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Introduction: The IL-12-IFNγ-Th1 and the IL-6-IL-23-Th17 axes are considered the dominant pathogenic pathways in Giant Cell Arteritis (GCA). Both pathways signal via activation of the downstream JAK/STAT proteins. We hypothesized that phosphorylated STAT (pSTAT) signatures in circulating immune cells may aid to stratify GCA-patients for personalized treatment., Methods: To investigate pSTAT expression, PBMCs from treatment-naive GCA-patients (n = 18), infection controls (INF, n = 11) and age-matched healthy controls (HC, n = 15) were stimulated in vitro with IL-6, IL-2, IL-10, IFN-γ, M-CSF or GM-CSF, and stained with CD3, CD4, CD19, CD45RO, pSTAT1, pSTAT3, pSTAT5 antibodies, and analyzed by flow cytometry. Serum IL-6, sIL-6-receptor and gp130 were measured by Luminex. The change in percentages of pSTAT3+CD4+T-cells was evaluated at diagnosis and at 3 months and 1-year of follow-up. Kaplan-Meier analyses was used to asses prognostic accuracy., Results: Analysis of IL-6 stimulated immune cell subsets revealed a significant decrease in percentages of pSTAT3+CD4+T-cells of GCA-patients and INF-controls compared to HCs. Following patient stratification according to high (median>1.5 pg/mL) and low (median<1.5 pg/mL) IL-6 levels, we observed a reduction in the pSTAT3 response in GCA-patients with high serum IL-6. Percentages of pSTAT3+CD4+T-cells in patients with high serum IL-6 levels at diagnosis normalized after glucocorticoid (GC) treatment. Importantly, we found that patients with low percentages of pSTAT3+CD4+T-cells at baseline require longer GC-treatment., Conclusion: Overall, in GCA, the percentages of in vitro IL-6-induced pSTAT3+CD4+T-cells likely reflect prior in vivo exposure to high IL-6 and may serve as a prognostic marker for GC-treatment duration and may assist improving personalized treatment options in the future., Competing Interests: Declaration of competing interest The other authors have declared nothing to disclose., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Giant cell arteritis (GCA) is an immune-mediated large-vessels vasculitis with complex etiology. Although the pathogenic mechanisms remain poorly understood, a central role for CD4 + T cells has been demonstrated. In this context, understanding the transcriptome dysregulation in GCA CD4 + T cells will yield new insights into its pathogenesis., Methods: Transcriptome analysis was conducted on CD4 + T cells from 70 patients with GCA with different disease activity and treatment status (active patients before treatment and patients in remission with and without glucocorticoid treatment), and 28 healthy controls. The study also evaluated potential impacts of DNA methylation on gene expression alterations and assessed cross-talk with CD14 + monocytes., Results: This study has uncovered a substantial number of genes and pathways potentially contributing to the pathogenicity of CD4 + T cells in GCA. Specifically, CD4 + T cells from GCA patients with active disease exhibited altered expression levels of genes involved in multiple immune-related processes, including various interleukins (IL) signaling pathways. Notably, IL-2, a decisive interleukin for regulatory T cells homeostasis, was among the most significant. Additionally, impaired apoptotic pathways appear crucial in GCA development. Our findings also suggest that histone-related epigenetic pathways may be implicated in promoting an inflammatory phenotype in GCA active patients. Finally, our study observed altered signaling communication, such as the Jagged-Notch signaling, between CD4 + T cells and monocytes that could have pathogenic relevance in GCA., Conclusions: Our study suggests the participation of novel cytokines and pathways and the occurrence of a disruption of monocyte-T cell crosstalk driving GCA pathogenesis., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: In giant cell arteritis, vessel-wall infiltrating CD4 T cells and macrophages form tissue-destructive granulomatous infiltrates, and the artery responds with a maladaptive response to injury, leading to intramural neoangiogenesis, intimal hyperplasia, and luminal occlusion. Lesion-residing