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Histamine (HA) is a potent mediator that plays a central role in inflammation and allergy, acting through four G-protein-coupled receptors (i.e. H1–H4). HA is an accepted promoter of type 2 immunity in CD4+ T cells during hypersensitivity. Previously, we demonstrated that HA can promote antigen cross-presentation, inducing the activation of antigen-specific CD8+ T cells in an asthmatic murine model. Non-classical CD8+ T-cell profiles, such as Tc2 or Tc17, are associated with allergic disease persistence and chronicity. In this paper, we focus on the role of the H3 receptor (H3R) and the H4 receptor (H4R) in the development of allergic contact dermatitis. We were able to show that induction of the type 2 profiles associated with interleukin 13 production, both by CD4 and CD8 lymphocytes, depend on the interaction of HA with H3R and H4R. Blocking both receptors using the selective H3/H4 receptor antagonist thioperamide or the selective H4R ligand JNJ777120 reduces the inflammatory response, inducing an immunosuppressive profile associated with the increased proportion of FOXp3+ regulatory T lymphocytes and CD11b+Gr-1+ myeloid suppressor cells. Interestingly, in dendritic cells, only H4R blockade, and not H3R blockade, is capable of modulating most of the inflammatory effects observed in our model. [ABSTRACT FROM AUTHOR]

In the past few years, huge advances have been made in techniques to analyse cells at an individual level using RNA sequencing, and many of these have precipitated exciting discoveries in the immunology of type 1 diabetes (T1D). This review will cover the first papers to use scRNAseq to characterise human lymphocyte phenotypes in T1D in the peripheral blood, pancreatic lymph nodes and islets. These have revealed specific genes such as IL-32 that are differentially expressed in islet –specific T cells in T1D. scRNAseq has also revealed wider gene expression patterns that are involved in T1D and can predict its development even predating autoantibody production. Single cell sequencing of TCRs has revealed V genes and CDR3 motifs that are commonly used to target islet autoantigens, although truly public TCRs remain elusive. Little is known about BCR repertoires in T1D, but scRNAseq approaches have revealed that insulin binding BCRs commonly use specific J genes, share motifs between donors and frequently demonstrate poly-reactivity. This review will also summarise new developments in scRNAseq technology, the insights they have given into other diseases and how they could be leveraged to advance research in the type 1 diabetes field to identify novel biomarkers and targets for immunotherapy. [ABSTRACT FROM AUTHOR]

Background: Lymphocytes play a key role in the pathogenesis of inflammatory bowel disease (IBD) and are widely explored as promising prognostic indicators. We aimed to outline the existing evidences on the capability of lymphocyte subpopulations to predict disease progression and treatment response in patients with IBD. Methods: The protocol for this review was registered in PROSPERO (registration ID: CRD 42022364126). Systematic retrieval was conducted using PubMed, Embase, and Web of Science databases. Original articles on the prognostic value of lymphocyte subsets in IBD published up to April 8, 2023 were eligible for inclusion. The Newcastle–Ottawa Scale was used to evaluate the risk of bias. Results: Twenty studies were ultimately included: eight evaluated the prediction of disease progression and 12 focused on the prediction of treatment response. According to the Newcastle–Ottawa Scale, three studies were of high quality, 16 were of moderate quality, and only one was of low quality. T-cell subpopulations, including CD4+ T cells, CD8+ T cells, and gd T cells, are revealed to have prognostic capacity. Transmembrane tumor necrosis factor a-bearing lymphocytes, CD4+ T cells, CD8+ T cells, and Plasma cells are found to have the potential to predict the response to anti-TNFα agents. In contrast memory T cells, CD4+ T cells, and naïve B cells may predict the response to vedolizumab. Conclusions: This systematic review identified several potential lymphocyte subset-related predictors. If verified in large cohort prospective studies, these findings could aid clinical decision-making. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a neurodegenerative disease characterized by progressive loss of dopaminergic neurons, appearance of Lewy bodies and presence of neuroinflammation. No treatments currently exist to prevent PD or delay its progression, and dopaminergic substitution treatments just relieve the consequences of dopaminergic neuron loss. Increasing evidence points to peripheral T lymphocytes as key players in PD, and recently there has been growing interest into the specific role of T helper (Th) 17 lymphocytes. Th17 are a proinflammatory CD4+ T cell lineage named after interleukin (IL)-17, the main cytokine produced by these cells. Th17 are involved in immune-related disease such as psoriasis, rheumatoid arthritis and inflammatory bowel disease, and drugs targeting Th17/IL-17 are currently approved for clinical use in such disease. In the present paper, we first summarized current knowledge about contribution of the peripheral immune system in PD, as well as about the physiopharmacology of Th17 and IL-17 together with its therapeutic relevance. Thereafter, we systematically retrieved and evaluated published evidence about Th17 and IL-17 in PD, to help assessing Th17/IL-17-targeting drugs as potentially novel antiparkinson agents. Critical appraisal of the evidence did not allow to reach definite conclusions: both animal as well as clinical studies are limited, just a few provide mechanistic evidence and none of them investigates the eventual relationship between Th17/IL-17 and clinically relevant endpoints such as disease progression, disability scores, intensity of dopaminergic substitution treatment. Careful assessment of Th17 in PD is anyway a priority, as Th17/IL-17-targeting therapeutics might represent a straightforward opportunity for the unmet needs of PD patients. [ABSTRACT FROM AUTHOR]

Sjögren's syndrome (SS) is a chronic systemic autoimmune disease that typically presents with lymphocyte, dendritic cell, and macrophage infiltration of exocrine gland ducts and the formation of ectopic germinal centers. The interactions of lymphocyte homing receptors and addressins and chemokines and their receptors, such as a4b7/MAdCAM-1, LFA-1/ICAM-1, CXCL13/CXCR5, CCL25/ CCR9, CX3CL1/CX3CR1, play important roles in the migration of inflammatory cells to the focal glands and the promotion of ectopic germinal center formation in SS. A variety of molecules have been shown to be involved in lymphocyte homing, including tumor necrosis factor-a, interferon (IFN)-a, IFN-b, and B cell activating factor. This process mainly involves the Janus kinase-signal transducer and activator of transcription signaling pathway, lymphotoxin-b receptor pathway, and nuclear factor-kB signaling pathway. These findings have led to the development of antibodies to cell adhesion molecules, antagonists of chemokines and their receptors, compounds interfering with chemokine receptor signaling, and gene therapies targeting chemokines and their receptors, providing new targets for the treatment of SS in humans. The aim of this study was to explore the relationship between lymphocyte homing and the pathogenesis of SS, and to provide a review of recent studies addressing lymphocyte homing in targeted therapy for SS. [ABSTRACT FROM AUTHOR]

We have previously argued that the antigen receptors of T and B lymphocytes evolved to be sufficiently specific to avoid massive deletion of clonotypes by negative selection. Their optimal 'specificity' level, i.e., probability of binding any particular epitope, was shown to be inversely related to the number of selfantigens that the cells have to be tolerant to. Experiments have demonstrated that T lymphocytes also become more specific during negative selection in the thymus, because cells expressing the most crossreactive receptors have the highest likelihood of binding a self-antigen, and hence to be tolerized (i.e., deleted, anergized, or diverted into a regulatory T cell phenotype). Thus, there are two --not mutually exclusive-- explanations for the exquisite specificity of T cells, one involving evolution and the other thymic selection. To better understand the impact of both, we extend a previously developed mathematical model by allowing for T cells with very different binding probabilities in the pre-selection repertoire. We confirm that negative selection tends to tolerize the most crossreactive clonotypes. As a result, the average level of specificity in the functional post-selection repertoire depends on the number of self-antigens, even if there is no evolutionary optimization of binding probabilities. However, the evolutionary optimal range of binding probabilities in the pre-selection repertoire also depends on the number of self-antigens. Species with more self antigens need more specific pre-selection repertoires to avoid excessive loss of T cells during thymic selection, and hence mount protective immune responses. We conclude that both evolution and negative selection are responsible for the high level of specificity of lymphocytes. [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative therapy for many hematologic malignancies as well as non-malignant conditions. Part of the curative basis underlying HSCT for hematologic malignancies relies upon induction of the graft versus leukemia (GVL) effect in which donor immune cells recognize and eliminate residual malignant cells within the recipient, thereby maintaining remission. GVL is a clinically evident phenomenon; however, specific cell types responsible for inducing this effect and molecular mechanisms involved remain largely undefined. One of the best examples of GVL is observed after donor lymphocyte infusions (DLI), an established therapy for relapsed disease or incipient/anticipated relapse. DLI involves infusion of peripheral blood lymphocytes from the original HSCT donor into the recipient. Sustained remission can be observed in 20-80% of patients treated with DLI depending upon the underlying disease and the intrinsic burden of targeted cells. In this review, we will discuss current knowledge about mechanisms of GVL after DLI, experimental strategies for augmenting GVL by manipulation of DLI (e.g. neoantigen vaccination, specific cell type selection/depletion) and research outlook for improving DLI and cellular immunotherapies for hematologic malignancies through better molecular definition of the GVL effect. [ABSTRACT FROM AUTHOR]

