Materiały źródłowe

• #1 Giant Cell Arteritis (Temporal Arteritis) – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK459376/

  Giant cell arteritis (GCA) is a chronic inflammatory vasculitis that predominantly affects large- and medium-sized arteries in individuals older than 50. This complex disorder commonly involves the cranial branches of the carotid arteries. The granulomatous nature of GCA contributes to the loss of vascular smooth muscle cells and elastic fibers, potentially leading to aneurysm formation and vascular remodeling. Intimal hyperplasia and lumen occlusion contribute to ischemic complications. […] GCA is a granulomatous vasculitis believed to occur as an immune-mediated disease leading to the activation of vascular dendritic cells. Activated dendritic cells produce chemokines, such as granulocyte-macrophage colony-stimulating factor, that attract and retain dendritic cells, lymphocytes, and macrophages. Upon activation, dendritic cells process and present antigens, expressing activation markers, major histocompatibility complex class II, and costimulatory molecules essential for antigen presentation and T-cell activation.

• #2 Temporal Arteritis Pathology: Definition, Epidemiology, Etiology

  https://emedicine.medscape.com/article/1612591-overview

  Temporal arteritis, also known as giant cell arteritis and cranial arteritis, is a chronic granulomatous inflammatory systemic vasculitis affecting small-sized, medium-sized, and large-sized arteries, primarily the superficial temporal arteries. […] Vascular-related symptoms arise secondary to arterial inflammation with luminal stenosis, occlusion, aneurysms, and resultant end-organ ischemia. […] Temporal arteritis occurs in three histologic patterns: classic, atypical, and healed. Classical histological findings include evidence of inflammation (arteritis) involving all three layers of the arterial wall (adventitia, media, and lamina) with fragmentation and disruption of the internal elastic lamina and a giant cell granuloma formation in its proximity. […] Both cellular and humoral immune systems contribute to the immunopathology of giant cell arteritis (GCA). Key events include the activation of vascular dendritic cells located in the adventitia-media junction, which trigger immune responses by presenting antigens and recruiting CD4+T helper cells to the vessel wall.

• #3 Pathogenesis of giant cell arteritis – UpToDate

  https://www.uptodate.com/contents/pathogenesis-of-giant-cell-arteritis

  Pathogenesis of giant cell arteritis […] Histopathology and immunopathology studies reveal inflammation of the artery wall with predominance of CD4+ T lymphocytes and macrophages, which frequently undergo granulomatous organization with formation of giant cells. […] There is a remarkable loss of vascular smooth muscle cells (VSMC) and elastic fibers that may eventually facilitate aneurysm formation. Inflammation-induced vascular remodeling leads to intimal hyperplasia and lumen occlusion, the source of the ischemic complications of the disease. […] The pathogenesis of GCA is incompletely understood. The current pathogenic model has been largely built on immunopathology and molecular studies performed with temporal artery biopsies. […] The role of particular cells, molecules, or pathways has been investigated in temporal artery biopsy xenografts into severe combined immunodeficiency (SCID) mice or in ex vivo cultured arteries. […] Clinical trials with targeted therapies are providing proof of concept about the relevance of specific pathways in the pathogenesis of vascular inflammation. […] Epidemiologic studies demonstrate predominance in older adults, females, and individuals of Northern European ancestry. Occasional family clustering has been reported. These data strongly suggest that senescence, sex, and genetic background all contribute to the pathogenesis of giant cell arteritis (GCA).

• #4 New Insights into the Pathogenesis of Giant Cell Arteritis: Mechanisms Involved in Maintaining Vascular Inflammation

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9143803/

  The giant cell arteritis (GCA) pathophysiology is complex and multifactorial, involving a predisposing genetic background, the role of immune aging and the activation of vascular dendritic cells by an unknown trigger. […] Once activated, dendritic cells recruit CD4 T cells and induce their activation, proliferation and polarization into Th1 and Th17, which produce interferon-gamma (IFN-) and interleukin-17 (IL-17), respectively. […] Recent data have shown that IL-17, IFN- and GM-CSF induce the differentiation of macrophage subpopulations, which play a role in the destruction of the arterial wall, in neoangiogenesis or intimal hyperplasia. […] Under the influence of different mediators, mainly endothelin-1 and PDGF, vascular smooth muscle cells migrate to the intima, proliferate and change their phenotype to become myofibroblasts that further proliferate and produce extracellular matrix proteins, increasing the vascular stenosis.