T cells receive local signals, which represent potential therapeutic targets., Objectives: The authors examined how CD28 signaling affects vasculitis induction and maintenance, and which pathogenic processes rely on CD28-mediated T-cell activation., Methods: Vasculitis was induced by transferring peripheral blood mononuclear cells from giant cell arteritis patients into immunodeficient NSG mice engrafted with human arteries. Human artery-NSG chimeras were treated with anti-CD28 domain antibody or control antibody. Treatment effects and immunosuppressive mechanisms were examined in vivo and in vitro applying tissue transcriptome analysis, immunohistochemistry, flow cytometry, and immunometabolic analysis., Results: Blocking CD28-dependent signaling markedly reduced tissue-infiltrating T cells and effectively suppressed vasculitis. Mechanistic studies implicated CD28 in activating AKT signaling, T-cell proliferation and differentiation of IFN-γ and IL-21-producing effector T cells. Blocking CD28 was immunosuppressive by disrupting T-cell metabolic fitness; specifically, the ability to utilize glucose. Expression of the glucose transporter Glut1 and of glycolytic enzymes as well as mitochondrial oxygen consumption were all highly sensitive to CD28 blockade. Also, induction and maintenance of CD4 + CD103 + tissue-resident memory T cells, needed to replenish the vasculitic infiltrates, depended on CD28 signaling. CD28 blockade effectively suppressed vasculitis-associated remodeling of the vessel wall., Conclusions: CD28 stimulation provides a metabolic signal required for pathogenic effector functions in medium and large vessel vasculitis. Disease-associated glycolytic activity in wall-residing T-cell populations can be therapeutically targeted by blocking CD28 signaling., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Rationale: Giant cell arteritis (GCA)-a primary vasculitis of medium and large arteries-is associated with vessel wall damage, elastic membrane fragmentation, and vascular remodeling. Proteinases are believed to contribute to pathogenesis by degrading extracellular matrix and causing tissue injury., Objective: The MMP (matrix metalloproteinase)-9-a type IV collagenase-is produced in the vasculitic lesions of GCA. It is unknown which pathogenic processes are MMP-9 dependent., Methods and Results: The tissue transcriptome of GCA-affected temporal arteries contained high amounts of MMP-9 transcripts, and immunostaining for pro-MMP-9 localized the enzyme to wall-infiltrating macrophages. MMP-2 and MMP-9 transcripts were also abundant in monocytes and monocyte-derived macrophages from patients with GCA. Patient-derived monocytes outperformed healthy monocytes in passing through engineered basement membranes. GCA CD (cluster of differentiation) 4 + T cells required MMP-9-producing monocytes to penetrate through matrix built from type IV collagen. In vivo functions of MMP-9 were tested in a human artery-SCID (severe combined immunodeficiency) chimera model by blocking enzyme activity with a highly specific monoclonal antibody or by injecting rMMP-9 (recombinant MMP-9). Inhibiting MMP-9 activity profoundly suppressed vascular injury, decreased the density of inflammatory infiltrates ( P<0.001), reduced intramural neoangiogenesis ( P<0.001), and prevented intimal layer hyperplasia ( P<0.001). rMMP-9 amplified all domains of vasculitic activity, promoted assembly of T-cell infiltrates ( P<0.05), intensified formation of new microvessels ( P<0.001), and worsened intimal thickening ( P<0.001). Systemic delivery of N-acetyl-proline-glycine-proline-a matrikine produced by MMP-9-mediated gelatinolysis-had limited vasculitogenic effects., Conclusions: In large vessel vasculitis, MMP-9 controls the access of monocytes and T cells to the vascular wall. T cells depend on MMP-9-producing monocytes to pass through collagen IV-containing basement membrane. Invasion of vasculitogenic T cells and monocytes, formation of neoangiogenic networks, and neointimal growth all require the enzymatic activity of MMP-9, identifying this protease as a potential therapeutic target to restore the immunoprivilege of the arterial wall in large vessel vasculitis.