There is increasing clinical evidence indicating that the immune system may either promote or inhibit tumor progression. Several studies have demonstrated that tumors undergoing remission are largely infiltrated by T lymphocytes [tumor-infiltrating lymphocytes (TILs)], but on the other hand, several studies have shown that tumors may be infiltrated by TILs endowed with suppressive features, suggesting that TILs are rather associated with tumor progression and unfavorable prognosis. γδ T lymphocytes are an important component of TILs that may contribute to tumor immunosurveillance, as also suggested by promising reports from several small phase-I clinical trials.Typically, γδ T lymphocytes perform effector functions involved in anti-tumor immune responses (cytotoxicity, production of IFN-g and TNF-a, and dendritic cell maturation), but under appropriate conditions they may divert from the typical Th1-like phenotype and polarize to Th2, Th17, and Treg cells thus acquiring the capability to inhibit anti-tumor immune responses and promote tumor growth. Recent studies have shown a high frequency of γδ T lymphocytes infiltrating different types of cancer, but the nature of this association and the exact mechanisms underlying it remain uncertain and whether or not the presence of tumor-infiltrating γδ T lymphocytes is a definite prognostic factor remains controversial. In this paper, we will review studies of tumor-infiltrating γδ T lymphocytes from patients with different types of cancer, and we will discuss their clinical relevance. Moreover,we will also discuss on the complex interplay between cancer, tumor stroma, and γδ T lymphocytes as a major determinant of the final outcome of the γδ T lymphocyte response. Finally, we propose that targeting γδ T lymphocyte polarization and skewing their phenotype to adapt to the microenvironment might hold great promise for the treatment of cancer. [ABSTRACT FROM AUTHOR]

The article introduces papers published within the issue which address such topics as the targeting of somatic hypermutation, T cell compartment development and new methods of extracting and analyzing comprehensive T and B cell phenotype and repertoire data.

Transfer of autologous tumor infiltrating lymphocytes (TIL) to patients with refractory melanoma has shown clinical efficacy in a number of trials. However, extending the clinical benefit to patients with other cancers poses a challenge. Inefficient costimulation in the tumor microenvironment can lead to T cell anergy and exhaustion resulting in poor anti-tumor activity. Here, we describe a chimeric costimulatory antigen receptor (CoStAR) comprised of FRα-specific scFv linked to CD28 and CD40 intracellular signaling domains. CoStAR signaling alone does not activate T cells, while the combination of TCR and CoStAR signaling enhances T cell activity resulting in less differentiated T cells, and augmentation of T cell effector functions, including cytokine secretion and cytotoxicity. CoStAR activity resulted in superior T cell proliferation, even in the absence of exogenous IL-2. Using an in vivo transplantable tumor model, CoStAR was shown to improve T cell survival after transfer, enhanced control of tumor growth, and improved host survival. CoStAR could be reliably engineered into TIL from multiple tumor indications and augmented TIL activity against autologous tumor targets both in vitro and in vivo. CoStAR thus represents a general approach to improving TIL therapy with synthetic costimulation. [ABSTRACT FROM AUTHOR]

Post-transplant lymphoproliferative disorder (PTLD) is a serious complication of solid organ and bone marrow transplantations. Rituximab (Rituxan, Mabthera), a chimeric monoclonal antibody to the CD20 antigen on the surface of B-cell lymphocytes, has been used increasingly in the treatment of PTLD. Rituximab was initially approved for the treatment of low-grade non-Hodgkin lymphomas, but multiple case studies, retrospective analyses, and phase II trials demonstrate the benefit of rituximab in PTLD. This paper reviews the current data on rituximab and its promising role in the management of PTLD. [ABSTRACT FROM AUTHOR]

Bipolar disorder (BD) is a chronic mental disorder characterized by recurrent episodes of mania and depression alternating with periods of euthymia. Although environmental and genetic factors have been described, their pathogenesis is not fully understood. Much evidence suggests a role for inflammatory mediators and immune dysregulation in the development of BD. The first-line treatment in BD are mood-stabilizing agents, one of which is lithium (Li) salts. The Li mechanism of action is not fully understood, but it has been proposed that its robust immunomodulatory properties might be one of the mechanisms responsible for its effectiveness. In this article, the authors present the current knowledge about immune system changes accompanying BD, as well as the immunomodulatory effect of lithium. The results of studies describing connections between immune system changes and lithium effectiveness are often incoherent. Further research is needed to understand the connection between immune system modulation and the therapeutic action of lithium in BD. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is a leading cause of cancer-associated death. In the tumor site, the interplay between effector immune cells and cancer cells determines the balance between tumor elimination or outgrowth. We discovered that the protein TMEM123 is over-expressed in tumour-infiltrating CD4 and CD8 T lymphocytes and it contributes to their effector phenotype. The presence of infiltrating TMEM123+ CD8+ T cells is associated with better overall and metastasis-free survival. TMEM123 localizes in the protrusions of infiltrating T cells, it contributes to lymphocyte migration and cytoskeleton organization. TMEM123 silencing modulates the underlying signaling pathways dependent on the cytoskeletal regulator WASP and the Arp2/3 actin nucleation complex, which are required for synaptic force exertion. Using tumoroid-lymphocyte coculture assays, we found that lymphocytes form clusters through TMEM123, anchoring to cancer cells and contributing to their killing. We propose an active role for TMEM123 in the anti-cancer activity of T cells within tumour microenvironment. [ABSTRACT FROM AUTHOR]

Background and aims: Preclinical data suggest that activation of the adaptive immune system is critical for myocardial repair processes in acute myocardial infarction. The aim of the present study was to determine the clinical value of baseline effector T cell chemokine IP-10 blood levels in the acute phase of STsegment elevation myocardial infarction (STEMI) for the prediction of the left ventricular function changes and cardiovascular outcomes after STEMI. Methods: Serum IP-10 levels were retrospectively quantified in two independent cohorts of STEMI patients undergoing primary percutaneous coronary intervention. Results: We report a biphasic response of the effector T cell trafficking chemokine IP-10 characterized by an initial increase of its serum levels in the acute phase of STEMI followed by a rapid reduction at 90min post reperfusion. Patients at the highest IP-10 tertile presented also with more CD4 effector memory T cells (CD4 TEM cells), but not other T cell subtypes, in blood. In the Newcastle cohort (n=47), patients in the highest IP-10 tertile or CD4 TEM cells at admission exhibited an improved cardiac systolic function 12 weeks after STEMI compared to patients in the lowest IP-10 tertile. In the Heidelberg cohort (n=331), STEMI patients were followed for a median of 540 days for major adverse cardiovascular events (MACE). Patients presenting with higher serum IP-10 levels at admission had a lower risk for MACE after adjustment for traditional risk factors, CRP and high-sensitivity troponin-T levels (highest vs. rest quarters: HR [95% CI]=0.420 [0.218-0.808]). Conclusion: Increased serum levels of IP-10 in the acute phase of STEMI predict a better recovery in cardiac systolic function and less adverse events in patients after STEMI. [ABSTRACT FROM AUTHOR]