• #5 Pathogenesis of giant cell arteritis – UpToDate

  https://www.uptodate.com/contents/pathogenesis-of-giant-cell-arteritis

  Pathogenesis of giant cell arteritis […] Histopathology and immunopathology studies reveal inflammation of the artery wall with predominance of CD4+ T lymphocytes and macrophages, which frequently undergo granulomatous organization with formation of giant cells. […] There is a remarkable loss of vascular smooth muscle cells (VSMC) and elastic fibers that may eventually facilitate aneurysm formation. Inflammation-induced vascular remodeling leads to intimal hyperplasia and lumen occlusion, the source of the ischemic complications of the disease. […] The pathogenesis of GCA is incompletely understood. The current pathogenic model has been largely built on immunopathology and molecular studies performed with temporal artery biopsies. […] The role of particular cells, molecules, or pathways has been investigated in temporal artery biopsy xenografts into severe combined immunodeficiency (SCID) mice or in ex vivo cultured arteries. […] Clinical trials with targeted therapies are providing proof of concept about the relevance of specific pathways in the pathogenesis of vascular inflammation. […] Epidemiologic studies demonstrate predominance in older adults, females, and individuals of Northern European ancestry. Occasional family clustering has been reported. These data strongly suggest that senescence, sex, and genetic background all contribute to the pathogenesis of giant cell arteritis (GCA).

• #6 Giant Cell Arteritis – EyeWiki

  https://eyewiki.org/Giant_Cell_Arteritis

  Giant cell arteritis (GCA) is the most common primary vasculitis in adults. Histopathologically, GCA is marked by generalized granulomatous inflammation of medium- to large-sized vessels that occurs in the elderly. […] There is a significant amount of research and discussion regarding the underlying etiology, pathogenesis, and appropriate management of patients with GCA. […] The underlying etiology of GCA is complex and has been widely researched, yet is still not well understood. This includes genetic and possibly infectious factors, which go on to trigger an immune response. […] A genetic predisposition for GCA has been suspected, due to increased reports of GCA among first degree relatives and rare familial forms of GCA. […] Certain genes within the human leukocyte antigen (HLA) class I and class II regions, specifically, HLA DRB1*04, DRW6, and DR3 have been associated with increased susceptibility to GCA as well.

• #7 Giant Cell Arteritis – EyeWiki

  https://eyewiki.org/Giant_Cell_Arteritis

  Giant cell arteritis (GCA) is the most common primary vasculitis in adults. Histopathologically, GCA is marked by generalized granulomatous inflammation of medium- to large-sized vessels that occurs in the elderly. […] There is a significant amount of research and discussion regarding the underlying etiology, pathogenesis, and appropriate management of patients with GCA. […] The underlying etiology of GCA is complex and has been widely researched, yet is still not well understood. This includes genetic and possibly infectious factors, which go on to trigger an immune response. […] A genetic predisposition for GCA has been suspected, due to increased reports of GCA among first degree relatives and rare familial forms of GCA. […] Certain genes within the human leukocyte antigen (HLA) class I and class II regions, specifically, HLA DRB1*04, DRW6, and DR3 have been associated with increased susceptibility to GCA as well.

• #8 Temporal Arteritis Pathology: Definition, Epidemiology, Etiology

  https://emedicine.medscape.com/article/1612591-overview

  Proinflammatory cytokine IL-6, responsible for the exaggerated acute phase of the immune response, is implicated in high levels of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). […] On the basis of its familial, ethnic, and geographic distribution, temporal arteritis appears to have a genetic predisposition. […] Most genetic factors center on the human leukocyte antigen (HLA) genes. […] It is likely that various HLA alleles predispose to temporal arteritis and mediate its severity. […] The precise role of genetic susceptibility in the pathogenesis of temporal arteritis remains unclear and requires further investigation.

