG levels were measured in plasma from non-stimulated blood. Results: All CF/MABSC patients had increased CD3+ and CD19+ lymphoblast formation upon PBMC stimulation with MABSC lysate. There was a higher rate of CD3+ than CD19+ lymphoblasts, predominance of CD4+ over CD8+ lymphoblasts, IFN-γ, TNF-α and IL-2 production, low production of the Th17-associated IL-17, and discrete or no production of Th2/B cell-associated cytokines soluble CD40 ligand (CD40L), IL-4 and IL-5, indicating a Th1-dominated phenotype and infection restricted to the lungs. A similar pattern was seen in C/BCG+ controls, and CF/MAC patients, pointing to cross-reactivity. MABSC-IgG levels were higher in CF/MABSC patients than in both control groups, but not CF/NTM- patients, most of whom also had CD3+ and/or CD19+ lymphoblast formation upon PBMC stimulation, indicating previous exposure, subclinical or latent infection with MABSC or other NTM. Conclusion: The anti-MABSC immune response is Th1-skewed and underlines the cross-reactivity in the anti-mycobacterial immune response. The results, together with published clinical observations, indicate that BCG vaccination may cross-react against NTM in CF patients, and this should be investigated. Due to cross-reactivity, it would also be interesting to investigate whether a combination of MABSC-induced cytokine production by blood cells and anti-MABSC IgG measurement can be useful for identifying latent or subclinical infection both with MABSC and other NTM in CF patients. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID-19) is especially severe in aged patients, defined as 65 years or older, for reasons that are currently unknown. To investigate the underlying basis for this vulnerability, we performed multimodal data analyses on immunity, inflammation, and COVID-19 incidence and severity as a function of age. Our analysis leveraged age-specific COVID-19 mortality and laboratory testing from a large COVID-19 registry, along with epidemiological data of ~3.4 million individuals, large-scale deep immune cell profiling data, and single-cell RNA-sequencing data from aged COVID-19 patients across diverse populations. We found that decreased lymphocyte count and elevated inflammatory markers (C-reactive protein, D-dimer, and neutrophil-lymphocyte ratio) are significantly associated with age-specific COVID-19 severities. We identified the reduced abundance of naïve CD8 T cells with decreased expression of antiviral defense genes (i.e., IFITM3 and TRIM22) in aged severe COVID-19 patients. Older individuals with severe COVID-19 displayed type I and II interferon deficiencies, which is correlated with SARS-CoV-2 viral load. Elevated expression of SARS-CoV-2 entry factors and reduced expression of antiviral defense genes (LY6E and IFNAR1) in the secretory cells are associated with critical COVID-19 in aged individuals. Mechanistically, we identified strong TGF-beta-mediated immune-epithelial cell interactions (i.e., secretory-non-resident macrophages) in aged individuals with critical COVID-19. Taken together, our findings point to immuno-inflammatory factors that could be targeted therapeutically to reduce morbidity and mortality in aged COVID-19 patients. [ABSTRACT FROM AUTHOR]

BackgroundWe aimed to characterise the adaptive immune response to Mycobacterium abscessus complex (MABSC) and its cross-reactivity with Mycobacterium avium complex (MAC) and Mycobacterium bovis (Bacille Calmette-Guérin, BCG) in cystic fibrosis (CF) patients and non-CF controls in terms of lymphocyte proliferation and immunophenotyping, cytokine production and anti-MABSC IgG plasma levels.MethodsIn this cross-sectional analysis, peripheral blood mononuclear cells (PBMC) from CF patients with MABSC (CF/MABSC, n=12), MAC infection history (CF/MAC, n=5), no NTM history (CF/NTM-, n=15), BCG-vaccinated (C/BCG+, n=9) and non-vaccinated controls (C/BCG-, n=8) were cultured for four days under stimulation with an in-house MABSC lysate and we used flow cytometry to assess lymphocyte proliferation (given by lymphoblast formation) and immunophenotypes. Cytokine production was assessed after overnight whole blood stimulation with the same lysate, and anti-MABSC IgG levels were measured in plasma from non-stimulated blood.ResultsAll CF/MABSC patients had increased CD3+ and CD19+ lymphoblast formation upon PBMC stimulation with MABSC lysate. There was a higher rate of CD3+ than CD19+ lymphoblasts, predominance of CD4+ over CD8+ lymphoblasts, IFN-γ, TNF-α and IL-2 production, low production of the Th17-associated IL-17, and discrete or no production of Th2/B cell-associated cytokines soluble CD40 ligand (CD40L), IL-4 and IL-5, indicating a Th1-dominated phenotype and infection restricted to the lungs. A similar pattern was seen in C/BCG+ controls, and CF/MAC patients, pointing to cross-reactivity. MABSC-IgG levels were higher in CF/MABSC patients than in both control groups, but not CF/NTM- patients, most of whom also had CD3+ and/or CD19+ lymphoblast formation upon PBMC stimulation, indicating previous exposure, subclinical or latent infection with MABSC or other NTM.ConclusionThe anti-MABSC immune response is Th1-skewed and underlines the cross-reactivity in the anti-mycobacterial immune response. The results, together with published clinical observations, indicate that BCG vaccination may cross-react against NTM in CF patients, and this should be investigated. Due to cross-reactivity, it would also be interesting to investigate whether a combination of MABSC-induced cytokine production by blood cells and anti-MABSC IgG measurement can be useful for identifying latent or subclinical infection both with MABSC and other NTM in CF patients.