Introduction: Melanoma is a common and aggressive type of skin cancer with rising incidence rate globally. Gender is one of the determining factors, and overall males have a higher risk of developing melanoma as well as worse prognosis. Emerging evidence show that GPR68, a G protein-coupled receptor that is sensitive to acid and mechanical stimulations for cellular microenvironment, plays an important role in tumor biology. However, whether GPR68 is involved in gender-dependent regulation of tumor growth is unclear. Methods: We established a syngeneic melanoma model in Gpr68-deficient mice and investigated tumor growth in males and females. The GPR68 activation-induced cellular responses of melanocytes, including intracellular calcium dynamics, proliferation and migration were measured. The landscape of tumor-infiltrating immune cells were analyzed by flow cytometry and the expression various cytokines were checked by qRT-PCR. Results: GPR68 is required for melanoma growth in males but dispensable in females. GPR68 is expressed and functional in B16-F10 melanocytes, but the activity of the receptor does not directly contribute to proliferation and migration of the cells. GPR68 inhibits infiltration of CD45+ lymphocytes, CD8+ T cells and NK cells in melanoma in male mice, but has no apparent effect in females. Furthermore, GPR68 functionally inhibits the expression of IFNγ in the tumor infiltrating CD8+ T cells and NK cells as well as the inflammatory cytokine expression in the spleen in male mice but not in females. Our results show the gender-dependent modulatory effect of GPR68 on tumor-infiltrating immune cells and their tumor-killing capacity. Discussion: GPR68 is sensor for acid and mechanical stimulations, which are two important factors in the microenvironment associated with tumor growth and metastasis. Our results suggest a prominent role of the receptor molecules in tumor biology in a gender-dependent manner. Since GPCRs are more feasible to develop small molecule drugs compared to transcription factors, our study demonstrates the potential of GPR68 as a novel druggable therapeutic target for melanoma in male patients. [ABSTRACT FROM AUTHOR]

Over the past decades, it has become increasingly clear that higher order chromatin folding and organization within the nucleus is involved in the regulation of genome activity and serves as an additional epigenetic mechanism that modulates cellular functions and gene expression programs in diverse biological processes. In particular, dynamic allelic interactions and nuclear locations can be of functional importance during the process of lymphoid differentiation and the regulation of immune responses. Analyses of the proximity between chromatin and/or nuclear regions can be performed on populations of cells with high-throughput sequencing approaches such as chromatin conformation capture ("3C"-based) or DNA adenine methyltransferase identification (DamID) methods, or, in individual cells, by the simultaneous visualization of genomic loci, their primary transcripts and nuclear compartments within the 3-dimensional nuclear space using Fluorescence In Situ Hybridization (FISH) and immunostaining. Here, we present a detailed protocol to simultaneously detect nascent RNA transcripts (3D RNA FISH), their genomic loci (3D DNA FISH) and/or their chromosome territories (CT paint DNA FISH) combined with the antibody-based detection of various nuclear factors (immunofluorescence). We delineate the application and effectiveness of this robust and reproducible protocol in several murine T lymphocyte subtypes (from differentiating thymic T cells, to activated splenic and peripheral T cells) as well as other murine cells, including embryonic stem cells, B cells, megakaryocytes and macrophages. [ABSTRACT FROM AUTHOR]

Introduction: Human adenovirus type 7 (HAdv-7) infection is the main cause of upper respiratory tract infection, bronchitis and pneumonia in children. At present, there are no anti-adenovirus drugs or preventive vaccines in the market. Therefore, it is necessary to develop a safe and effective antiadenovirus type 7 vaccine. Methods: In this study, In this study, we used the baculovirus-insect cell expression system to design a recombinant subunit vaccine expressing adenovirus type 7 hexon protein (rBV-hexon) to induce high-level humoral and cellular immune responses. To evaluate the effectiveness of the vaccine, we first detected the expression of molecular markers on the surface of antigen presenting cells and the secretion of proinflammatory cytokines in vitro. We then measured the levels of neutralizing antibodies and T cell activation in vivo. Results: The results showed that the rBV-hexon recombinant subunit vaccine could promote DC maturation and improve its antigen uptake capability, including the TLR4/NF-kB pathway which upregulated the expression of MHCI, CD80, CD86 and cytokines. The vaccine also triggered a strong neutralizing antibody and cellular immune response, and activated T lymphocytes. Discussion: Therefore, the recombinant subunit vaccine rBV-hexon promoted promotes humoral and cellular immune responses, thereby has the potential to become a vaccine against HAdv-7. [ABSTRACT FROM AUTHOR]

Introduction: The aim of this study is to identify factors that may predict the response of locally advanced rectal cancer tumors (LARC) to neoadjuvant chemoradiotherapy (CRT) and to evaluate the effect of circulating lymphocytes on pathological tumor response. Methods: This retrospective study included neoadjuvant CRT-treated, LARCdiagnosed patients at the Rambam Health Care Campus in Haifa, Israel. CHAID analysis, t-test, χ² test, and ROC curve analyses were performed to explore the association between pathological complete response (pCR) and several factors including patient demographics, tumor characteristics, type of treatment, and levels of circulating lymphocytes measured on a weekly basis. Results: Out of 198 patients enrolled in the study, pCR was achieved in 50 patients (25%). ROC curve and CHAID analyses showed that absolute lymphopenia was significantly associated with lower pCR rates (p=0.046 and p=0.001, respectively). Other factors that were found to have a significant impact were radiation therapy type (p=0.033) and tumor distance from the anal verge (p= 0.041). Conclusion: An absolute decrease in the level of circulating lymphocytes during preoperative CRT to LARC is associated with poorer tumor response to treatment and thus may serve as a predictive biomarker for treatment resistance. [ABSTRACT FROM AUTHOR]

Introduction: People with schizophrenia have been reported to show deficits in tests of olfactory function. DNA methylation and GABAergic input have been implicated in biochemical processes controlling odor in animal studies, but this has not been investigated in human studies. Methods: In a study of measures of DNA methylation and GABAergic mRNAs in lymphocytes, we also measured odor identification and discrimination with the Sniffin' Sticks battery in 58 patients with chronic schizophrenia (CSZ) and 48 controls. mRNAs in lymphocytes were assessed by qPCR using TaqManTM probes. Cognition was assessed by the MATRICS battery (Measurement and Treatment Research to Improve Cognition in Schizophrenia) in CSZ and controls, and symptoms in CSZ were assessed by PANSS scale (Positive and Negative Symptom Scale). The relationships of odor deficits with mRNA, cognition, and symptoms were explored by correlation analysis. Variables which significantly differentiated CSZ from controls were explored by logistic regression. Results: Overall, CSZ showed significantly (P≤.001) lower scores on odor discrimination compared to controls, with a moderate effect size, but no difference in odor identification. Deficits in odor discrimination, which has not been standardly assessed in many prior studies, strongly differentiated CSZ from controls. In logistic regression analysis, odor discrimination, but not odor identification, was a significant variable predicting schizophrenia versus control class membership. This is the first study to report relationship between odor deficits and DNA methylation and GABAergic mRNAs in blood cells of human subjects. There were negative correlations of odor identification with DNA methylation enzymes mRNAs and significant negative correlations with odor discrimination and GABAergic mRNAs. Lower odor scores were significantly associated with lower cognitive scores on the MATRICS battery in CSZ but not control subjects. In CSZ, lower odor scores were significantly associated with negative symptom scores, while higher odor identification scores were associated with PANNS Excitement factor. Discussion: Odor discrimination was a more powerful variable than odor identification in discriminating CSZ from controls and should be used more regularly as an odor measure in studies of schizophrenia. The substantive meaning of the negative correlations of odor discrimination and GABAergic mRNA variables in peripheral lymphocytes of CSZ needs more investigation and comparison with results in neural tissue. [ABSTRACT FROM AUTHOR]