Background: Giant cell arteritis (GCA) is the most common form of vasculitis affecting elderly people. It is one of the few true ophthalmic emergencies but symptoms and signs are variable thereby making it a challenging disease to diagnose. A temporal artery biopsy is the gold standard to confirm GCA, but there are currently no specific biochemical markers to aid diagnosis. We aimed to identify a less invasive method to confirm the diagnosis of GCA, as well as to ascertain clinically relevant predictive biomarkers by studying the transcriptome of purified peripheral CD4+ and CD8+ T lymphocytes in patients with GCA., Methods: We recruited 16 patients with histological evidence of GCA at the Royal Victorian Eye and Ear Hospital, Melbourne, Australia, and aimed to collect blood samples at six time points: acute phase, 2-3 weeks, 6-8 weeks, 3 months, 6 months and 12 months after clinical diagnosis. CD4+ and CD8+ T-cells were positively selected at each time point through magnetic-assisted cell sorting. RNA was extracted from all 195 collected samples for subsequent RNA sequencing. The expression profiles of patients were compared to those of 16 age-matched controls., Results: Over the 12-month study period, polynomial modelling analyses identified 179 and 4 statistically significant transcripts with altered expression profiles (FDR < 0.05) between cases and controls in CD4+ and CD8+ populations, respectively. In CD8+ cells, two transcripts remained differentially expressed after 12 months; SGTB, associated with neuronal apoptosis, and FCGR3A, associatied with Takayasu arteritis. We detected genes that correlate with both symptoms and biochemical markers used for predicting long-term prognosis. 15 genes were shared across 3 phenotypes in CD4 and 16 across CD8 cells. In CD8, IL32 was common to 5 phenotypes including Polymyalgia Rheumatica, bilateral blindness and death within 12 months., Conclusions: This is the first longitudinal gene expression study undertaken to identify robust transcriptomic biomarkers of GCA. Our results show cell type-specific transcript expression profiles, novel gene-phenotype associations, and uncover important biological pathways for this disease. In the acute phase, the gene-phenotype relationships we have identified could provide insight to potential disease severity and as such guide in initiating appropriate patient management.

