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PubMed2006

The IFN-independent response to virus particle entry provides a first line of antiviral defense that is independent of TLRs and retinoic acid-inducible gene I.

The innate immune system responds to pathogen infection by eliciting a nonspecific immune response following the recognition of various pathogen-associated molecular patterns. TLRs and the RNA helicases retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 recognize foreign nucleic acid within endosomal and cytoplasmic compartments, respectively, initiating a signaling cascade that involves the induction of type I IFN through the transcription factors IFN regulatory factor (IRF) 3 and NF-kappaB. However, a recent paradigm has emerged in which bacterial DNA and double-stranded B-form DNA trigger type I IFN production through an uncharacterized TLR- and RIG-I-independent pathway. We have previously described a response in primary fibroblasts wherein the entry of diverse RNA- and DNA-enveloped virus particles is sufficient to induce a subset of IFN-stimulated genes and a complete antiviral response in an IRF3-dependent, IFN-independent manner. In this study, we show that the innate immune response to virus particle entry is independent of both TLR and RIG-I pathways, confirming the existence of novel innate immune mechanisms that result in the activation of IRF3. Furthermore, we propose a model of innate antiviral immunity in which exposure to increasing numbers of virus particles elevates the complexity of the cellular response from an intracellular, IFN-independent response to one involving secretion of cytokines and activation of infiltrating immune cells.

DEAD Box Protein 58↗

PubMed2002

Microglia as liaisons between the immune and central nervous systems: functional implications for multiple sclerosis.

Multiple sclerosis is a chronic demyelinating inflammatory disease of the central nervous system (CNS). As the tissue macrophage of the CNS, microglia have the potential to regulate and be regulated by cells of the CNS and by CNS-infiltrating immune cells. The exquisite sensitivity of microglia to these signals, coupled with their ability to develop a broad range of effector functions, allows the CNS to tailor microglial function for specific physiological needs. However, the great plasticity of microglial responses can also predispose these cells to amplify disproportionately the irrelevant or dysfunctional signals provided by either the CNS or immune systems. The consequences of such an event could be the conversion of self-limiting inflammatory responses into chronic neurodegeneration and may explain in part the heterogeneous nature of multiple sclerosis.

Animals↗

PubMed1994

Cellular aspects of myositis.

Polymyositis, dermatomyositis, and inclusion-body myositis are characterized by muscle cell infiltration and specific alterations on or within muscle fibers. Infiltrating immune cells (ie, T or B lymphocytes, macrophages, and natural killer cells) have distinctive distributions in these conditions: increased presence of CD8+/MHC I-restricted T lymphocytes at endomysial sites in polymyositis and more B than T lymphocytes perivascularly in muscles of dermatomyositis patients. Muscle-infiltrating T lymphocytes mainly express alpha beta T cell receptors (TCRs) in polymyositis; they also express TCRs characterized by oligoclonal V beta repertoire, with a consensus motif indicating a conventional antigen as target of the immune attack. In inclusion-body myositis, TCRs with oligoclonal V beta also are found, but no consensus motif has been identified, suggesting possible superantigen involvement in lymphocyte recruitment. Sequence analysis of TCRs in these lymphocytes has provided insight into the probable nature of the antigenic stimulus and into recruitment of these cells to the inflammation sites. T cell- or natural killer cell-mediated cytotoxic agents have been characterized by messenger RNA or protein expression in these inflammatory myopathies, and the roles of other cytokines in the inflammation processes have been determined. In vivo and in vitro studies on muscle cells have assessed their functions as target cells or antigen-presenting cells. Combined molecular and cellular immunology studies on effector and target cells are expected to clarify the pathogenetic mechanisms underlying these inflammatory myopathies in the near future.

Humans↗

PubMed2003

Modern aspects of cutaneous neurogenic inflammation.