Regulatory molecules have recently been recognized for their beneficial effects in the treatment of immune-mediated diseases, rather than using cytotoxic immunesuppressing drugs, which are associated with many unwanted side effects. Semaphorin3A (sema3A), a unique regulatory master of the immune system, was shown to be decreased in the serum of systemic lupus erythematosus (SLE) patients, in association with disease severity. Later, we were able to show its extremely beneficial effect in treating lupus nephritis in the NZB/W mice model. The mechanisms by which sema3A maintains its regulatory effect is by binding the regulatory receptor CD72 on B cells, thereby reducing the threshold of BCR signaling on B cells and reducing the production of pro-inflammatory cytokines. The aim of this study was to generate a stable sema3A molecule, easy to produce with a higher binding capacity to CD72 receptor rather than to Neuropilin-1 (NRP-1) receptor, which is expressed in many cell types. Using the crystallographic structure of parental sema3A, we synthesized a new secreted (shorter) sema3A derivative, which we called truncated sema3A (T-sema3A). The new molecule lacked the NRP-1 binding domain (the C-terminal site) and has an artificial dimerization site at position 257 (serine residue was exchanged with a cysteine residue). To facilitate the purification of this molecule we added Histidine epitope tag in frame upstream to a stop codon. This construct was transfected using a viral vector to 293HEK cells to generate cells stably expressing T-sema3A. T-sema3A is shown to be with a higher binding ability to CD72 than to NRP-1 as demonstrated by a homemade ELISA. In addition, T-sema3A was shown to be a regulatory agent which can induce the expression of IL-10 and TGF-ß and reduce the secretion of pro-inflammatory cytokines such as IL-6, IFN-N, and IL-17A from human T and B-lymphocytes. Keeping this in mind, T-sema3A is highly effective in maintaining immune homeostasis, therefore, becoming a potential agent in restoring the regulatory status of the immune system in immune-mediated diseases. [ABSTRACT FROM AUTHOR]

Background: Intensified training coupled with sufficient recovery is required to improve athletic performance. A stress-recovery imbalance can lead to negative states of overtraining. Hormonal alterations associated with intensified training, such as blunted cortisol, may impair the immune response. Cortisol promotes the maturation and migration of dendritic cells which subsequently stimulate the T cell response. However, there are currently no clear reliable biomarkers to highlight the overtraining syndrome. This systematic review and meta-analysis examined the effect of intensified training on immune cells. Outcomes from this could provide insight into whether these markers may be used as an indicator of negative states of overtraining. Methods: SPORTDiscus, PUBMED, Academic Search Complete, Scopus and Web of Science were searched until June 2022. Included articles reported on immune biomarkers relating to lymphocytes, dendritic cells, and cytokines before and after a period of intensified training, in humans and rodents, at rest and in response to exercise. Results: 164 full texts were screened for eligibility. Across 57 eligible studies, 16 immune biomarkers were assessed. 7 were assessed at rest and in response to a bout of exercise, and 9 assessed at rest only. Included lymphocyte markers were CD3+, CD4+ and CD8+ T cell count, NK cell count, NK Cytolytic activity, lymphocyte proliferation and CD4/CD8 ratio. Dendritic cell markers examined were CD80, CD86, and MHC II expression. Cytokines included IL-1β, IL-2, IL-10, TNF-α and IFN-γ. A period of intensified training significantly decreased resting total lymphocyte (d= -0.57, 95% CI -0.30) and CD8+ T cell counts (d= -0.37, 95% CI -0.04), and unstimulated plasma IL-1β levels (d= -0.63, 95% CI -0.17). Resting dendritic cell CD86 expression significantly increased (d = 2.18, 95% CI 4.07). All other biomarkers remained unchanged. Conclusion: Although some biomarkers alter after a period of intensified training, definitive immune biomarkers are limited. Specifically, due to low study numbers, further investigation into the dendritic cell response in human models is required. [ABSTRACT FROM AUTHOR]

Current evidence highlights the critical role of the gut-kidney axis in the pathogenesis of IgA nephropathy (IgAN). However, few attempts have been made to explore targeted intestinal immunity therapy. This research aims to develop an oral intestine targeting medication based on extracellular vesicles (EVs) and investigate its therapeutic efficacy in IgAN. EVs were isolated from orange juice and electroporated with dexamethasone sodium phosphate (DexP). After oral administration, EVs-DexP was picked up by lymphocytes in the submucosal area of ileocecum. EVs-DexP outperformed DexP not only in suppressing lymphocyte stimulation in vitro but also in alleviating renal pathological lesions in the IgAN mouse model. Clinical improvement was accompanied by a reducing IgA secreted by the intestine and a decreasing IgA + B220 + lymphocytes in Peyer's patches. The present study develops a cost-effective, biofriendly EVs-based glucocorticoid strategy for IgAN. [ABSTRACT FROM AUTHOR]

Upon antigen stimulation and co-stimulation, CD4+ T lymphocytes produce soluble factors that promote the activity of other immune cells against pathogens or modified tissues; this task must be performed in presence of a variety of environmental cytokines, nutrient, and oxygen conditions, which necessarily impact T cell function. The complexity of the early intracellular processes taking place upon lymphocyte stimulation is addressed by means of a mathematical model based on a network that integrates variable microenvironmental conditions with intracellular activating, regulatory, and metabolic signals. Besides the phenotype subsets considered in previous works (Th1, Th2, Th17, and Treg) the model includes the main early events in differentiation to the TFH phenotype. The model describes how cytokines, nutrients and oxygen availability regulate the differentiation of naïve CD4+ T cells into distinct subsets. Particularly, it shows that elevated amounts of an alltype mixture of effector cytokines under optimal nutrient and oxygen availability conduces the system towards a highly-polarized Th1 or Th2 state, while reduced cytokine levels allow the expression of the Th17, Treg or TFH subsets, or even hybrid phenotypes. On the other hand, optimal levels of an alltype cytokine mixture in combination with glutamine or tryptophan restriction implies a shift from Th1 to Th2 expression, while decreased levels of the Th2-inducing cytokine IL-4 leads to the rupture of the Th1-Th2 axis, allowing the manifestation of different (or hybrid) subsets. Modeling proposes that, even under reduced levels of pro-inflammatory cytokines, the sole action of hypoxia boost Th17 expression. [ABSTRACT FROM AUTHOR]

Innate lymphoid cells (ILCs) play important roles in tissue homeostasis and host defense, but the proliferative properties and migratory behavior of especially human ILCs remain poorly understood. Here we mapped at single-cell resolution the spatial distribution of quiescent and proliferative human ILCs within the vascular versus tissue compartment. For this purpose, we employed MISTRG humanized mice as an in-vivo model to study human ILCs. We uncovered subset-specific differences in the proliferative status between vascular and tissue ILCs within lymphoid and non-lymphoid organs. We also identified CD117-CRTH2-CD45RA+ ILCs in the spleen that were highly proliferative and expressed the transcription factor TCF-1. These proliferative ILCs were present during the neonatal period in human blood and emerged early during population of the human ILC compartment in MISTRG mice transplanted with human hematopoietic stem and progenitor cells (HSPCs). Single-cell RNA-sequencing combined with intravascular cell labeling suggested that proliferative ILCs actively migrated from the local vasculature into the spleen tissue. Collectively, our comprehensive map reveals the proliferative topography of human ILCs, linking cell migration and spatial compartmentalization with cell division. [ABSTRACT FROM AUTHOR]