• #9 Giant Cell Arteritis – EyeWiki

  https://eyewiki.org/Giant_Cell_Arteritis

  These genes encode amino acids in the antigen-binding pocket of the HLA molecule, which suggests that the disease may be antigen-driven and further highlights the role of adaptive immunity in the pathogenesis. […] After the initial trigger, regardless of etiology, a dual immune response begins. One involves a systemic inflammatory reaction and the other is a maladaptive, antigen-specific immune response. […] The systemic inflammatory reaction results from over-activation of the innate acute phase response: a non-antigen-driven, non-adaptive defense mechanism to overall stress and injury. […] GCA preferentially affects three-layered vessels. These layers include an outer adventitia, a muscular medial layer, and an elastic lamina separating the inner intimal layer. The primary site of injury is in the adventitial layer.

• #10 Giant Cell Arteritis (Temporal Arteritis): Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/332483-overview

  Giant cell arteritis (GCA) is primarily a disease of cell-mediated immunity, which is thought to arise as a maladaptive response to endothelial injury. Actinic damage to the temporal artery from chronic sun exposure has been proposed as one source of the injury. […] The primary inflammatory response involves the activation of dendritic cells in the adventitia of arteries by an unknown antigen, with production of chemokines that recruit CD4+T helper cells. Activated CD4+ T helper cells polarize into Th1 cells (producing interferon gamma) and Th17 cells (producing interleukin 17). […] Interferon gamma causes endothelial cells and vascular smooth muscle to recruit more Th1 cells, CD8+ T cells, and monocytes. The monocytes differentiate into macrophages and the characteristic giant cells that produce growth factors, other interleukins and proteolytic enzymes that progressively narrow and obstruct the vessel wall.

• #11 Research in Temporal Arteritis Suggests Link with Infection, Autoimmune Disease – The Rheumatologist

  https://www.the-rheumatologist.org/article/research-in-temporal-arteritis-suggests-link-with-infection-autoimmune-disease/

  Temporal arteritis is now recognized to be a form of the medium- to large-vessel arteritis named giant cell arteritis (GCA) because of characteristic giant cells seen on histology. […] The pathologic features, however, dont provide an etiology. […] In the May 12, 2015, issue of Neurology, Don Gilden, MD, professor of neurology at the University of Colorado in Aurora, and colleagues published provocative evidence that varicella zoster virus (VZV) may trigger GCA. […] Strikingly, immunohistochemical analysis of the arterial wall for VZV gE antigen (produced in infected cells) was positive in 74% of the GCA cases compared with only one positive finding in the control arteries. […] GCA pathology in 89% of cases tended to be adjacent to regions containing the VZV antigen. […] VZV DNA was detected using polymerase chain reaction (PCR) in 40% of the lesions that were positive using immunohistochemistry. […] Electron microscopy on a single specimen showed enveloped viral particles within the vessel wall.

• #12 Giant cell arteritis: pathogenic mechanisms and new potential therapeutic targets | BMC Rheumatology | Full Text

  https://bmcrheumatol.biomedcentral.com/articles/10.1186/s41927-017-0004-5

  The immunopathology of GCA appears to originate from a dysregulated interaction between the vessel wall and both the innate and adaptive immune systems. […] Activated vasDCs are able to attract and activate T lymphocytes and macrophages through production of specific chemokine and cytokine signatures, providing a microenvironment necessary for initiating and sustaining arterial inflammation and granuloma formation. […] GCA is a granulomatous vasculitis and multinucleated giant cells, a key feature of macrophage involvement, are a considered a pathognomonic hallmark of arterial lesions. […] The Th17 pathway appears to be very responsive to treatment and glucocorticoids (GCs) rapidly reduce the Th17 effector cytokine production of IL-1, IL-6, IL-17 and IL-23 with simultaneous depletion of both circulating and tissue infiltrative Th17 cells.