Recent findings have shed new light on the role of peripheral nerves in the skin and established a modern concept of cutaneous neurobiology. Closely related monodirectional and/or bidirectional pathways exist in which the central and peripheral nervous system, the endocrine and immune system, and almost all skin cells are involved. Information is emerging about the factors involved in these immunomodulatory mechanisms, which are defined as neuropeptides, neurotransmitters, neurotrophins, and neurohormones. The interaction between peripheral nerves and the immune system is mediated by different types of cutaneous nerve fibers that release neuromediators and activate specific receptors on target cells in the skin such as keratinocytes, mast cells, Langerhans cells, microvascular endothelial cells, fibroblasts, and infiltrating immune cells. These interactions influence a variety of physiologic and pathophysiologic functions including cellular development, growth, differentiation, immunity, vasoregulation, leukocyte recruitment, pruritus, and wound healing. A variety of mechanisms lead to the termination of cellular responses to released neuropeptides under physiologic circumstances. Herein, we highlight some of the recent advances of neurocutaneous biology and discuss the role of nerves in mediating cutaneous inflammation. Understanding the mechanisms and the factors controlling neuromediators and their receptors and degrading enzymes will lead to the identification of novel therapeutic targets for the treatment of cutaneous diseases.

Dermatitis↗

PubMedDate not supplied

Different efficacy of in vivo herpes simplex virus thymidine kinase gene transduction and ganciclovir treatment on the inhibition of tumor growth of murine and human melanoma cells and rat glioblastoma cells.

Initial studies have demonstrated the therapeutic efficacy for cancer treatment of in vivo transfer of the herpes simplex virus thymidine kinase gene followed by ganciclovir (GCV) treatment. However, recent studies have questioned the validity of this approach. Using retroviral vector-producing cells (VPC) as a source for in vivo gene transfer, we evaluated the efficacy of in vivo transduction of malignant cells using three different tumor cell models: B16 murine and IIB-MEL-LES human melanomas and a C6 rat glioblastoma. In vitro studies showed a bystander effect only in C6 cells. In vivo studies showed an inhibition of tumor growth in the two melanoma models when tumor cells were coinjected with VPC-producing retroviral vectors carrying the herpes simplex virus thymidine kinase gene, followed by GCV treatment; however, 100% of mice developed tumors in both models. Under similar experimental conditions, 70% (7 of 10) of syngeneic rats completely rejected stereotactically transferred C6 tumor cells; most of them (5 of 10) showed a prolonged survival. Treating established C6 tumors with VPC-producing retroviral vectors carrying the herpes simplex virus thymidine kinase gene and GCV led to the cure of 33% (4 of 12) of the animals. Rats that rejected tumor growth developed an antitumor immune memory, leading to a rejection of a stereotactic contralateral challenge with parental cells. The immune infiltrate, which showed the presence of T lymphocytes, macrophages, and polymorphonuclear cells at the site of the first injection and mainly T lymphocytes and macrophages at the site of tumor challenge, strengthened the importance of the immune system in achieving complete tumor rejection.