Objectives: Guidelines for preventing Pneumocystis pneumonia (PCP) in HIV patients are based on CD4 below 200/mm3. Such cut-off value is suggested to guide prophylaxis in non-HIV conditions (NHIV) especially in autoimmune and inflammatory diseases (AD). We aimed to determine if CD4 could be used to guide PCP prophylaxis in AD., Methods: CD4 and lymphocyte-count were retrospectively studied in patients diagnosed with PCP between January 2013 and February 2016., Results: 129 patients were included. The median CD4-count was 302/mm3 in AD, which was significantly higher than in HIV patients (19/mm3; p<0.0001). Fifty percent (n=10) of AD patients had CD4 counts greater than 300/mm3., Conclusions: Prophylaxis for PCP cannot rely solely on CD4-count in NHIV patients especially in AD.

Giant cell arteritis (GCA) is the most common vasculitis in adults affecting large and medium-sized arteries. IL-6 and T cell accumulation within the arterial wall contribute to the pathogenesis of GCA, and blockade of IL-6 activity is efficacious in its treatment. We examined the relationship between levels of IL-6 expression and immunological processes that control the expansion of T cells in GCA-positive temporal artery biopsies. CD4 T cells accumulated in clusters within the media and deep intima of all GCA lesions. There was a significant positive correlation between the expression of IL-6 mRNA and increased frequency of proliferating CD4 T cells. The expansion of T cells can be inhibited by T regs but IL-6 expression was not correlated with differences in T reg accumulation. Increased IL-6 levels were also significantly correlated with lower frequencies of CD4 T cells undergoing apoptotic cell death. In conclusion, IL-6 may contribute to the accumulation of CD4 T cells in GCA by supporting their proliferation and survival within the arterial wall through mechanisms that are independent of effects on local T reg expansion., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Giant cell arteritis is an autoimmune disease defined by explicit tissue tropism to the walls of medium and large arteries. Pathognomic inflammatory lesions are granulomatous in nature, emphasizing the functional role of CD4T cells and macrophages. Evidence for a pathogenic role of antibodies and immune complexes is missing. Analysis of T cell populations in giant cell arteritis, both in the tissue lesions and in the circulation, has supported a model of broad, polyclonal T cell activation, involving an array of functional T cell lineages. The signature of T cell cytokines produced by vasculitic lesions is typically multifunctional, including IL-2, IFN-γ, IL-17, IL-21, and GM-CSF, supportive for a general defect in T cell regulation. Recent data describing the lack of a lymph node-based population of anti-inflammatory T cells in giant cell arteritis patients offers a fresh look at the immunopathology of this vasculitis. Due to defective CD8 + NOX2 + regulatory T cells, giant cell arteritis patients appear unable to curtail clonal expansion within the CD4T cell compartment, resulting in widespread CD4T cell hyperimmunity. Why unopposed expansion of committed CD4 effector T cells would lead to invasion of the walls of medium and large arteries needs to be explored in further investigations., (Copyright © 2016 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.)

Giant cell arteritis (GCA) is a granulomatous vasculitis of the aorta and its medium-sized branch vessels. CD4 T cells, macrophages, and dendritic cells (DCs) build granulomatous infiltrates that injure the vessel wall and elicit a maladaptive response to injury. Pathological consequences include fragmentation of elastic membranes, destruction of the medial layer, microvascular neoangiogenesis, massive outgrowth of myofibroblasts, and lumen-occlusive intimal hyperplasia. Antigens have been suspected to drive the local activation of vasculitogenic CD4 T cells, but recent data have suggested a more generalized defect in the threshold setting of such T cells, rendering them hyperreactive. Under physiological conditions, immune checkpoints provide negative signals to curb T cell activation and prevent inflammation-associated tissue destruction. This protective mechanism is disrupted in GCA. Vessel wall DCs fail to express the immunoinhibitory ligand programmed cell death ligand-1, leaving lesional T cells unchecked. Consequently, programmed cell death protein-1-positive CD4 T cells can enter the immunoprivileged vessel wall, where they produce a broad spectrum of inflammatory cytokines (interferon-γ, IL-17, and IL-21) and have a direct role in driving intimal hyperplasia and intramural neoangiogenesis. The deficiency of the programmed cell death protein-1 immune checkpoint in GCA, promoting unopposed T cell immunity, contrasts with checkpoint hyperactivity in cancer patients in whom excessive programmed cell death ligand-1 expression paralyzes the function of antitumor T cells. Excessive checkpoint activity is the principle underlying cancer-immune evasion and is therapeutically targeted by immunotherapy with checkpoint inhibitors. Such checkpoint inhibitors, which unleash anticancer T cells and induce immune-related toxicity, may lead to drug-induced vasculitis., (Copyright © 2017 the American Physiological Society.)

Immune aging results in progressive loss of both protective immunity and T cell-mediated suppression, thereby conferring susceptibility to a combination of immunodeficiency and chronic inflammatory disease. Here, we determined that older individuals fail to generate immunosuppressive CD8+CCR7+ Tregs, a defect that is even more pronounced in the age-related vasculitic syndrome giant cell arteritis. In young, healthy individuals, CD8+CCR7+ Tregs are localized in T cell zones of secondary lymphoid organs, suppress activation and expansion of CD4 T cells by inhibiting the phosphorylation of membrane-proximal signaling molecules, and effectively inhibit proliferative expansion of CD4 T cells in vitro and in vivo. We identified deficiency of NADPH oxidase 2 (NOX2) as the molecular underpinning of CD8 Treg failure in the older individuals and in patients with giant cell arteritis. CD8 Tregs suppress by releasing exosomes that carry preassembled NOX2 membrane clusters and are taken up by CD4 T cells. Overexpression of NOX2 in aged CD8 Tregs promptly restored suppressive function. Together, our data support NOX2 as a critical component of the suppressive machinery of CD8 Tregs and suggest that repairing NOX2 deficiency in these cells may protect older individuals from tissue-destructive inflammatory disease, such as large-vessel vasculitis.