Graves’ disease (GD) is a well-known organ-specific autoimmune disease characterized by hyperthyroidism, goiter, and exophthalmos. The incidence of GD is approximately 2.0–3.0% in China and 0.5–2.0% in Western countries. Due to the complex pathogenesis and etiology of GD, current treatment methods have great side effects that seriously endanger human health. Therefore, it is particularly important to understand the pathogenesis of GD. Various studies have shown that genetics, epigenetics, cellular immunology, and gut microbiota are all involved in the development of GD. Genetically, CD25 gene and VDR gene polymorphisms are involved in the development of GD by increasing the ratio of Th17/Treg cells. Epigenetically, miR-23a-3p and lncRNA-MEG3 lead to Th17/Treg imbalance and participate in the progression of GD. Moreover, commensal microbe deletion can disrupt Th17/Treg balance and participate in the occurrence of GD. The imbalance of Th17/Treg cells induced by genetics, epigenetics, and gut microbiota plays a vital role in the pathogenesis of GD. Therefore, this article reviews the role of genetics, epigenetics, cellular immunology, and gut microbiota in the pathogenic mechanism of GD. This may lead to the development of novel therapeutic strategies and providing promising therapeutic targets.

Introduction: Modulating specific biological effects through the changes in cytokine receptors' expression level remains poorly understood. This study aimed to investigate the influence of the dose-dependent effect of TNF on the balance between proapoptotic and proliferation response depending on the parameters of TNFR1/2 expression density. Methods: Tumor cell lines (HEp-2, K-562, MCF-7, ZR-75/1, MOLT-4, IM-9, and Raji) were characterized for TNFR1/2 co-expression using flow cytometry and were studied to reveal the dose-dependent effect of rhTNF on cell cycle and apoptosis parameters. The associations among the studied parameters were estimated by correlation and regression analysis. Results: It was found for ZR-75/1 cells (the cell line characterized by high expression of both types) that a dose-dependent increase in expression of both types of TNF-α receptors on cells reduces the proliferative activity of cells. For MOLT-4 cells (which are characterized by lower expression), an increase in proliferative response of cells was positively associated with the percentage of both TNFR1+ and TNFR2+ cells. However, opposite effects on the cells were shown for the K-562 and MCF-7 lines having a similar expression profile. A similarity (a large percentage of double-positive cells) was revealed for the lines having similar effects (K-562 and ZR-75/1). Conclusions: High expression of TNF receptor type 1 is not always associated with predominant activation of proapoptotic pathways. However, in the case of simultaneous high expression of both types of receptors, the proportion of double-positive cells is crucial for the activation of either the proapoptotic or proliferation pathways. [ABSTRACT FROM AUTHOR]

One of the mechanisms of cellular dysfunction during the chronization of immune-system-mediated inflammatory diseases is a change in the profile of expression and co-expression of receptors on cells. The aim of this study was to compare patterns of redistribution of TNF receptors (TNFRs) among patients with different durations of rheumatoid arthritis (RA) or asthma. Subgroup analysis was performed on RA (n = 41) and asthma (n = 22) patients with disease duration10 years and on 30 comparable healthy individuals. The co-expression profile of TNFR1 and TNFR2 was assessed in T cells, B cells, monocytes, regulatory T cells, T-helper subsets, and cytotoxic T-lymphocyte subsets. Percentages of cells with different co-expression combinations and receptor density per cell were estimated. Longer disease duration was significantly associated with a redistribution of receptors in immunocompetent cell subsets with an increase in the expression of TNFR1 in asthma but did not correlate with significant unidirectional changes in receptor expression in RA. In asthma, a higher proportion of cells with a certain type of TNF receptor (as compared with the healthy group) was correlated with a simultaneous greater density of this receptor type. In RA, an inverse correlation was observed (compensatory lower receptor density). Mechanisms of long-term changes in the expression of TNF receptors differ significantly between the diseases of autoimmune and allergic etiology. The formation of irreversible morphostructural alterations was strongly correlated with changes in the expression of TNFR1 in asthma and with changes in the expression of TNFR2 in RA.