• #13 New Insights into the Pathogenesis of Giant Cell Arteritis: Mechanisms Involved in Maintaining Vascular Inflammation

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9143803/

  In addition, several defects in the immune regulatory mechanisms probably contribute to chronic vascular inflammation in GCA: a defect in the PD-1/PD-L1 pathway, a quantitative and qualitative Treg deficiency, the implication of resident cells, the role of GM-CSF and IL-6, the implication of the NOTCH pathway and the role of mucosal-associated invariant T cells and tissue-resident memory T cells. […] The immunopathological model of GCA can be divided into four main phases. […] Step 1: an undefined danger signal activates vascular dendritic cells (DC) that then acquire a mature phenotype (CD83+CD80/86+CCR7+MHC-IIhigh) and produce chemokines (CCL18, CCL19, CCL20 and CCL21), leading to the recruitment of CCR6+CD161+CD4+ T cells. […] Step 2: CD4+ T cells are activated by DCs and polarize into Th1 and Th17 cells through the effect of IL-12, IL-23, IL-6 and IL-1, which are produced by activated DC.

• #14 New Insights into the Pathogenesis of Giant Cell Arteritis: Mechanisms Involved in Maintaining Vascular Inflammation

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9143803/

  In addition, several defects in the immune regulatory mechanisms probably contribute to chronic vascular inflammation in GCA: a defect in the PD-1/PD-L1 pathway, a quantitative and qualitative Treg deficiency, the implication of resident cells, the role of GM-CSF and IL-6, the implication of the NOTCH pathway and the role of mucosal-associated invariant T cells and tissue-resident memory T cells. […] The immunopathological model of GCA can be divided into four main phases. […] Step 1: an undefined danger signal activates vascular dendritic cells (DC) that then acquire a mature phenotype (CD83+CD80/86+CCR7+MHC-IIhigh) and produce chemokines (CCL18, CCL19, CCL20 and CCL21), leading to the recruitment of CCR6+CD161+CD4+ T cells. […] Step 2: CD4+ T cells are activated by DCs and polarize into Th1 and Th17 cells through the effect of IL-12, IL-23, IL-6 and IL-1, which are produced by activated DC.

• #15 New Insights into the Pathogenesis of Giant Cell Arteritis: Mechanisms Involved in Maintaining Vascular Inflammation

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9143803/

  In addition, several defects in the immune regulatory mechanisms probably contribute to chronic vascular inflammation in GCA: a defect in the PD-1/PD-L1 pathway, a quantitative and qualitative Treg deficiency, the implication of resident cells, the role of GM-CSF and IL-6, the implication of the NOTCH pathway and the role of mucosal-associated invariant T cells and tissue-resident memory T cells. […] The immunopathological model of GCA can be divided into four main phases. […] Step 1: an undefined danger signal activates vascular dendritic cells (DC) that then acquire a mature phenotype (CD83+CD80/86+CCR7+MHC-IIhigh) and produce chemokines (CCL18, CCL19, CCL20 and CCL21), leading to the recruitment of CCR6+CD161+CD4+ T cells. […] Step 2: CD4+ T cells are activated by DCs and polarize into Th1 and Th17 cells through the effect of IL-12, IL-23, IL-6 and IL-1, which are produced by activated DC.

• #16 New Insights into the Pathogenesis of Giant Cell Arteritis: Mechanisms Involved in Maintaining Vascular Inflammation

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9143803/

  Step 3: IFN- induces the activation of vascular smooth muscle cells (VSMC) in the media and enables them to produce chemokines (CCL2, CXCL9, CXCL10, CXCL11), which trigger the recruitment of additional T cells (CD4+ and CD8+) and monocytes. […] Step 4: vascular remodeling is characterized by the destruction of the internal elastic lamina and the proliferation and migration of VSMC into the intima. […] Macrophages play a key role in this process through the release of several factors such as Platelet-Derived Growth Factor (PDGF), reactive oxygen species (ROS), Matrix metalloproteinase-9 (MMP-9), IL-6, IL-1, Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) and TNF-, which contribute to tissue damage and intimal hyperplasia. […] Current knowledge also suggests that IFN-, which is produced by Th1 cells, is the main lymphocytic cytokine inducing vascular remodeling.