Background: Cannabis use is a component risk factor for the manifestation of schizophrenia. The biological effects of cannabis include effects on epigenetic systems, immunological parameters, in addition to changes in cannabinoid receptors 1 and 2, that may be associated with this risk. However, there has been limited study of the effects of smoked cannabis on these biological effects in human peripheral blood cells. We analyzed the effects of two concentrations of tetrahydrocannabinol (THC) vs. placebo in lymphocytes of a subset of participants who enrolled in a double-blind study of the effects of cannabis on driving performance (outcome not the focus of this study). Methods: Twenty four participants who regularly use cannabis participated in an experiment in which they smoked cannabis cigarettes (5.9 or 13.4% THC) or placebo (0.02%) ad libitum. Blood samples were drawn at baseline and several times after smoking. Lymphocytes were separated and stored at -80°C for further analysis. Samples were analyzed for mRNA content for cannabinoid receptors 1 (CB1) and 2 (CB2), methylation and demethylating enzymes (DNMT, TET), glucocorticoid receptor (NRC3) and immunological markers (IL1B, TNFa) by qPCR using TaqMan probes. The results were correlated with THC whole blood levels during the course of the day, as well as THCCOOH baseline levels. Statistical analyses used analysis of variance and covariance and t-tests, or non-parametric equivalents for those values which were not normally distributed. Results: There were no differences in background baseline characteristics of the participants except that the higher concentration THC group was older than the low concentration and placebo groups, and the low concentration THC group had higher baseline CB2 mRNA levels. Both the 5.9 and 13.4% THC groups showed increased THC blood levels that then decreased toward baseline within the first hour. However, there were no significant differences between THC blood levels between the 5.9 and 13.4% groups at any time point. At the 4-h time point after drug administration the 13.4% THC group had higher CB2 (P = 0.021) and DNMT3A (P = 0.027) mRNA levels than the placebo group. DNMT1 mRNA levels showed a trend in the same direction (P = 0.056). The higher 13.4% THC group had significantly increased CB2 mRNA levels than the 5.9% concentration group at several post drug administration time points and showed trends for difference in effects for between 5.9 and 13.4% THC groups for other mRNAs. TET3 mRNA levels were higher in the 13.4% THC group at 55 min post-cannabis ingestion. When the high and lower concentration THC groups were combined, none of the differences in mRNA levels from placebo remained statistically significant. Changes in THC blood levels were not related to changes in mRNA levels. Conclusion: Over the time course of this study, CB2 mRNA increased in blood lymphocytes in the high concentration THC group but were not accompanied by changes in immunological markers. The changes in DNMT and TET mRNAs suggest potential epigenetic effects of THC in human lymphocytes. Increases in DNMT methylating enzymes have been linked to some of the pathophysiological processes in schizophrenia and, therefore, should be further explored in a larger sample population, as one of the potential mechanisms linking cannabis use as a trigger for schizophrenia in vulnerable individuals. Since the two THC groups did not differ in post-smoking blood THC concentrations, the relationship between lymphocytic changes and the THC content of the cigarettes remains to be determined. [ABSTRACT FROM AUTHOR]

Non-Hodgkin lymphomas (NHLs) are a diverse group of blood cancers derived from lymphocytes that vary significantly in their severity. Surgery is not often used as a treatment because of the efficacy of chemotherapy, biological therapy, radiotherapy and hematopoietic stem cell transplantation. We reviewed the natural history and possible role of surgery for NHL. Surgery may be useful in confirming or refuting an equivocal radiological diagnosis through biopsy, removing symptomatic limited disease from an affected organ and in splenectomy for primary splenic lymphoma. Emergency abdominal surgery for acute complications of NHL provides palliation and diagnosis. There is as yet no consensus as to the optimum treatment for symptomatic limited disease affecting an organ and timing of chemotherapy perioperatively. Prospective randomized trials are required. Introduction Hodgkin lymphoma (HL, Hodgkin disease), described by Thomas Hodgkin in 1832, was the first form of lymphoma described and defined.1 Other forms were later described but because Hodgkin lymphoma was much more radiation-sensitive than other forms, its diagnosis was important for oncologists and their patients and thus research originally focused on it. The Rappaport classification, proposed in 1956 and 1966, became the first widely accepted classification of lymphomas other than Hodgkin.2 Surgery is not often used as a treatment because of the efficacy of chemotherapy, biological therapy, radiotherapy and hematopoietic stem cell transplantation.3-5 However, it may have some definitive roles in planned (elective) surgery but usually a palliative one in the acute abdomen.6,7 Despite the difficulty and paucity of prospective randomized trials this paper reviewed the possible role of surgery in non-Hodgkin’s lymphoma (NHL). [ABSTRACT FROM AUTHOR]

Excessive proinflammatory cytokine production induced by abnormal activation of Toll-like receptor (TLR) signaling, for example, by SARS-CoV-2 infection, can cause a fatal cytokine storm. The selective serotonin reuptake inhibitors (SSRIs) fluoxetine and fluvoxamine, used to treat depression, were recently reported to reduce the risk of severe disease in patients with coronavirus disease 2019 (COVID-19), but the mechanisms of the anti-inflammatory effects of SSRIs, and which SSRI would be most suitable as an anti-inflammatory drug, remain unclear. Here, we examined the inhibitory effects of 5 FDA-approved SSRIs, paroxetine, fluoxetine, fluvoxamine, sertraline and escitalopram, on the production of interleukin-6 (IL-6) induced by stimulation with multiple TLR agonists in murine macrophages and dendritic cells, and on the production of cytokines induced by concanavalin A in murine lymphocytes. In J774.1 murine macrophage cells, pretreatment with SSRIs significantly suppressed IL-6 release induced by TLR3 agonist poly(I:C), TLR4 agonist LPS or TLR9 agonist CpG ODN, but did not affect IL-6 release induced by TLR7 agonists imiquimod or resiquimod. In accordance with the results obtained in J774.1 cells, pretreatment with SSRIs also suppressed IL-6 release induced by a TLR3, TLR4 or TLR9 agonist in bone marrow-derived dendritic cells and peritoneal cells of C57BL/6 mice. On the other hand, interestingly, sertraline alone among the SSRIs amplified IL-6 production induced by TLR7 agonists in murine dendritic cells, though not in macrophages. Concanavalin A-induced production of IL-6 or IL-2 in murine lymphocytes was suppressed by SSRIs, suggesting that SSRIs also inhibit TLRs-independent IL-6 production. Since SSRIs suppressed both IL-6 production induced by multiple TLR agonists in macrophages or dendritic cells and TLR-independent IL-6 production in lymphocytes, they are promising candidates for treatment of patients with cytokine storm, which is mediated by overactivation of multiple TLRs in a complex manner, leading to the so-called IL-6 amplifier, an IL-6 overproduction loop. However, the 5 SSRIs examined here all showed different effects. Overall, our results suggest that fluoxetine may be the most promising candidate as an anti-inflammatory drug. An examination of the structural requirements indicated that the N -methyl group of fluoxetine has a critical role in the inhibition of IL-6 production. [ABSTRACT FROM AUTHOR]

In systemic lupus erythematosus, T cells display multiple abnormalities. They are abnormally activated, secrete pro-inflammatory cytokines, help B cells to generate pathogenic autoantibodies, and provoke the accumulation of autoreactive memory T cells. P140, a synthetic peptide evaluated in phase-III clinical trials for lupus, binds HSPA8/HSC70 chaperone protein. In vitro and in vivo , it interferes with hyperactivated chaperone-mediated autophagy, modifying overexpression of major histocompatibility complex class II molecules and antigen presentation to autoreactive T cells. Here, we show that in P140-treated lupus mice, abnormalities affecting T and B cells are no longer detectable in secondary lymphoid tissue and peripheral blood. Data indicate that P140 acts by depleting hyper-activated autoreactive T and B cells and restores normal immune homeostasis. Our findings suggest that P140 belongs to a new family of non-immunosuppressive immunoregulators that do not correct T and B cell abnormalities but rather contribute to the clearance of deleterious T and B cells. [ABSTRACT FROM AUTHOR]

The role of CD4 T regulatory cells is well established in peripheral tolerance and the pathogenesis of the murine model and human autoimmune diseases. CD4 T regulatory cells (CD4 Tregs) have been investigated in common variable immunodeficiency (CVID). Recently, additional members have been added to the club of regulatory lymphocytes. These include CD8 T regulatory (CD8 Tregs), B regulatory (Bregs), and T follicular helper regulatory (TFR) cells. There are accumulating data to suggest their roles in both human and experimental models of autoimmune disease. Their phenotypic characterization and mechanisms of immunoregulation are evolving. Patients with CVID may present or are associated with an increased frequency of autoimmunity and autoimmune diseases. In this review, we have primarily focused on the characteristics of CD4 Tregs and new players of the regulatory club and their changes in patients with CVID in relation to autoimmunity and emphasized the complexity of interplay among various regulatory lymphocytes. We suggest future careful investigations of phenotypic and functional regulatory lymphocytes in a large cohort of phenotypic and genotypically defined CVID patients to define their role in the pathogenesis of CVID and autoimmunity associated with CVID. [ABSTRACT FROM AUTHOR]