The term 'macrophage' encompasses tissue cells that typically share dependence on the same transcriptional regulatory pathways (e.g. the transcription factor PU.1) and growth factors (e.g. CSF1/IL‐34). They share a core set of functions that largely arise from a uniquely high phagocytic capacity manifest in their ability to clear dying cells, pathogens and scavenge damaged, toxic or modified host molecules. However, macrophages demonstrate a remarkable degree of tissue‐specific functionality and have diverse origins that vary by tissue site and inflammation status. With our understanding of this diversity has come an appreciation of the longevity and replicative capacity of tissue‐resident macrophages and thus the realisation that macrophages may persist through tissue perturbations and inflammatory events with important consequences for cell function. Here, we discuss our current understanding of the parameters that regulate macrophage survival and function, focusing on the relative importance of the tissue environment versus cell‐intrinsic factors, such as origin, how long a cell has been resident within a tissue and prior history of activation. Thus, we reconsider the view of macrophages as wholly plastic cells and raise many unanswered questions about the relative importance of cell life‐history versus environment in macrophage programming and function. [ABSTRACT FROM AUTHOR]

Abstract Background To assess the effects of differently sized titanium (Ti) and zirconia (Zr) particles on (1) the metabolic activity of osteosarcoma-derived osteoblasts (SaOs-2) and human gingival fibroblasts (HGF) and (2) the cytokine expression of monocytes (THP-1) Methods Ti (60–80 nm and 100 nm) and Zr (2 μm and 75 μm) particles were incubated with SaOs-2, HGF, and THP-1 cells. At days 0, 2, 4, and 7 and 0, 1, 2, and 4 (THP-1), the mitochondrial activity was assessed and enzyme-linked immunosorbent assays were used to determine interleukin (IL)-1 beta and IL-6 concentrations of stimulated THP-1 at day 1. Results Ti60–80, Ti100, Zr2, and Zr75 particles were associated with gradual and significant within-group decreases in the viability of SaOs-2 and HGF cells. These effects were less pronounced in the Zr group. Similar to control cells, THP-1 did not reveal any significant increases in IL-1 beta and IL-6 concentrations. Viability of THP-1 was merely impaired in the presence of Ti100. Conclusions Ti and Zr particles had a detrimental effect on the viability of SaOs-2 and HGF, but no proinflammatory effect on THP-1.

Specialized pro‐resolving mediators actively limit inflammation and support tissue regeneration, but their role in age‐related muscle dysfunction has not been explored. We profiled the mediator lipidome of aging muscle via liquid chromatography‐tandem mass spectrometry and tested whether treatment with the pro‐resolving mediator resolvin D1 (RvD1) could rejuvenate the regenerative ability of aged muscle. Aged mice displayed chronic muscle inflammation and this was associated with a basal deficiency of pro‐resolving mediators 8‐oxo‐RvD1, resolvin E3, and maresin 1, as well as many anti‐inflammatory cytochrome P450‐derived lipid epoxides. Following muscle injury, young and aged mice produced similar amounts of most pro‐inflammatory eicosanoid metabolites of cyclooxygenase (e.g., prostaglandin E2) and 12‐lipoxygenase (e.g., 12‐hydroxy‐eicosatetraenoic acid), but aged mice produced fewer markers of pro‐resolving mediators including the lipoxins (15‐hydroxy‐eicosatetraenoic acid), D‐resolvins/protectins (17‐hydroxy‐docosahexaenoic acid), E‐resolvins (18‐hydroxy‐eicosapentaenoic acid), and maresins (14‐hydroxy‐docosahexaenoic acid). Similar absences of downstream pro‐resolving mediators including lipoxin A4, resolvin D6, protectin D1/DX, and maresin 1 in aged muscle were associated with greater inflammation, impaired myofiber regeneration, and delayed recovery of strength. Daily intraperitoneal injection of RvD1 had minimal impact on intramuscular leukocyte infiltration and myofiber regeneration but suppressed inflammatory cytokine expression, limited fibrosis, and improved recovery of muscle function. We conclude that aging results in deficient local biosynthesis of specialized pro‐resolving mediators in muscle and that immunoresolvents may be attractive novel therapeutics for the treatment of muscular injuries and associated pain in the elderly, due to positive effects on recovery of muscle function without the negative side effects on tissue regeneration of non‐steroidal anti‐inflammatory drugs. [ABSTRACT FROM AUTHOR]

(1) Background: Pemphigus is a blistering autoimmune disease of the skin and/or mucous membranes, characterised by the presence of specific autoantibodies directed against structural proteins of the human skin. Recent reports indicate that new haematological parameters, termed Extended Inflammation Parameters (EIP), can be used to assess the activation of immune cells during active inflammation. These include parameters assessing both neutrophil activation (NEUT-RI, NEUT-GI) and the number of activated lymphocytes (RE-LYMP). The aim of this study was to investigate the relationship between changes in NEUT-RI, NEUT-GI and RE-LYMP and the disease activity in patients with pemphigus. (2) Results: The study involved 32 patients with diagnosed different types of pemphigus. Neutrophil activation parameters (NEUT-RI and NEUT-GI) and lymphocytes (RE-LYMP) were significantly higher in these patients compared to the parameters in healthy participants (respectively p = 0.0127, p = 0.0011 and p = 0.0033). The increased quantity of activated lymphocytes (RE-LYMP) also correlated significantly with the extent of skin and/or mucosal lesions in patients assessed by the PDAI scale (p < 0.02). (3) Conclusions: The NEUT-RI, NEUT-GI and RE-LYMP parameters proved to be appropriate markers of inflammation severity in pemphigus, also in relation to local lesions, which was not possible with the inflammation markers (CRP, ESR) used so far on a routine basis.