Animals↗

PubMed2026

scRNA-seq and bulk RNA-seq reveal the characteristics of macrophage copper metabolism and establish a risk signature in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is a prevalent malignancy with an urgent need for improved prognostic stratification and treatment-response prediction. This study aimed to explore a macrophage copper metabolism-associated prognostic model and to investigate the relationship between this risk model and the tumor immune microenvironment. METHODS: The FindClusters function was used to analyze cell clusters, and CellChat and CellPhoneDB/LIANA were employed for cell-cell communication analysis. Copper metabolism-related genes were sourced from the MSigDB database. A prognostic risk model was established using least absolute shrinkage and selection operator (LASSO) analysis and multivariate Cox regression analysis, and a nomogram was constructed by integrating the prognostic model with clinicopathological factors. Additional analyses were performed to map the seven model genes in single-cell data, assess model uncertainty and robustness, evaluate macrophage/copper/cuproptosis-related transcriptional programs, and examine the correlations between risk score, immune infiltration and predicted drug sensitivity. RESULTS: Using single-cell RNA sequencing (scRNA-seq) data, we identified four macrophage subpopulations. Macrophages with high SPP1 expression showed close interaction with T cell populations and were associated with copper ion metabolism. By incorporating 141 copper metabolism-related genes and using The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) cohort, we constructed a seven-gene risk prediction model. Additional single-cell mapping showed that the model genes were detectable in the HCC single-cell dataset and showed a macrophage-associated expression pattern. The model showed moderate prognostic discrimination in TCGA-LIHC, whereas its external performance was heterogeneous and remained evaluable across external cohorts, with performance varying among datasets. Immune and mechanism-related analyses suggested that the risk signature was associated with macrophage-related infiltration, copper metabolism and cuproptosis-related transcriptional programs. Drug sensitivity analysis nominated Daporinad as a computationally predicted candidate compound, supporting Daporinad as a pharmacogenomic candidate for follow-up investigation. CONCLUSIONS: By integrating scRNA-seq and bulk RNA sequencing (RNA-seq) data, we constructed a macrophage copper metabolism-associated prognostic signature for HCC. The risk score was associated with survival, immune microenvironment features and predicted drug response, providing a transcriptomic framework for risk stratification and therapeutic hypothesis generation.

Hepatocellular carcinoma (HCC)↗

PubMed1992

M-CSF (monocyte colony stimulating factor) and M-CSF receptor expression by breast tumour cells: M-CSF mediated recruitment of tumour infiltrating monocytes?

Infiltrating immune cells in 30 primary human epithelial breast tumours were studied using specific anti-CD3 (T cells), anti-CD68 (macrophages), anti-CD57 (NK cells), and an anti-pan-B cell antibody (L26). The majority of tumour infiltrating inflammatory cells are T cells (40-50%) and monocytes/macrophages (15-35%). The macrophage specific chemo-attractant and growth factor CSF-1 is detected by immunohistochemical techniques (IHC) at the level of invasive breast cancer cells in 46/50 tumours but not at the level of in-situ (pre-invasive) cancer. A mosaic staining pattern was usually observed, with a very high expression in areas of obvious stromal invasion (90% cells positive) and absent or trace staining in intraductal carcinoma. Macrophages and plasma cells are equally intensely positive. In-situ hybridisation experiments confirm the production of CSF-1 (mRNA) by tumour cells and show the same pattern of expression. Expression of the CSF-1 receptor protein (fms) was also observed by IHC in 41/48 invasive tumours, albeit at weaker intensities than in tumour infiltrating monocytes/macrophages. A concomitant expression of both CSF-1 and fms in in-situ carcinoma was never seen (n = 14). It is therefore proposed that the associated expression of CSF-1 and its receptor may be linked to the invasive potential of breast cancer, the monocytic infiltrate being an indication of the quantitative importance of CSF-1 production by the tumour.

Antibodies, Monoclonal↗

PubMed2007

Immune response to retroviral infections of the brain.

Various neurological manifestations of retroviral infections have been reported, including peripheral neuropathy, encephalopathy and neuronal degeneration. After penetration into the central nervous system (CNS) the invading retroviruses meet a unique immunological situation that differs significantly from that in the periphery. Due to the blood-brain barrier with its general access restrictions peripheral T-cells, monocytes and B-cells are only "guests" in the brain; instead the immune balance is shifted in favour of the local innate immunity with microglia, astrocytes, cytokines/chemokines and complement forming the dominating defence network. The present article focuses on the most important retroviral infections and highlights the immunological aspects of the neuropathogenesis induced by selected retroviruses. These aspects include: (i) local and infiltrated immune cells as targets of retroviral infection; (ii) stimulation of the cerebral immunity network by retroviruses and subsequent steps of antiviral defence; and (iii) immune activation products as potential contributors to neural damage in the sensitive brain tissue.