The CD80/86 molecule is one of the important co-stimulatory ligands and involves antigen-specific immune responses by ligating with CD28 and then delivering the required second signal to T-cell activation. In this study, a CD80/86 homolog was identified, and its expression characteristics were studied in flounder (Paralichthys olivaceus). The open reading frame (ORF) of CD80/86 is 906 bp, encoding 301 aa, and the extracellular amino acid sequence encoded two IgV- and IgC-like structural domains; fCD80/86 is highly expressed in head kidney, peripheral blood leukocytes (PBLs), and spleen, and has relatively high expression in muscle. Antibodies specific for CD80/86 were produced, and CD80/86 was colocalized with MHCII+, CD40+, and CD83+ leukocytes but not with IgM+, CD3+, or CD4+ lymphocytes. The cloned CD80/86 in flounder shares conserved structural features with its mammalian counterparts and is mainly distributed on antigen-presenting cells. Based on these data, CD80/86 as an adjuvant to enhance the immune response of DNA vaccine was investigated. A bicistronic DNA vaccine expressing both CD80/86 and the outer membrane protein (OmpK) of Vibrio anguillarum (p-OmpK-CD80/86) was successfully constructed. After immunization, p-OmpK-CD80/86 could induce the upregulation of the proportion of IgM+ and CD4+ cells in flounder, compared to the p-OmpK- or p-CD80/86-immunized group; CD28 genes were significantly induced in the p-CD80/86 and p-OmpK-CD80/86 groups. Compared to the p-OmpK group, the higher expression of CD83 , MHCI , CD4 , CD8 , and IL-2 was detected at the injection site. The relative percent survival (RPS) produced by p-OmpK-CD80/86 is 66.11% following the V. anguillarum challenge, while the RPS of p-OmpK or p-CD80/86 is 46.30% and 5.56%, respectively. The results revealed that CD80/86 is mainly found in antigen-presenting cells, and could help elicit humoral immune responses in teleost through the CD80/86-CD28 signaling pathway involving CD4+ lymphocytes. [ABSTRACT FROM AUTHOR]

Pathological correlates of potential autoimmune gastritis (AIG), defined by anti-parietal cell antibody (PCA) positivity in the absence of gastric atrophy, have never been described. We herein aimed to assess intraepithelial lymphocyte (IEL) infiltration in gastric corpus of AIG patients. From 2000 to 2021, among 53 potential AIG patients, we focused on nine (median age 61 years, IQR 53-82; four females) who subsequently developed overt AIG. IEL infiltration of the oxyntic mucosa was assessed before and after developing overt AIG by measuring deep and superficial CD3+ IEL. AIG patients with different degrees of corpus atrophy, healthy controls (HC), active H. pylori gastritis, celiac disease (CD), and Hashimoto's thyroiditis patients were included as controls. Of note, deep, but not superficial, CD3+ IEL count was higher (p<0.001) in potential AIG compared to HC and H. pylori gastritis. Deep CD3+ IEL infiltration did not change before or after the evolution into atrophy (median 9.6, IQR 8.8-12.4, vs 11.3, IQR 9.4-12.9). No difference was found in deep CD3+ IEL infiltration among potential, mild, and severe AIG, and compared to Hashimoto's thyroiditis or CD. A deep CD3+ IEL cut-off of >7/100 epithelial cells allowed discrimination of any AIG stage and severity (AUC=0.842). We conclude that an increased deep CD3+ IEL infiltration of the oxyntic mucosa could represent a marker of potential AIG. Prospective studies including a larger number of potential AIG patients are needed. [ABSTRACT FROM AUTHOR]

Copper oxide nanoparticles (CuO NPs) are increasingly used in various industry sectors. Moreover, medical application of CuO NPs as antimicrobials also contributes to human exposure. Their toxicity, including toxicity to the immune system and blood, raises concerns, while information on their immunotoxicity is still very limited. The aim of our work was to evaluate the effects of CuO NPs (number concentration 1.40×106 particles/cm3, geometric mean diameter 20.4 nm) on immune/inflammatory response and antioxidant defense in mice exposed to 32.5 µg CuO/m3 continuously for 6 weeks. After six weeks of CuO NP inhalation, the content of copper in lungs and liver was significantly increased, while in kidneys, spleen, brain, and blood it was similar in exposed and control mice. Inhalation of CuO NPs caused a significant increase in proliferative response of T-lymphocytes after mitogenic stimulation and basal proliferative activity of splenocytes. CuO NPs significantly induced the production of IL-12p70, Th1-cytokine IFN-γ and Th2-cytokines IL-4, IL-5. Levels of TNF-α and IL-6 remained unchanged. Immune assays showed significantly suppressed phagocytic activity of granulocytes and slightly decreased respiratory burst. No significant differences in phagocytosis of monocytes were recorded. The percentage of CD3+, CD3+CD4+, CD3+CD8+, and CD3-CD19+ cell subsets in spleen, thymus, and lymph nodes did not differ between exposed and control animals. No changes in hematological parameters were found between the CuO NP exposed and control groups. The overall antioxidant protection status of the organism was expressed by evaluation of GSH and GSSG concentrations in blood samples. The experimental group exposed to CuO NPs showed a significant decrease in GSH concentration in comparison to the control group. In summary, our results indicate that sub-chronic inhalation of CuO NPs can cause undesired modulation of the immune response. Stimulation of adaptive immunity was indicated by activation of proliferation and secretion functions of lymphocytes. CuO NPs elicited pro-activation state of Th1 and Th2 lymphocytes in exposed mice. Innate immunity was affected by impaired phagocytic activity of granulocytes. Reduced glutathione was significantly decreased in mice exposed to CuO NPs. [ABSTRACT FROM AUTHOR]

Dynamic modeling of lymphocyte behavior has primarily been based on populations based differential equations or on cellular agents moving in space and interacting each other. The final steps of this modeling effort are expressed in a code written in a programing language. On account of the complete lack of standardization of the different steps to proceed, we have to deplore poor communication and sharing between experimentalists, theoreticians and programmers. The adoption of diagrammatic visual computer language should however greatly help the immunologists to better communicate, to more easily identify the models similarities and facilitate the reuse and extension of existing software models. Since immunologists often conceptualize the dynamical evolution of immune systems in terms of "state-transitions" of biological objects, we promote the use of unified modeling language (UML) state-transition diagram. To demonstrate the feasibility of this approach,we present a UML refactoring of two published models on thymocyte differentiation. Originally built with different modeling strategies, a mathematical ordinary differential equation-based model and a cellular automata model, the two models are now in the same visual formalism and can be compared. [ABSTRACT FROM AUTHOR]

Introduction: Alemtuzumab is highly effective in the treatment of patients with relapsing multiple sclerosis (PwRMS) and selectively targets the CD52 antigen, with a consequent profound lymphopenia, particularly of CD4+ T lymphocytes. However, the immunological basis of its long-term efficacy has not been clearly elucidated. Methods: We followed up 29 alemtuzumab-treated RMS patients over a period of 72 months and studied the immunological reconstitution of their CD4+ T cell subsets by means of phenotypic and functional analysis and through mRNA-related molecule expression, comparing them to healthy subject (HS) values (rate 2:1). Results: In patients receiving only two-course alemtuzumab, the percentage of CD4+ lymphocytes decreased and returned to basal levels only at month 48. Immune reconstitution of the CD4+ subsets was characterized by a significant increase (p < 0.001) in Treg cell percentage at month 24, when compared to baseline, and was accompanied by restoration of the Treg suppressor function that increased within a range from 2- to 6.5-fold compared to baseline and that persisted through to the end of the follow-up. Furthermore, a significant decrease in self-reactive myelin basic protein-specific Th17 (p < 0.0001) and Th1 (p < 0.05) cells reaching HS values was observed starting from month 12. There was a change in mRNA of cytokines, chemokines, and transcriptional factors related to Th17, Th1, and Treg cell subset changes, consequently suggesting a shift toward immunoregulation and a reduction of T cell recruitment to the central nervous system. Conclusions: These data provide further insight into the mechanism that could contribute to the long-term 6-year persistence of the clinical effect of alemtuzumab on RMS disease activity. [ABSTRACT FROM AUTHOR]