Background: The co-expression patterns of type 1 and 2 tumor necrosis factor (TNF)-α membrane receptors (TNFR1/TNFR2) are associated with the presence, stage, and activity of allergic diseases. The aim of this study was to assess the expression levels and dynamics of TNFRs on immune cells and to assess associations between their expression and severity of bronchial asthma (BA). Methods: Patients with severe (n = 8), moderate (n = 10), and mild (n = 4) BA were enrolled. As a comparison group, data from 46 healthy volunteers (HV) were accessed. Co-expression of TNFR1/2 was evaluated as a percentage of cells and the number of receptors of each type per cell. Multivariate logistic regression analysis was used to identify diagnostic biomarkers of BA. Results: More than 90% of the monocytes in patients with mild BA were TNFR1+TNFR2+ but had significantly lower TNFR1 expression density compared with HV (7.82- to 14.08-fold, depending on disease severity). Lower percentages of the TNFR+ B-lymphocytes were observed in combination with significantly lower receptors density in BA compared with HV (2.59- to 11.64-fold for TNFR1 and 1.72- to 3.4-fold for TNFR2, depending on disease severity). The final multivariate model for predicting the presence of BA included the percentage of double-positive CD5+ B-lymphocytes and average number of TNFR1 molecules expressed on cytotoxic naive T-lymphocytes and T-helper cells (R2 = 0.87). Conclusions: The co-expression patterns of TNFRs on immune cells in BA differed significantly compared with HV. The expression differences were associated with disease severity. TNFR1 expression changes were key parameters that discriminated patients with BA from those with HV.

Age impacts alloimmunity. Effects of aging on T‐cell metabolism and the potential to interfere with immunosuppressants have not been explored yet. Here, we dissected metabolic pathways of CD4+ and CD8+ T cells in aging and offer novel immunosuppressive targets. Upon activation, CD4+ T cells from old mice failed to exhibit adequate metabolic reprogramming resulting into compromised metabolic pathways, including oxidative phosphorylation (OXPHOS) and glycolysis. Comparable results were also observed in elderly human patients. Although glutaminolysis remained the dominant and age‐independent source of mitochondria for activated CD4+ T cells, old but not young CD4+ T cells relied heavily on glutaminolysis. Treating young and old murine and human CD4+ T cells with 6‐diazo‐5‐oxo‐l‐norleucine (DON), a glutaminolysis inhibitor resulted in significantly reduced IFN‐γ production and compromised proliferative capacities specifically of old CD4+ T cells. Of translational relevance, old and young mice that had been transplanted with fully mismatched skin grafts and treated with DON demonstrated dampened Th1‐ and Th17‐driven alloimmune responses. Moreover, DON diminished cytokine production and proliferation of old CD4+ T cells in vivo leading to a significantly prolonged allograft survival specifically in old recipients. Graft prolongation in young animals, in contrast, was only achieved when DON was applied in combination with an inhibition of glycolysis (2‐deoxy‐d‐glucose, 2‐DG) and OXPHOS (metformin), two alternative metabolic pathways. Notably, metabolic treatment had not been linked to toxicities. Remarkably, immunosuppressive capacities of DON were specific to CD4+ T cells as adoptively transferred young CD4+ T cells prevented immunosuppressive capacities of DON on allograft survival in old recipients. Depletion of CD8+ T cells did not alter transplant outcomes in either young or old recipients. Taken together, our data introduce an age‐specific metabolic reprogramming of CD4+ T cells. Targeting those pathways offers novel and age‐specific approaches for immunosuppression. [ABSTRACT FROM AUTHOR]

Cancer, being the most prevalent and resistant disease afflicting any gender, age or social status, is the ultimate challenge for the scientific community. The new generation therapeutics for cancer management has shifted the approach to personalized/precision medicine, making use of patient- and tumor-specific markers for specifying the targeted therapies for each patient. Peptides targeting these cancer-specific signatures hold enormous potential for cancer therapy and diagnosis. The rapid advancements in the combinatorial peptide libraries served as an impetus to the development of multifunctional peptide-based materials for targeted cancer therapy. The present review outlines benefits and shortcomings of peptides as cancer therapeutics and the potential of peptide modified nanomedicines for targeted delivery of anticancer agents. [ABSTRACT FROM AUTHOR]

Summary: JQ1 is a BET-bromodomain inhibitor that has immunomodulatory effects. However, the precise molecular mechanism that JQ1 targets to elicit changes in antibody production is not understood. Our results show that JQ1 induces apoptosis, reduces cell proliferation, and as a consequence, inhibits antibody-secreting cell differentiation. ChIP-sequencing reveals a selective displacement of Brd4 in response to acute JQ1 treatment (