Animals↗

PubMed2003

Renal-cell carcinoma: tumour markers, T-cell epitopes, and potential for new therapies.

Advanced renal-cell carcinoma is a very difficult tumour to treat, and response rates to biological therapies are less than 20%. The identification of various molecular and cellular markers has led to the development of novel therapies. Despite evaluation of their association with histological subtype, immune infiltration, molecular markers of cell proliferation, p53 mutation, and growth-factor-receptor expression, none of these markers has proved better predictive factors than tumour stage and histological grade. The identification of tumour-associated antigens and the specificity of cellular immune responses have led to the development of targeted immunotherapy with monoclonal antibodies, radioimmunotherapy, and T-cell therapies. In this review, we evaluate a range of markers associated with renal-cell carcinoma and new treatment approaches based on tumour-associated antigens and, in particular, T-cell epitopes.

Antigens, Neoplasm↗

PubMed2026

Efferocytosis related KCTD12 is a clinico-immune target in lung adenocarcinoma.

BACKGROUND: Efferocytosis, the clearance of apoptotic cells by phagocytes, contributes to immune homeostasis but may also promote tumor immune tolerance. However, its transcriptional landscape and clinical relevance in lung adenocarcinoma (LUAD) remain incompletely understood. METHODS: We systematically analyzed efferocytosis-associated genes across TCGA and multiple GEO datasets to classify LUAD subtypes and construct a prognostic risk model. The prognostic and immunological relevance of this model was validated in four independent cohorts and further assessed through immune infiltration, genomic, and immunotherapy datasets. Functional and pharmacogenomic analyses were performed to identify potential therapeutic vulnerabilities, and the efferocytosis-associated signature gene KCTD12 was subsequently validated in vitro. RESULTS: Unsupervised clustering identified two efferocytosis-based LUAD subtypes with distinct prognostic and immune-metabolic characteristics. The derived risk model robustly predicted overall survival across validation cohorts. Among the model genes, KCTD12 emerged as an efferocytosis-associated candidate linked to an immune-active tumor microenvironment. Across the analyzed single-cell, spatial transcriptomic, and immunotherapy-treated cohorts, higher KCTD12 expression was associated with enhanced cytotoxic T-cell activity and more favorable treatment outcomes. Functional experiments confirmed that KCTD12 suppresses tumor cell proliferation, reduces colony formation, and enhances OT-1 CD8+ T-cell activation and cytotoxicity. CONCLUSIONS: Our study identifies an efferocytosis-associated transcriptional program linked to immune heterogeneity and prognosis in LUAD. The efferocytosis-related risk signature provides a framework for prognostic and immune stratification, while KCTD12 represents a candidate biomarker associated with immune activation and clinical outcomes in immunotherapy-treated cohorts. Its treatment-specific predictive value requires prospective validation in appropriately controlled studies.

KCTD12↗

PubMed2003

Tmevpg1, a candidate gene for the control of Theiler's virus persistence, could be implicated in the regulation of gamma interferon.

The Tmevp3 locus controls the load of Theiler's virus RNA during persistent infection of the mouse central nervous system (CNS). We identified a candidate gene at this locus, Tmevpg1, by using a positional cloning approach. Tmevpg1 and its human ortholog, TMEVPG1, are expressed in the immune system and encode what appears to be a noncoding RNA. They are located in a cluster of cytokine genes that includes the genes for gamma interferon and one or two homolog of interleukin-10. We now report that Tmevpg1 is expressed in CNS-infiltrating immune cells of resistant B10.S mice, but not in those of susceptible SJL/J mice, following inoculation with Theiler's virus. The pattern of expression of Tmevpg1 is the same in B10.S mice and in SJL/J mice congenic for the resistant B10.S haplotype of Tmevp3. Nineteen polymorphisms were identified when the Tmevpg1 genes of B10.S and SJL/J mice were compared. Interestingly, Tmevpg1 is down regulated after in vitro stimulation of murine CD4(+) or CD8(+) splenocytes, whereas Ifng is up regulated. Similar patterns of expression of TMEVPG1 and IFNG were observed in human NK cells and CD4(+) and CD8(+) T lymphocytes. Therefore, Tmevpg1 is a strong candidate gene for the Tmevp3 locus and may be involved in the control of Ifng gene expression.