T cells and B cells have been identified in human and murine islets, but the phenotype and role of islet lymphocytes is unknown. Resident immune populations set the stage for responses to inflammation in the islets during homeostasis and diabetes. Thus, we sought to identify the phenotype and effector function of islet lymphocytes to better understand their role in normal islets and in islets under metabolic stress. Lymphocytes were located in the islet parenchyma, and were comprised of a mix of naïve, activated, and memory T cell and B cell subsets, with an enrichment for regulatory B cell subsets. Use of a Nur77 reporter indicated that CD8 T cells and B cells both received local antigen stimulus, indicating that they responded to antigens present in the islets. Analysis of effector function showed that islet T cells and B cells produced the regulatory cytokine IL-10. The regulatory phenotype of islet T cells and B cells and their response to local antigenic stimuli remained stable under conditions of metabolic stress in the diet induced obesity (DIO) model. T cells present in human islets retained a similar activated and memory phenotype in non-diabetic and T2D donors. Under steady-state conditions, islet T cells and B cells have a regulatory phenotype, and thus may play a protective role in maintaining tissue homeostasis. [ABSTRACT FROM AUTHOR]

The author focuses on the articles by Martin C. Raff regarding the isoantigen and peripheral lymphocytes in mice. Topics discussed include the death of thymus lymphocytes due to antiserum, the analysis of the cells involved an adoptive cell-transfer system for the evaluation of the spleen cells, and the prolonged and frustrating search for T cells.

The author reflects on the paper "The transformation of column-purified lymphocytes with nonspecific and specific antigenic stimuli," by Joost J. Oppenheim, Brigid G. Leventhal, and Evan M. Hersh. It discusses the chromosome analyses concerning the chromosome abnormalities induced by neoplastic changes and damage from chemotherapeutic and radiation treatments. It discusses the role of major histocompatibility complex (MHC) in antigen presentation and antigen processing.

The etiology and pathogenesis of rheumatoid arthritis (RA) have not yet been fully elucidated, with greater adverse drug effects in traditional treatment of RA. It is particularly necessary to develop and study Chinese herbal formula as a supplement and alternative drug for the treatment of RA. The traditional Chinese medicine compound Longteng Decoction (LTD), as an empirical prescription in the treatment of RA in Dongzhimen Hospital of Beijing University of Chinese Medicine, has been widely used in clinic. Type 2 innate lymphocytes (ILC2s) have specific transcription factors and signature cytokines that are very similar to Th cells, which have been proved to be necessary in addressing RA inflammation, and are potential targets for RA prevention and treatment. Our previous studies have confirmed that LTD can intervene in the differentiation of peripheral blood Th17 and Treg cells, reduce joint pain index and swelling degree, shorten the time of morning stiffness, reduce ESR, and inhibit joint inflammation. However, it is unclear whether LTD can promote the regression of RA synovial inflammation by regulating the immune response mechanism of ILC2s.Therefore, our team established a collagen-induced arthritis mouse model and conducted an experimental study with LTD as the intervention object. The results showed that joint swelling, synovial inflammatory infiltration, and articular cartilage destruction were alleviated in CIA mice after intervention with LTD. The proliferation and differentiation of Th17 inflammatory cells and the secretion of proinflammatory cytokines (IL-17 and IFN-γ) were inhibited. In addition, LTD can also activate ILC2s to secrete the anti-inflammatory cytokine IL-4, activate the STAT6 signaling pathway, and act synergistic with Treg cells to inhibit the infiltration of type M1 macrophages in synovial tissue and promote its transformation to M2 phenotype. Taken together, these results confirm that LTD can be used as an adjunct or alternative to RA therapy by modulating the ILC2s immune response network and slowing down the inflammatory process of synovial tissue. [ABSTRACT FROM AUTHOR]

Theileria parva is the causative agent of East Coast fever and Corridor disease, which are fatal, economically important diseases of cattle in eastern, central and southern Africa. Improved methods of control of the diseases are urgently required. The parasite transforms host lymphocytes, resulting in a rapid, clonal expansion of infected cells. Resistance to the disease has long been reported in cattle from T. parva -endemic areas. We reveal here that first- and second-generation descendants of a single Bos indicus bull survived severe challenge with T. parva , (overall survival rate 57.3% compared to 8.7% for unrelated animals) in a series of five field studies. Tolerant cattle displayed a delayed and less severe parasitosis and febrile response than unrelated animals. The in vitro proliferation of cells from surviving cattle was much reduced compared to those from animals that succumbed to infection. Additionally, some pro-inflammatory cytokines such as IL1β, IL6, TNFα or TGFβ which are usually strongly expressed in susceptible animals and are known to regulate cell growth or motility, remain low in tolerant animals. This correlates with the reduced proliferation and less severe clinical reactions observed in tolerant cattle. The results show for the first time that the inherited tolerance to T. parva is associated with decreased proliferation of infected lymphocytes. The results are discussed in terms of whether the reduced proliferation is the result of a perturbation of the transformation mechanism induced in infected cells or is due to an innate immune response present in the tolerant cattle. [ABSTRACT FROM AUTHOR]

In the past few years, huge advances have been made in techniques to analyse cells at an individual level using RNA sequencing, and many of these have precipitated exciting discoveries in the immunology of type 1 diabetes (T1D). This review will cover the first papers to use scRNAseq to characterise human lymphocyte phenotypes in T1D in the peripheral blood, pancreatic lymph nodes and islets. These have revealed specific genes such as IL-32 that are differentially expressed in islet –specific T cells in T1D. scRNAseq has also revealed wider gene expression patterns that are involved in T1D and can predict its development even predating autoantibody production. Single cell sequencing of TCRs has revealed V genes and CDR3 motifs that are commonly used to target islet autoantigens, although truly public TCRs remain elusive. Little is known about BCR repertoires in T1D, but scRNAseq approaches have revealed that insulin binding BCRs commonly use specific J genes, share motifs between donors and frequently demonstrate poly-reactivity. This review will also summarise new developments in scRNAseq technology, the insights they have given into other diseases and how they could be leveraged to advance research in the type 1 diabetes field to identify novel biomarkers and targets for immunotherapy.

Acute infection of bovine viral diarrhea virus (BVDV) is associated with immune dysfunction and can cause peripheral blood lymphopenia and lymphocyte apoptosis. Our previous study has confirmed that programmed death-1 (PD-1) blockade inhibits peripheral blood lymphocytes (PBL) apoptosis and restores proliferation and anti-viral immune functions of lymphocytes after BVDV infection in vitro. However, the situation in vivo remains to be further studied and confirmed. Therefore, in this study, we established a BALB/c mouse model of acute BVDV infection with cytopathic (CP) BVDV (strain NADL) and non-cytopathic (NCP) BVDV (strain NY-1). Then, we examined the mRNA and protein levels of PD-1 and programmed death-ligand 1 (PD-L1) in peripheral blood mononuclear cells (PBMC) from BVDV-infected mice and analyzed the effects of PD-1 blockade on the proportions of CD3+, CD4+, and CD8+ T cell subsets, the apoptosis and proliferation of PBL, and the production of IL-2 and IFN-γ. We found that leukopenia, lymphocytopenia, and thrombocytopenia were developed in both CP and NCP BVDV-infected mice at day 7 of post-infection. The mRNA and protein expression of PD-1 and PD-L1 were significantly upregulated in CP and NCP BVDV-infected mice. Moreover, PD-1/PD-L1 upregulation was accompanied by leukopenia and lymphopenia. Additionally, PD-1 blockade inhibited PBL apoptosis and virus replication, restored the proportions of CD3+, CD4+, and CD8+ T cell subsets, and increased IFN-γ production and p-ERK expression in BVDV-infected mice. However, blocking PD-1 did not significantly affect PBL proliferation and IL-2 production in NCP BVDV-infected mice. Our findings further confirmed the immunomodulatory role of PD-1 in peripheral blood lymphocytopenia in vivo and provided a scientific basis for exploring the molecular mechanism of immune dysfunction caused by acute BVDV infection. [ABSTRACT FROM AUTHOR]