The characterization of cell‐mediated and humoral adaptive immune responses to SARS‐CoV‐2 is fundamental to understand COVID‐19 progression and the development of immunological memory to the virus. In this study, we detected T‐cells reactive to SARS‐CoV‐2 proteins M, S, and N, as well as serum virus‐specific IgM, IgA, IgG, in nearly all SARS‐CoV‐2 infected individuals, but not in healthy donors. Virus‐reactive T cells exhibited signs of in vivo activation, as suggested by the surface expression of immune‐checkpoint molecules PD1 and TIGIT. Of note, we detected antigen‐specific adaptive immune response both in asymptomatic and symptomatic SARS‐CoV‐2 infected subjects. More importantly, symptomatic patients displayed a significantly higher magnitude of both cell‐mediated and humoral adaptive immune response to the virus, as compared to asymptomatic individuals. These findings suggest that an uncontrolled adaptive immune response contribute to the development of the life‐threatening inflammatory phase of the disease. Finally, this study might open the way to develop effective vaccination strategies. [ABSTRACT FROM AUTHOR]

This review article addresses the largely unanticipated convergence of two landmark discoveries. The first is the discovery of interferons, critical signaling molecules for all aspects of both innate and adaptive immunity, discovered originally by Isaacs and Lindenmann at the National Institute for Medical Research, London, in 1957 (Proceedings of the Royal Society of London. Series B: Biological Sciences, 1957, 147, 258). The second, formerly unrelated discovery, by Leonard Hayflick and Paul Moorhead (Wistar Institute, Philadelphia) is that cultured cells undergo an irreversible but viable growth arrest, termed senescence, after a finite and predictable number of cell divisions (Experimental Cell Research, 1961, 25, 585). This phenomenon was suspected to relate to organismal aging, which was confirmed subsequently (Nature, 2011, 479, 232). Cell senescence has broad‐ranging implications for normal homeostasis, including immunity, and for diverse disease states, including cancer progression and response to therapy (Nature Medicine, 2015, 21, 1424; Cell, 2019, 179, 813; Cell, 2017, 169, 1000; Trends in Cell Biology, 2018, 28, 436; Journal of Cell Biology, 2018, 217, 65). Here, we critically address the bidirectional interplay between interferons (focusing on type I) and cell senescence, with important implications for health and healthspan. [ABSTRACT FROM AUTHOR]

The aging process is characterized by a chronic, low‐grade inflammatory state, termed "inflammaging." It has been suggested that macrophage activation plays a key role in the induction and maintenance of this state. In the present study, we aimed to elucidate the mechanisms responsible for aging‐associated changes in the myeloid compartment of mice. The aging phenotype, characterized by elevated cytokine production, was associated with a dysfunction of the hypothalamic–pituitary–adrenal (HPA) axis and diminished serum corticosteroid levels. In particular, the concentration of corticosterone, the major active glucocorticoid in rodents, was decreased. This could be explained by an impaired expression and activity of 11β‐hydroxysteroid dehydrogenase type 1 (11β‐HSD1), an enzyme that determines the extent of cellular glucocorticoid responses by reducing the corticosteroids cortisone/11‐dehydrocorticosterone to their active forms cortisol/corticosterone, in aged macrophages and peripheral leukocytes. These changes were accompanied by a downregulation of the glucocorticoid receptor target gene glucocorticoid‐induced leucine zipper (GILZ) in vitro and in vivo. Since GILZ plays a central role in macrophage activation, we hypothesized that the loss of GILZ contributed to the process of macroph‐aging. The phenotype of macrophages from aged mice was indeed mimicked in young GILZ knockout mice. In summary, the current study provides insight into the role of glucocorticoid metabolism and GILZ regulation during aging. [ABSTRACT FROM AUTHOR]

Introduction: Density and co-expression of tumor necrosis factor (TNF) receptors may vary among cell populations. However, the role and potential of these changes remain unclear. This study aimed to determine the density of expression and co-expression of TNFR1/2 and the dose-dependent effect of soluble TNF on these parameters. Methods: Epithelial-like (HEp-2, K-562, MCF-7, ZR-75/1) and lymphoblast-like (MOLT-4, HL-60, Raji, RPMI-8226, IM-9) cell lines were characterized for co-expression of TNFR1/2 using a modified flow cytometry protocol. The dose-dependent effects of rhTNF on TNF receptor expression in these lines were studied. Results: This study reports a protocol for the simultaneous quantitative evaluation of the of TNF receptor number and co-expression of membrane-bound TNFR1/2. Cells within one tumor cell line were found to differ regarding their expression of type 1 and 2 TNFα receptors; simultaneously, cells with all 4 variants of co-expression may be present in culture. Conclusion: We demonstrated a dose-dependent effect of TNF on changes in the expression of TNFR1/2 by the percentage of positive cells and by the number of receptors, which may be used to control TNF-mediated processes in target cells. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this present study was to evaluate the levels of Netrin‐1 and Unc5b in periodontal health and disease. Background: Netrin‐1, acting via its receptor UNC5b, regulates the inflammatory response and takes apart in bone destructive diseases. Methods: Samples of gingival crevicular fluid (GCF), whole saliva, and serum were taken from systemically healthy, nonsmoking 20 periodontitis , 20 gingivitis patients, and 20 periodontally healthy subjects at baseline and 4 weeks after nonsurgical periodontal treatment (NSPT). Whole‐mouth and site‐specific clinical periodontal parameters were recorded. Netrin‐1 and Unc5b levels were measured by enzyme‐linked immunosorbent assay. Data were analyzed by nonparametric tests. Results: Total amount of Netrin‐1 in GCF was significantly higher in periodontitis than the others, and the levels were significantly reduced after NSPT. Salivary and serum concentrations of Netrin‐1 were significantly different among the study groups (P =.000), and NSPT significantly increased the concentration levels of both salivary and serum Netrin‐1 (P <.05). Healthy subjects had significantly lower GCF (P =.001) and conversely, higher salivary and serum levels of Unc5b than the other groups (P =.002). The GCF levels of Unc5b were significantly reduced (P <.01), and conversely, serum concentrations were significantly increased after NSPT (P <.05). GCF Netrin‐1 and Unc5b total amounts were positively correlated with clinical parameters (P <.01 and P <.05) whereas salivary Netrin‐1 and Unc5b concentrations were negatively correlated with clinical parameters (P <.01 and P <.05). Conclusions: The results of this study indicate that Netrin‐1 and its receptor Unc5b may have essential roles in periodontal inflammation and those can be assumed as useful therapeutic agent to control inflammation and periodontal breakdown. [ABSTRACT FROM AUTHOR]