Animals↗

PubMed2005

Neutrophils and macrophages promote angiogenesis in the early stage of endometriosis in a mouse model.

Substantial evidence suggests that inflammatory cytokines, immune cells, and angiogenesis are important for endometriosis. In this study, we investigated the role of the sequential events in the development of endometriosis in a mouse model. Uterine tissue was transplanted into the peritoneum of ovariectomized mice and then supplemented with estrogen or vehicle. On different days after transplantation, cell proliferation, angiogenesis, and infiltrated immune cells in ectopic tissue were examined using immunochemical staining. Many disintegrated blood vessels but no bromodeoxyuridine-positive cells in ectopic tissue were observed in the estrogen-treated group on posttransplantation d 1 and 2. On d 4-7, bromodeoxyuridine-positive cells were detected in the blood vessels of ectopic tissue, indicating that angiogenesis was initiated in this stage. Angiogenesis also occurred in ectopic tissue in the vehicle-treated group. Profound infiltration of neutrophils in ectopic tissue occurred on d 1-4, when the number of neutrophils and levels of macrophage inflammatory protein (MIP)-1alpha and MIP-2 chemokines in peritoneal fluids also reached their peak. Peritoneal macrophage numbers did not change, but secretions of TNFalpha, IL-6, MIP-1alpha, and MIP-2 from macrophages isolated on d 2 were higher than on d 0. In vitro studies showed that peritoneal neutrophils and macrophages secreted vascular endothelial growth factor, which was up-regulated by TNFalpha and IL-6. Our results suggest that neutrophils and macrophages may promote angiogenesis in the early stage of endometriosis and that chemokines and cytokines amplify the angiogenic signal for the growth of endometriotic tissue.

Animals↗

PubMed2006

Tumor-infiltrating cytotoxic T cells but not regulatory T cells predict outcome in anal squamous cell carcinoma.

PURPOSE: Tumor-infiltrating lymphocytes (TIL) are a possible prognostic factor in solid tumors. Cytotoxic TILs are generally considered as prognostically favorable, whereas regulatory T cells (Treg) may have adverse effects by virtue of their ability to inhibit effector cells. We have evaluated the effect of T-cell subsets on survival in patients with anal squamous cell carcinoma following radiochemotherapy. METHODS: Biopsy specimens from 38 patients with anal carcinomas were evaluated using tissue microarrays and immunohistochemistry for the presence of tumor-infiltrating immune cells using CD3, CD4, CD8, and CD68 antibodies. Treg were identified using an antibody directed against the transcription factor FoxP3, and granzyme B served as a marker for cytotoxic cells. Intratumoral immune cells were enumerated using a semiautomatic image analysis program. Prognostic effect of TIL subsets was evaluated by the log-rank test comparing no evidence of disease survival for groups with high and low numbers using median values as cutoff. RESULTS: CD3+ and CD4+ TILs influenced no evidence of disease survival: 3-year rates for patients with low numbers were 89% and 95%, respectively, and 54% (P = 0.02) and 48%, (P = 0.01), respectively, in cases with high numbers. Large numbers of tumor-infiltrating granzyme B+ cytotoxic cells had a significant negative prognostic effect (P = 0.008), whereas no effect was observed for Treg. CONCLUSIONS: TILs were identified as negative prognostic indicators in anal squamous cell carcinomas with granzyme B+ cytotoxic cells showing highest effect on outcome. This is possibly explained by the selection of therapy-resistant tumor cell clones. No prognostic influence of Treg was found. Knowledge of local immune responses is important for the development of immunotherapeutic strategies.