Giant cell arteritis (GCA) is a granulomatous large-vessel vasculitis that usually affects the aorta and/or its major branches, especially the branches of the carotid arteries. Histo-pathological lesions are observed in all layers of the artery leading to segmental and focal panarteritis with a polymorphic cell infiltrate that includes T cells, macrophages and multinucleated giant cells, a fragmented internal elastic lamina and intimal hyperplasia. The pathophysiology of GCA is complex and not fully understood. In this review, we discuss the immunological aspects of GCA pathogenesis with a particular emphasis on T cell responses. Upon dendritic cell activation in the adventitia, CD4 T cells co-expressing CD161 are recruited in the arterial wall and polarised into Th1 and Th17 cells that produce IFN-γ and IL-17, respectively. These cytokines activate macrophages, giant cells and vascular smooth muscle cells, thus inducing vascular remodelling which leads to the ischaemic manifestations of GCA. Macrophages infiltrating the adventitia produce IL-1β and IL-6, which are responsible for the general symptoms encountered in GCA.

Giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) are linked conditions that occur in the elderly. GCA is a vasculitis of large- and medium-sized vessels causing critical ischemia. It is a medical emergency owing to the high incidence of neuro-ophthalmic complications. PMR is an inflammatory disease characterized by abrupt-onset pain and stiffness of the shoulder and pelvic girdle muscles. Both conditions are associated with a systemic inflammatory response and constitutional symptoms. The pathogeneses are unclear. The initiating step may be the recognition of an infectious agent by activated dendritic cells. The key cell type involved is CD4(+) T cells and the key cytokines are IFN-γ (implicated in granuloma formation) and IL-6 (key to the systemic response). The pathogenesis of PMR may be similar to that of GCA, however, PMR exhibits less clinical vascular involvement. The mainstay of therapy is corticosteroids, and disease-modifying therapy is indicated in relapsing disease. This article reviews recent guidelines on early recognition, investigations and management of these diseases, as well as advances in imaging.

The aim of the study was to investigate T cell receptor (TCR) usage at the time of diagnosis of giant cell arteritis (GCA) and to estimate the degree of clonality of T-cells infiltrating the lesion. Seven patients with biopsy-proven giant cell arteritis were included in the study. Immunocytochemistry in biopsies from the temporal arteries and flow cytometric analysis of peripheral blood lymphocytes (PBL) was performed using monoclonal antibodies specific for CD3, CD4 and CD8 and 13 TCR Valpha and Vbeta gene segment products. The CDR3 fragment length polymorphism was assessed by gel electrophoresis of PCR-amplified TCR segments. The T lymphocytes were found to be concentrated to the adventitia rather than the media or intima. Six of the seven patients with GCA had expansions of T lymphocytes, expressing selected TCR V genes in the arterial wall. None of these expansions was found in PBL. The infiltrating T-cells were poly- or oligoclonal. In conclusion, the dominating part of the inflammatory infiltrate in GCA emanates from the adventitial microvessels. There is an uneven expression of TCR V genes by T lymphocytes in the inflammatory infiltrates as compared to peripheral blood T lymphocytes at the time of diagnosis, consistent with an antigen-driven immunological reaction in the arterial wall.