Tumor-infiltrating lymphocytes (TILs), found in patients with advanced pancreatic ductal adenocarcinoma (PDAC), are shown to correlate with overall survival (OS) rate. Although majority of TILs consist of CD8+/CD4+ T cells, the presence of NK cells and their role in the pathogenesis of PDAC remains elusive. We performed comprehensive analyses of TIL, PBMC, and autologous tumor cells from 80 enrolled resectable PDAC patients to comprehend the NK cell defects within PDAC. Extremely low frequencies of NK cells (

Regulatory B (Breg) cells are a special subset of immunoregulatory cells with unique phenotypes and functions. In this study, human CD19+CD25high Breg cells were purified from human peripheral blood. Based on the coculture system of Breg cells and CD4+ T cells in vitro, Breg cells were found to promote the increase in regulatory T (Treg) cells while decreasing the number of Th17 cells. Breg cells regulate Treg cells through two processes: cell-cell contact and cytokines. TGF-βsRII, a blocker of transforming growth factor-β (TGF-β), can attenuate the effects of Treg elevation, suggesting that TGF-β is the main cytokine, while Breg cells rather than interleukin-10 (IL-10) regulate the differentiation of Treg cells. However, Th17 cells were mainly regulated by cytokines, without an obvious regulatory effect on cell-cell contacts. Breg cells may regulate Th17 cells by a pathway independent of TGF-β and IL-6. The coculture of Breg cells and CD4+ T cells led to changes in the cytokine spectrum, which included significant increases in IL-4, IL-6 and IL-10 but not obvious changes in IL-2, IFN-γ and TNF. The inhibitory effect of Breg cells was weakened by blocking cell-cell contacts in cultures separated with the Transwell chamber because IL-10 decreased while IL-6 increased when compared with cocultured Breg and CD4+ T cells. When the IL-10 inhibitor IL-10sRα was added, IL-6 and TNF levels significantly increased, while treatment with the TGF-β inhibitor TGF-βsRII did not result in similar changes, suggesting that IL-10 is an important molecule to inhibit the proinflammatory factors IL-6 and TNF in this culture system. [ABSTRACT FROM AUTHOR]

Summary: There is currently scarce knowledge of the immunological profile of patients with latent autoimmune diabetes mellitus in the adult (LADA) when compared with healthy controls (HC) and patients with classical type 1 diabetes (T1D) and type 2 diabetes (T2D). The objective of this study was to investigate the cellular immunological profile of LADA patients and compare to HC and patients with T1D and T2D. All patients and age‐matched HC were recruited from Uppsala County. Peripheral blood mononuclear cells were isolated from freshly collected blood to determine the proportions of immune cells by flow cytometry. Plasma concentrations of the cytokine interleukin (IL)‐35 were measured by enzyme‐linked immunosorbent assay (ELISA). The proportion of CD11c+CD123– antigen‐presenting cells (APCs) was lower, while the proportions of CD11c+CD123+ APCs and IL‐35+ tolerogenic APCs were higher in LADA patients than in T1D patients. The proportion of CD3–CD56highCD16+ natural killer (NK) cells was higher in LADA patients than in both HC and T2D patients. The frequency of IL‐35+ regulatory T cells and plasma IL‐35 concentrations in LADA patients were similar to those in T1D and T2D patients, but lower than in HC. The proportion of regulatory B cells in LADA patients was higher than in healthy controls, T1D and T2D patients, and the frequency of IL‐35+ regulatory B cells was higher than in T1D patients. LADA presents a mixed cellular immunological pattern with features overlapping with both T1D and T2D. [ABSTRACT FROM AUTHOR]