Anus Neoplasms↗

PubMed2005

Iodine and IFN-gamma synergistically enhance intercellular adhesion molecule 1 expression on NOD.H2h4 mouse thyrocytes.

NOD.H2(h4) mice spontaneously develop autoimmune lymphocytic thyroiditis that mimics human Hashimoto's thyroiditis, a disease where iodine, IFN-gamma, and adhesion molecules have all been implicated in the pathogenesis. To study how iodine and IFN-gamma modulate the expression of ICAM-1, we analyzed NOD.H2(h4) thyrocytes in baseline conditions (day 0) and at several time points following supplementation of iodine in the drinking water. On day 0, a small percentage ( approximately 10%) of thyrocytes constitutively expressed ICAM-1. The expression gradually increased to 13, 25, and 41% on days 7, 14 and 28, respectively, returning to baseline (9%) on day 35. The initial ICAM-1 kinetics was paralleled by thyroidal infiltration of CD45(+) hemopoietic cells, which increased from an average of 4% on day 0 to an average of 13, 21, and 24% on days 14, 28, and 35, respectively. To distinguish whether the observed ICAM-1 increase was a direct effect of iodine or a consequence of the immune infiltrate, we treated mouse primary thyrocyte cultures with 0.01 mM sodium iodine and showed a 3-fold increased ICAM-1 expression. To assess interaction between IFN-gamma and iodine, we analyzed CD45 and ICAM-1expression on thyrocytes from NOD.H2(h4) wild-type and NOD.H2(h4) thyr-IFN-gamma transgenic littermates. Strikingly, IFN-gamma interacted synergistically with iodine to enhance ICAM-1 expression on thyrocytes. These findings suggest that iodine and IFN-gamma cooperate to promote thyroidal expression of ICAM-1 in this mouse model of thyroiditis, highlighting the complex interplay present in the pathogenesis of Hashimoto's thyroiditis.

Adjuvants, Immunologic↗

PubMed1992

A placebo controlled observer blind immunocytochemical and histologic study of epithelium adjacent to anogenital warts in patients treated with systemic interferon alpha in combination with cryotherapy or cryotherapy alone.

OBJECTIVE: To examine biopsy specimens of tissue immediately adjacent to anogenital (AG) warts which had been treated with either cryotherapy plus subcutaneous interferon (IFN) alpha 2a or cryotherapy alone, for histological features of (a) human papilloma virus (HPV) infection (b) localised cellular immune responses, to further characterise any cellular immune infiltrates with tissue immunocytochemistry, and to relate any histological, immunocytochemical findings to the treatment response of nearby AG warts. DESIGN: A randomised placebo controlled observer blind study. SETTING: Genitourinary Medicine clinic, Department of Immunopathology, Royal Victoria Hospital, Belfast, N. Ireland. SUBJECTS: Thirty patients with AG warts; 16 treated with IFN alpha 2a plus cryotherapy, and 14 treated with cryotherapy alone. OUTCOME MEASURES: (1) Light microscopic features associated with HPV infection and local cellular immune responses. (2) Indirect immunofluorescence detection of the following cell surface markers: HLA DR, alpha one antitrypsin, CD1, CD3, CD4, CD8, CD22. (3) Clinical response of AG warts to treatment. RESULTS: In pre-treatment biopsies only non specific indicators of HPV infection (acanthosis, 29/30 biopsies, and hyperkeratosis, 7/30 biopsies) were seen on light microscopy. Mononuclear cells were seen both throughout the upper dermis and centred around dermal blood vessels in 19/30 (63.3%) biopsies, and infiltrating into the epidermis in 12/30 (40%) biopsies. On indirect immunofluorescence CD3, CD8, CD4 antigen was detected on the surface of cells throughout the upper dermis in 24/29 (82.7%), 15/29 (51.7%), and 3/29 (10.3%), of biopsy specimens respectively. CD3 antigen, CD8 antigen and CD4 antigen was detected on the surface of cells infiltrating into the epidermis in 18/29 (62%), 7/29 (24.1%), and 6/29 (20.7%) of biopsy specimens respectively. CD1 antigen was seen on the surface of dendritic cells throughout the epidermis in all specimens; CD1 positive cells infiltrated into the upper dermis in 5/29 (17.2%). HLA DR was detected on the surface of dendritic cells throughout the epidermis in 22/29 (75.9%) of specimens, and on the surface of cells scattered both diffusely throughout the upper dermis and centred around dermal blood vessels in all specimens. Alpha one antitrypsin (A1AT) antigen was seen on the surface of cells in the upper dermis in 6/29 (20.7%) of biopsy specimens; no cells expressing CD22 surface antigen were seen. The nature of this local cellular immune response was not altered by treatment of nearby warts with either cryotherapy alone or cryotherapy plus systemic IFN alpha 2a, or related to the therapeutic outcome of these warts. CONCLUSIONS: (1) No convincing histological evidence of HPV infection was seen in epithelium surrounding AG warts. (2) A predominantly T cell-mediated immune response (the target of which is uncertain) was seen in this perilesional epithelium. (3) In the dosage regimens used in this study, treatment of AG warts with either systemic IFN alpha 2a plus cryotherapy or cryotherapy alone did not appear to augment localised cellular immune responses (against any presumed subclinical HPV infection) in epithelium surrounding AG warts.