• #17 New Insights into the Pathogenesis of Giant Cell Arteritis: Mechanisms Involved in Maintaining Vascular Inflammation

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9143803/

  Step 3: IFN- induces the activation of vascular smooth muscle cells (VSMC) in the media and enables them to produce chemokines (CCL2, CXCL9, CXCL10, CXCL11), which trigger the recruitment of additional T cells (CD4+ and CD8+) and monocytes. […] Step 4: vascular remodeling is characterized by the destruction of the internal elastic lamina and the proliferation and migration of VSMC into the intima. […] Macrophages play a key role in this process through the release of several factors such as Platelet-Derived Growth Factor (PDGF), reactive oxygen species (ROS), Matrix metalloproteinase-9 (MMP-9), IL-6, IL-1, Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) and TNF-, which contribute to tissue damage and intimal hyperplasia. […] Current knowledge also suggests that IFN-, which is produced by Th1 cells, is the main lymphocytic cytokine inducing vascular remodeling.

• #18 Giant Cell Arteritis (Temporal Arteritis) – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK459376/

  T lymphocytes also play an essential role in disease pathogenesis. GCA is characterized by a predominant Th1-immunemediated response with significant expression of interferon- and interleukin-17 (IL-17). Activated vascular dendritic cells residing in the adventitia of large vessels initiate the disease process by recruiting T-cells in the arterial wall, which differentiate into interferon-producing Th1 and IL-17-producing Th17 cells. Subsequently, these cytokines activate macrophages, leading to the proliferation of vascular smooth muscle cells and the formation of giant cells. The macrophages also release IL-1 and IL-6, triggering a systemic inflammatory response responsible for the constitutional symptoms of the disease.

• #19 Giant Cell Arteritis (Temporal Arteritis) – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK459376/

  T lymphocytes also play an essential role in disease pathogenesis. GCA is characterized by a predominant Th1-immunemediated response with significant expression of interferon- and interleukin-17 (IL-17). Activated vascular dendritic cells residing in the adventitia of large vessels initiate the disease process by recruiting T-cells in the arterial wall, which differentiate into interferon-producing Th1 and IL-17-producing Th17 cells. Subsequently, these cytokines activate macrophages, leading to the proliferation of vascular smooth muscle cells and the formation of giant cells. The macrophages also release IL-1 and IL-6, triggering a systemic inflammatory response responsible for the constitutional symptoms of the disease.

• #20 Giant Cell Arteritis (Temporal Arteritis): Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/332483-overview

  Giant cell arteritis (GCA) is primarily a disease of cell-mediated immunity, which is thought to arise as a maladaptive response to endothelial injury. Actinic damage to the temporal artery from chronic sun exposure has been proposed as one source of the injury. […] The primary inflammatory response involves the activation of dendritic cells in the adventitia of arteries by an unknown antigen, with production of chemokines that recruit CD4+T helper cells. Activated CD4+ T helper cells polarize into Th1 cells (producing interferon gamma) and Th17 cells (producing interleukin 17). […] Interferon gamma causes endothelial cells and vascular smooth muscle to recruit more Th1 cells, CD8+ T cells, and monocytes. The monocytes differentiate into macrophages and the characteristic giant cells that produce growth factors, other interleukins and proteolytic enzymes that progressively narrow and obstruct the vessel wall.

• #21 Giant cell arteritis: pathogenic mechanisms and new potential therapeutic targets | BMC Rheumatology | Full Text

  https://bmcrheumatol.biomedcentral.com/articles/10.1186/s41927-017-0004-5

  The immunopathology of GCA appears to originate from a dysregulated interaction between the vessel wall and both the innate and adaptive immune systems. […] Activated vasDCs are able to attract and activate T lymphocytes and macrophages through production of specific chemokine and cytokine signatures, providing a microenvironment necessary for initiating and sustaining arterial inflammation and granuloma formation. […] GCA is a granulomatous vasculitis and multinucleated giant cells, a key feature of macrophage involvement, are a considered a pathognomonic hallmark of arterial lesions. […] The Th17 pathway appears to be very responsive to treatment and glucocorticoids (GCs) rapidly reduce the Th17 effector cytokine production of IL-1, IL-6, IL-17 and IL-23 with simultaneous depletion of both circulating and tissue infiltrative Th17 cells.