The aim of the present study was to investigate the expression of TP53 (p53) and CDKN1A (CIP1; p21) in the arterial wall in giant cell arteritis (GCA). Cross-sections from 18 temporal artery biopsies displaying GCA and 8 control arteries were double-stained with monoclonal antibody directed at p53 or p21 on the one hand and alpha-smooth muscle actin, CD68 (macrophage) or CD3 (T-cell) on the other. Nuclear p53 was expressed in CD68-positive cells and smooth muscle cells in 16 of the 18 inflamed arteries. P21-positive nuclei were found in CD68-positive cells in 14 biopsies and in smooth muscle cells in all the specimens. All p53-positive giant cells also contained p21-positive nuclei. In the giant cells, immunopositive nuclei were mixed with negative ones. CD3-positive T-cells did not express p53 or p21. Only one p53-positive smooth muscle cell nucleus was found in the non-GCA controls and, compared with GCA, p21 expression was noted in few smooth muscle nuclei. The presence of p53 and p21 in the same types of cell in GCA indicates that the former protein is functional; p21 expression is induced by wild-type, functional p53 but not by its mutant form. The current observations suggest cellular stress in GCA, the nature of which requires further investigation.

Objective: Giant cell arteritis (GCA) is a vasculitis predominantly affecting medium- and large-sized arteries. Recent data show the co-localization of dendritic cells and Chlamydia pneumoniae in vascular biopsies from GCA patients. Here we define the topographical relation of dendritic cells and these activated T-cells to determine the antigen presenting cell in GCA, and to examine several auxiliary biochemical and genetic aspects relating to the role of bacteria such as C. pneumoniae in eliciting GCA., Methods: 18 paraffin-embedded temporal artery biopsy specimens from 14 patients with GCA that were PCR-positive for C. pneumoniae were examined by two-color immunohistochemistry for the topographical relationship between dendritic cells and activated T-cells. In addition the presence of GTP-binding proteins. Tumor necrosis factor alpha (TNF alpha), and Toll-like receptor 4 (TLR4) was investigated. 15 temporal artery specimens from 10 patients without GCA served as controls., Results: In all GCA specimens, dendritic cells co-localized in the immediate vicinity of activated CD4+ Talin-expressing T cells, and these were predominantly found in granulomatous infiltrates. Confocal microscopy confirmed the cell-cell contact of dendritic cells with activated T cells. Results further showed that RhoA and Rac1 were predominantly present in the region of granulomatous infiltrates. TNF alpha production and expression was found in dendritic cells and macrophages, predominantly in granulomatous infiltrates and in endothelial cells of the vasa vasorum dispersed in the adventitial and medial layers of the temporal artery. No control specimens showed TNF alpha expression. More than 95% of dendritic cells were positive for TLR4; macrophages and endothelial cells localized in the adventitia showed TLR4 production., Conclusions: The immediate co-localization of dendritic cells and activated T cells indicate a high probability that the former represent the antigen presenting cells in GCA. In addition, because of the presence of Rho A and Rac1 in the granulomatous infiltrates, we speculate that they provide the right environment for cell-cell contact and adhesion, and that they may promote the internalization of bacteria. TNF alpha is expressed at high levels in the granulomatous infiltrates of temporal artery specimens from patients with GCA. Since TLR4 is produced in the same cell types, and predominantly in the adventitial layer of the temporal artery, we suggest that these receptors are coupled to signal transduction pathways that control TNF alpha expression.

Objective: To investigate T cell receptor (TCR) V alpha/V beta (and in selected cases, J beta) usage in CD4+ and CD8+ peripheral blood lymphocytes of patients with giant cell arteritis (GCA), before and after treatment, as well as to analyze the HLA types of these patients., Methods: Flow cytometry, with 10 anti-TCR V-specific monoclonal antibodies (MAb), was used. To analyze J beta usage by cell populations expressing certain V beta, we used the polymerase chain reaction (PCR) technique, with V beta- and C beta-specific primers, Southern blotting of PCR products, and subsequent hybridization with radiolabeled J beta-specific probes. HLA typing was performed using the microlymphocytotoxicity technique., Results: Seven of the 9 GCA patients had increased anti-TCR V MAb reactivities (interpreted as T cell expansions), which in many cases, correlated with clinical signs of disease. A strict preference for particular J beta segments was found in 3 of 3 expanded CD4+ T cell populations., Conclusion: T lymphocytes expressing specific antigen receptors are implicated in the pathogenesis of GCA.