Adolescent↗

PubMed2004

Angiotensin II type 1 and type 2 receptors reciprocally modulate pro-inflammatory/ pro-fibrotic reactions in activated splenic lymphocytes.

Angiotensin II (Ang II) type 1 receptor (AT1R) has been confirmed to confer renoprotection in the progressive, immune-mediated nephritis in animal models as well as in humans. However, the relative contributions of direct AT1R blockade, indirect counteractivation of Ang II type 2 receptor (AT2R), or both, to renoprotection through AT1R antagonism remains to be clarified. Immunohistochemical studies in the nephritic kidney revealed that tubular epithelial cells and infiltrating immune cells were positive for AT1R and AT2R. In the present study, we investigated the action of Ang II on both receptors on immune cells. A subpopulation of lipopolysaccharide-activated splenic lymphocytes (mixed lymphocyte populations) was positive for AT1R and AT2R. Ang II alone could not induce gene expression of a pro-inflammatory chemokine JE or a pro-fibrotic cytokine transforming growth factor-beta1 in those cells. However, Ang II could significantly suppress the expression of both genes in those cells under AT1R blockade, and this action was mediated through AT2R. Conversely, the pro-inflammatory/pro-fibrotic gene expression could be enhanced by AT2R blockade, and this was mediated through AT1R. AT1R and AT2R expressed in activated immune cells can modulate pro-inflammatory and pro-fibrotic reactions reciprocally. In advanced immune-mediated nephritic kidneys, AT1R antagonism likely confers renoprotection via activation of AT2R.

Animals↗

PubMed2000

Chronic myocarditis induced by T cells reactive to a single cardiac myosin peptide: persistent inflammation, cardiac dilatation, myocardial scarring and continuous myocyte apoptosis.