Tumor-infiltrating lymphocytes (TILs), found in patients with advanced pancreatic ductal adenocarcinoma (PDAC), are shown to correlate with overall survival (OS) rate. Although majority of TILs consist of CD8+/CD4+ T cells, the presence of NK cells and their role in the pathogenesis of PDAC remains elusive. We performed comprehensive analyses of TIL, PBMC, and autologous tumor cells from 80 enrolled resectable PDAC patients to comprehend the NK cell defects within PDAC. Extremely low frequencies of NK cells (<0.5%) were found within PDAC tumors, which was attributable not to the low expression of tumor chemokines, but to the lack of chemokine receptor, CXCR2. Forced expression of CXCR2 in patients' NK cells rendered them capable of trafficking into PDAC. Furthermore, NK cells exhibited impaired cell-mediated killing of autologous PDAC cells, primarily due to insufficient ligation of NKG2D and DNAM-1, and failed to proliferate within the hypoxic tumor microenvironment. Importantly, these defects could be overcome by ex-vivo stimulation of NK cells from such patients. Importantly, when the proliferative capacity of NK cells in vitro was used to stratify patients on the basis of cell expansion, patients whose NK cells proliferated <250-fold experienced significantly lower DFS and OS than those with ≥250-fold. Ex-vivo activation of NK cells restored tumor trafficking and reactivity, hence provided a therapeutic modality while their fold expansion could be a potentially significant prognostic indicator of OS and DFS in such patients. [ABSTRACT FROM AUTHOR]

The expression of cytokine receptors has a crucial role in many cellular processes. Recent studies reported that changes of receptor expression could control the action of mediators on target cells. The initiation of different signaling pathways and, therefore, specific effects on cells, depends on certain components forming the cytokine-receptor complex. These mechanisms control the immune response and affect both the course of diseases (oncological, autoimmune, inflammatory) and the effectiveness of therapy. This review describes the potential of immune mediator receptors to regulate the efficiency of cytokine activity during pathologic processes and ensure the variability of their biological effects. Our aim was to investigate the spectrum of potential roles of changes in mediator receptor expression for main classes of pathologies. For all major types of immune mediators (cytokines, interleukins, chemokines, growth factors, and tumor necrosis factors), it has been shown that changes in their receptor expression are associated with impaired functioning of the organism in chronic diseases. [ABSTRACT FROM AUTHOR]

Highlights • Among T cells there are at least 30% cells with TNF receptors in each subset. • T cell subsets differed in their co-expression of TNFα receptors. • Presence of both TNFR1 and TNFR2 is associated with the increased expression density. Abstract The immunoregulatory cytokine tumor necrosis factor α plays crucial roles in the pathogenesis of a broad spectrum of disorders. However, its effect may depend on the expression and co-expression of receptors on the target cell. The aim of the present study was to evaluate the expression levels of type 1 and 2 tumor necrosis factor α receptors (TNFR1/2) on individual cell subsets from peripheral blood of healthy volunteers. Flow cytometry analysis was used to study whole populations as well as subsets (T regulatory cells, T memory cells, cytotoxic T cells, T helper cells). Significant differences in the co-expression of TNFR1/2 were seen within subsets and total pools. Further studies are necessary to explore the implications of the observed differences in the modulation of tumor necrosis factor α function in health and pathology. [ABSTRACT FROM AUTHOR]

The role of HIV-specific CD8 T cell activity in the course of HIV infection and the way it affects the virus that resides in the latent reservoir resting memory cells is debated. The PBMC of HIV-infected patients contain HIV-specific CD8 T cells and their potential targets, CD4 T cells latently infected by HIV. CD4 T cells and CD8 T cells procured from PBMC of HIV-infected patients were co-incubated and analyzed: Formation of CD8 T cells and HIV-infected CD4 T cell conjugates and apoptosis of these CD4 T cells were observed by fluorescence microscopy with in situ PCR of HIV LTR DNA. Furthermore, conjugation of CD8 T cells with CD4 T cells and apoptosis of CD4 T cells was observed and quantified by imaging flow cytometry using anti-human activated caspase 3 antibody and TUNEL assay. The conjugation activity and apoptosis were found to be much higher in patients with acute HIV infection or AIDS compared to patients in chronic infection on antiretroviral therapy (ART) or not. Patients on ART had low grade conjugation and apoptosis of isolated CD69, CD25, and HLA-DR-negative CD4 T cells (latent reservoir cells) by CD8 T cells. Using in situ PCR The latent reservoir CD4 T cells were shown to contain most of the HIV DNA. We demonstrate in HIV-infected patients, that CD8 T cells conjugate with and kill HIV-infected CD4 T cells, including HIV-infected resting memory CD4 T cells, throughout the course of HIV infection. We propose that in HIV-infected patients CD4 T cell annihilation is caused in part by ongoing activity of HIV-specific CD8 T cells. HIV Nef protein interacts with ASK 1 and inhibits its pro-apoptotic death signaling by Fas/FasL, thus protecting HIV-infected cells from CD8 T cells killing. A peptide that interrupts Nef-ASK1 interaction that had been delivered into CD4 T cells procured from patients on ART resulted in the increase of their apoptosis inflicted by autologous CD8 T cells. We suggest that elimination of the HIV-infected latent reservoir CD4 T cells can be achieved by Nef inhibition.