The prognostic role of lymphocyte doubling time (LDT) in chronic lymphocytic leukemia (CLL) was recognized more than three decades ago when the neoplastic clone's biology was almost unknown. LDT was defined as the time needed for the peripheral blood lymphocyte count to double the of the initial observed value. Herein, the LDT prognostic value for time to first treatment (TTFT) was explored in our prospective O-CLL cohort and validated in in two additional CLL cohorts. Specifically, newly diagnosed Binet stage A CLL patients from 40 Italian Institutions, representative of the whole country, were prospectively enrolled into the O-CLL1-GISL protocol (clinicaltrial.gov identifier: NCT00917540). Two independent cohorts of newly diagnosed CLL patients recruited respectively at the Division of Hematology in Novara, Italy, and at the Hospital Clinic in Barcelona, Spain, were utilized as validation cohorts. In the training cohort, TTFT of patients with LDT >12 months was significantly longer related to those with a shorter LDT. At Cox multivariate regression model, LDT ≤ 12 months maintained a significant independent relationship with shorter TTFT along with IGHV unmutated (IGHV unmut) status, 11q and 17p deletions, elevated β2M, Rai stage I-II, and NOTCH1 mutations. Based on these statistics, two regression models were constructed including the same prognostic factors with or without the LDT. The model with the LTD provided a significantly better data fitting (χ2 = 8.25, P=0.0041). The risk prediction developed including LDT had better prognostic accuracy than those without LDT. Moreover, the Harrell'C index for the scores including LDT were higher than those without LDT, although the accepted 0.70 threshold exceeded in both cases. These findings were also confirmed when the same analysis was carried out according to TTFT's explained variation. When data were further analyzed based on the combination between LDT and IGHV mutational status in the training and validation cohorts, IGHV unmut and LDT>12months group showed a predominant prognostic role over IGHV mut LTD ≤ 12 months (P=0.006) in the O-CLL validation cohort. However, this predominance was of borden-line significance (P=0.06) in the Barcelona group, while the significant prognostic impact was definitely lost in the Novara group. Overall, in this study, we demonstrated that LDT could be re-utilized together with the more sophisticated prognostic factors to manage the follow-up plans for Binet stage A CLL patients. [ABSTRACT FROM AUTHOR]

Background: Tumor-infiltrating lymphocytes (TILs) are considered a manifestation of the host immune response against cancer and tertiary lymphoid structures (TLS) may contribute to lymphocytes recruitment. Both of them have been reported as potential prognostic parameters in some human malignancies. However, the roles of TILs, TLS, and their correlation in Epstein-Barr Virus-associated gastric carcinoma (EBVaGC) and EBV-negative gastric carcinoma (EBVnGC) are largely unknown. Methods: To observe the correlation among TILs, TLS, and clinicopathological characteristics and their prognostic significance in EBVaGC and EBVnGC, respectively. TILs and TLS were assessed by morphology and/or immunohistochemistry, and accompanied by clinicopathological analysis from 846 gastric cancer patients in multiple institutions. Results: Forty-two (5.0%) cases of EBVaGC and 804 cases of EBVnGC were identified by in situ hybridization, respectively. For EBVnGC, higher TILs grade was correlated with TLS-present. EBVnGC patients with high TILs grade and TLS-present exhibited survival benefits. TILs (P = 0.001) and TLS (P = 0.003), especially TILs & TLS (P < 0.001) were independent prognostic factors in EBVnGC. A nomogram was constructed and validated for predicting the probability of overall survival and performed well with a good calibration. No significant prognostic value was detected in EBVaGC. Conclusion: TILs and TLS, especially TILs & TLS were promising prognostic indicators for overall survival in EBVnGC. TILs and TLS were highly overlapping in their extent and prognostic abilities, and may be considered as a coindicator of prognosis of gastric cancer. The evaluations of TILs and TLS are simple and can be assessed routinely in pathological diagnosis. [ABSTRACT FROM AUTHOR]

The immune infiltrate within tumors has proved to be very powerful in the prognostic stratification of patients and much attention is also being paid towards its predictive value. In this work we therefore aimed at clarifying the significance and impact of PD-L1 and PD-1 expression on the prognostic value of CD8+ tumor infiltrating lymphocytes (TILs) in a cohort of consecutive patients with primary resected non-small cell lung cancer (NSCLC). Tissue microarrays (TMA) were built using one representative formalin fixed paraffin embedded block for every case, with 5 cores for each block. TMA sections were stained with PD-L1 (clone SP263), PD-1 (clone NAT105) and CD8 (clone SP57). Number of CD8+ cells per mm2 were automatically counted; median, 25th and 75th percentiles of CD8+ cells were used as threshold for statistical clinical outcome analysis and evaluated in patients subgroups defined by expression of PD-L1 and PD-1 within tumors. We found an overall strong prognostic value of CD8+ cells in our cohort of 314 resected NSCLC, especially in PD-L1 negative tumors lacking PD-1+ TILs, and demonstrated that in PD-L1 positive tumors a higher density of CD8+ lymphocytes is necessary to improve the prognosis. Our data strengthen the concept of the importance of the assessment and quantification of the immune contexture in cancer and, similarly to what has been carried on in colorectal cancer, promote the efforts for the establishment of an Immunoscore for NSCLC for prognostic and possibly predictive purposes. [ABSTRACT FROM AUTHOR]

Background: Inflammatory factors and nutritional status are critical to the prognosis of colorectal cancer patients. This study aimed to investigate the prognostic value of the combination of preoperative lymphocytes, albumin, and neutrophils (LANR) in patients with resectable colorectal cancer. Methods: A total of 753 patients with pathologically diagnosed primary colorectal cancer were included in the study. The value of LANR was defined as follows: LANR, lymphocyte × albumin/neutrophil. The ROC curve, subgroup analysis and Cox proportional hazard regression analysis were used to assess the prognostic value of LANR in overall survival and progression-free survival. Results: The median age of the patients was 60 years (range 52–67 years). In overall survival, the area under the curve of LANR was 0.6276, and the HR (95% CI) was 0.551 (0.393–0.772). And in progression-free survival, the area under the curve of LANR was 0.5963, and the HR (95% CI) was 0.697 (0.550–0.884). The results indicate that preoperative LANR may be a reliable predictor of overall and progression-free survival in resectable colorectal cancer patients. Conclusions: LANR is an important prognostic indicator for patients with resectable colorectal cancer, and it can also provide a reference for clinicians and patients to choose a treatment plan. [ABSTRACT FROM AUTHOR]

Mucosal surfaces, as a first barrier with the environment are especially susceptible to damage from both pathogens and physical trauma. Thus, these sites require tightly regulated repair programs to maintain barrier function in the face of such insults. Barrier sites are also enriched for unconventional lymphocytes, which lack rearranged antigen receptors or express only a limited range of such receptors, such as ILCs (Innate Lymphoid Cells), γδ T Cells and MAIT (Mucosal-Associated Invariant T Cells). Recent studies have uncovered critical roles for unconventional lymphocytes in regulating mucosal barrier function, and, in particular, have highlighted their important involvement in barrier repair. The production of growth factors such as amphiregulin by ILC2, and fibroblast growth factors by γδ T cells have been shown to promote tissue repair at multiple barrier sites. Additionally, MAIT cells have been shown to exhibit pro-repair phenotypes and demonstrate microbiota-dependent promotion of murine skin healing. In this review we will discuss how immune responses at mucosal sites are controlled by unconventional lymphocytes and the ways in which these cells promote tissue repair to maintain barrier integrity in the skin, gut and lungs. [ABSTRACT FROM AUTHOR]