Recent recognition that an autoimmune myocarditis may precede, and result in, dilated cardiomyopathy has focused attention on immune mechanisms of myocardial injury. In this paper, we describe a model of chronic autoimmune myocarditis in the Lewis rat. The production of myocarditis has been previously described by this group and in brief is accomplished by a single tail vein infusion of activated T cells specific for a 17-amino acid peptide from rat cardiac myosin. In this report, animals were followed for approximately 6 months post-T-cell infusion. Hearts from animals which received cardiac myosin specific T cells all showed extensive fibrosis associated with ongoing inflammation. Apoptosis, identified by TdT-mediated dUTP nick end labelling (TUNEL), was identified as a mode of myocyte death in hearts with acute and chronic myocarditis but not in age- and sex-matched controls. Immunohistochemistry was used to characterize the immune infiltrate and adhesion molecules in hearts with chronic myocarditis and these findings were compared to hearts with acute myocarditis. We propose that this rat model of chronic myocarditis mimics human disease, since inflammation results in ventricular dilatation and myocyte hypertrophy reminiscent of dilated cardiomyopathy. This model offers potential for further investigation of immune, functional and possible therapeutic aspects of autoimmune related cardiomyopathies.

Adoptive Transfer↗

PubMed2026

Manual, digital, and AI tumour-infiltrating lymphocyte scoring: a secondary analysis of the APHINITY randomised trial.

BACKGROUND: Stromal tumour-infiltrating lymphocytes (sTILs) are prognostic in early-stage HER2-positive breast cancer, but their role in the context of dual HER2 blockade remains undefined. We evaluated manual, digital, and artificial intelligence (AI)-based sTIL quantification, together with AI-derived spatial metrics, for prognostic and treatment-benefit stratification using tumour samples from the phase 3 APHINITY trial. METHODS: In the APHINITY trial, 4805 patients were randomly assigned to receive chemotherapy plus trastuzumab with pertuzumab or chemotherapy plus trastuzumab with placebo. Median follow-up was 74·1 months (IQR 68·3-75·4). We analysed 4262 haematoxylin and eosin-stained images using manual assessment, an automated digital approach, AI-based lymphocyte quantification (AI percentage lymphocytes), and two AI-derived spatial features (AI-TIL and immune hotspot). Interobserver reproducibility was assessed in 262 randomly chosen tumour samples scored independently by five pathologists. Multivariable Cox models were used to assess associations between TIL levels and invasive disease-free survival (primary outcome in APHINITY), distant recurrence-free interval, and overall survival. The heterogeneity of pertuzumab benefit was evaluated using subgroup analyses, subpopulation treatment effect pattern plot analyses, and nested Cox models with treatment-by-biomarker interaction terms. FINDINGS: Manual scoring showed high interobserver reproducibility (intraclass correlation coefficient 0·84 [95% CI 0·79-0·88]). Concordance between manual and automated methods was modest. AI-based scoring (AI percentage lymphocytes) reclassified 120 (11·6%) of 1035 node-positive tumours from immune-low (by manual scoring) to immune-high; this subgroup of patients showed greater separation of 5-year invasive disease-free survival curves between pertuzumab and placebo groups compared with patients whose tumours were concordantly classified as immune-low by both manual and AI-based approaches. Higher levels of TILs were associated with improved invasive disease-free survival for all sTIL measurement approaches and spatial measurements (hazard ratios [HRs] 0·41-0·93). Pertuzumab was associated with improved invasive disease-free survival at higher sTIL levels across all measurement approaches (HRs 0·36-0·48), but was not associated with higher values of spatial measures. The largest 6-year absolute improvements with pertuzumab were observed in patients with node-positive disease whose tumours scored in the highest level of immune infiltration of manual sTIL scoring (≥70·0%; mean absolute improvement 12·1 percentage points [SD 2·8]). In nested prognostic and predictive models, AI-based immune hotspot scores provided the most consistent additional information when combined with any sTIL measurement (all p<0·010). INTERPRETATION: Standardised manual sTIL scoring was reproducible, and digital and AI-based methods showed consistent prognostic stratification and potential for treatment-benefit stratification despite only modest correlation between platforms. AI spatial metrics provided complementary information beyond sTIL density and could support more scalable immune assessment. Future studies are needed to validate these approaches in independent cohorts and to clarify their clinical utility for stratifying contemporary HER2-directed therapies. FUNDING: None.

Humans↗