Highlights • Proinsulin specific T cells are predominant in peripheral blood. • Subjects with type 1 diabetes exhibit different patterns of T cell reactivity. • The breadth of responses targeted by CD8+ and CD4+ T cells are correlated. Abstract CD4+ T cell responses are thought to play a role in type 1 diabetes (T1D). However, detection and characterization of T cells that respond to beta cell epitopes in subjects with T1D has been limited by technical obstacles, including the inherently low frequencies in peripheral blood and variable responsiveness of individual subjects to single epitopes. We implemented a multicolor staining approach that allows direct ex vivo characterization of multiple CD4+ T cell specificities in a single sample. Here we demonstrate and apply that multicolor approach to directly measure the frequency and phenotype of beta cell specific CD4+ T cells in T1D patients and HLA matched controls. For this work we utilized five DR0401 restricted peptides from proinsulin, GAD65, IA-2, and IGRP, which were previously reported as disease relevant epitopes. Surprisingly, although responses to each of these peptides can be readily detected after in vitro expansion, our results indicated that only proinsulin specific T cells were consistently detectable at moderate frequencies in subjects with T1D. Characterization of beta cell specific CD4+ T cells revealed only modest differences between subjects with T1D and healthy controls. Subjects with T1D did have higher proportions of CD45RA negative epitope specific T cells than controls. In patients epitope specific T cells were often CXCR3 positive and a substantial proportion were CCR7 negative, suggesting a Th1-like effector phenotype. Finally, we demonstrated that our multicolor staining approach is compatible with class I multimer analysis, facilitating the characterization of self-reactive CD4+ and CD8+ T cells using a single sample. [ABSTRACT FROM AUTHOR]

Abstract Identifying HIV-1-associated B cell defects and responses to activation may direct interventions to circumvent their impaired antibody responses to infection and vaccines. Among 34 viremic HIV-1-infected and 20 seronegative control adults, we measured baseline frequencies and activation of B and T cell subsets, expression of activation-induced cytidine deaminase (AID), potential determinants of B cell activation in vivo and B and T cell responses in vitro. At baseline, HIV-1 infection was associated with increased IgM memory and decreased anergic cell frequencies, as well as increased activation in all 10 B cell subsets compared with controls. HIV-1 status, T FH activation, and BAFF were significant potential drivers of B cell activation. Despite high baseline activation among HIV-1-infected subjects, stimulation in vitro with combined surrogates for antigen (anti-IgM), cognate (CD40 ligand) and soluble T cell factors (IL-4) elicited comparable B cell activation, transitions from naïve to class-switched memory cells and AID expression in both groups. In summary, viremic HIV-1 infection perturbs circulating B cell subsets and activation at each stage of B cell maturation. However, that appropriate stimulation of B cells elicits effective activation and maturation provides impetus for advancing vaccine development to prevent secondary infections by circumventing early B cell defects. [ABSTRACT FROM AUTHOR]

The role of HIV-specific CD8 T cell activity in the course of HIV infection and the way it affects the virus that resides in the latent reservoir resting memory cells is debated. The PBMC of HIV-infected patients contain HIV-specific CD8 T cells and their potential targets, CD4 T cells latently infected by HIV. CD4 T cells and CD8 T cells procured from PBMC of HIV-infected patients were co-incubated and analyzed: Formation of CD8 T cells and HIV-infected CD4 T cell conjugates and apoptosis of these CD4 T cells were observed by fluorescence microscopy with in situ PCR of HIV LTR DNA. Furthermore, conjugation of CD8 T cells with CD4 T cells and apoptosis of CD4 T cells was observed and quantified by imaging flow cytometry using anti-human activated caspase 3 antibody and TUNEL assay. The conjugation activity and apoptosis were found to be much higher in patients with acute HIV infection or AIDS compared to patients in chronic infection on antiretroviral therapy (ART) or not. Patients on ART had low grade conjugation and apoptosis of isolated CD69, CD25, and HLA-DR-negative CD4 T cells (latent reservoir cells) by CD8 T cells. Using in situ PCR The latent reservoir CD4 T cells were shown to contain most of the HIV DNA. We demonstrate in HIV-infected patients, that CD8 T cells conjugate with and kill HIV-infected CD4 T cells, including HIV-infected resting memory CD4 T cells, throughout the course of HIV infection. We propose that in HIV-infected patients CD4 T cell annihilation is caused in part by ongoing activity of HIV-specific CD8 T cells. HIV Nef protein interacts with ASK 1 and inhibits its pro-apoptotic death signaling by Fas/FasL, thus protecting HIV-infected cells from CD8 T cells killing. A peptide that interrupts Nef-ASK1 interaction that had been delivered into CD4 T cells procured from patients on ART resulted in the increase of their apoptosis inflicted by autologous CD8 T cells. We suggest that elimination of the HIV-infected latent reservoir CD4 T cells can be achieved by Nef inhibition. [ABSTRACT FROM AUTHOR]