• #22 Giant cell arteritis: pathogenic mechanisms and new potential therapeutic targets | BMC Rheumatology | Full Text

  https://bmcrheumatol.biomedcentral.com/articles/10.1186/s41927-017-0004-5

  Despite the effective reduction of the Th17 pathway, a Th1 cell response persists, both in blood samples and arterial specimens from patients treated with high-dose GC. […] The receptor molecule PD-1 provides inhibitory signals by binding to programmed cell death ligand 1 and 2 (PD-L1 and PD-L2), resulting in T cell anergy, apoptosis, or polarization to Tregs. […] Recent transcriptome analysis of temporal arteries positive for GCA has demonstrated an inefficiency of the PD-1/PD-L1 checkpoint. […] The Janus kinasesignal transducers and activators of transcription (JAK-STAT) signalling pathway is involved in cellular regulation and has been implicated in the pathogenesis of several inflammatory and autoimmune conditions, including rheumatoid arthritis, inflammatory bowel disease, and psoriasis.

• #23 New Insights into the Pathogenesis of Giant Cell Arteritis: Mechanisms Involved in Maintaining Vascular Inflammation

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9143803/

  The giant cell arteritis (GCA) pathophysiology is complex and multifactorial, involving a predisposing genetic background, the role of immune aging and the activation of vascular dendritic cells by an unknown trigger. […] Once activated, dendritic cells recruit CD4 T cells and induce their activation, proliferation and polarization into Th1 and Th17, which produce interferon-gamma (IFN-) and interleukin-17 (IL-17), respectively. […] Recent data have shown that IL-17, IFN- and GM-CSF induce the differentiation of macrophage subpopulations, which play a role in the destruction of the arterial wall, in neoangiogenesis or intimal hyperplasia. […] Under the influence of different mediators, mainly endothelin-1 and PDGF, vascular smooth muscle cells migrate to the intima, proliferate and change their phenotype to become myofibroblasts that further proliferate and produce extracellular matrix proteins, increasing the vascular stenosis.

• #24 New Insights into the Pathogenesis of Giant Cell Arteritis: Mechanisms Involved in Maintaining Vascular Inflammation

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9143803/

  The giant cell arteritis (GCA) pathophysiology is complex and multifactorial, involving a predisposing genetic background, the role of immune aging and the activation of vascular dendritic cells by an unknown trigger. […] Once activated, dendritic cells recruit CD4 T cells and induce their activation, proliferation and polarization into Th1 and Th17, which produce interferon-gamma (IFN-) and interleukin-17 (IL-17), respectively. […] Recent data have shown that IL-17, IFN- and GM-CSF induce the differentiation of macrophage subpopulations, which play a role in the destruction of the arterial wall, in neoangiogenesis or intimal hyperplasia. […] Under the influence of different mediators, mainly endothelin-1 and PDGF, vascular smooth muscle cells migrate to the intima, proliferate and change their phenotype to become myofibroblasts that further proliferate and produce extracellular matrix proteins, increasing the vascular stenosis.

• #25 New Insights into the Pathogenesis of Giant Cell Arteritis: Mechanisms Involved in Maintaining Vascular Inflammation

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9143803/

  Step 3: IFN- induces the activation of vascular smooth muscle cells (VSMC) in the media and enables them to produce chemokines (CCL2, CXCL9, CXCL10, CXCL11), which trigger the recruitment of additional T cells (CD4+ and CD8+) and monocytes. […] Step 4: vascular remodeling is characterized by the destruction of the internal elastic lamina and the proliferation and migration of VSMC into the intima. […] Macrophages play a key role in this process through the release of several factors such as Platelet-Derived Growth Factor (PDGF), reactive oxygen species (ROS), Matrix metalloproteinase-9 (MMP-9), IL-6, IL-1, Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) and TNF-, which contribute to tissue damage and intimal hyperplasia. […] Current knowledge also suggests that IFN-, which is produced by Th1 cells, is the main lymphocytic cytokine inducing vascular remodeling.

• #26 Giant Cell Arteritis | Internet Book of Emergency Medicine

  https://internetbookofemergencymedicine.com/temporal-arteritis/

  Exact cause is unknown. […] Thought to be an abnormal immune response to endothelial injury. […] Granulomatous inflammation within the wall layers of medium and large arteries. […] Granulomatous infiltrates are composed of CD4 T cells and highly activated macrophages and multinucleated giant cells. […] Giant cells are a mass formed by the union of several distinct cells (usually histiocytes), often forming a granuloma (clump of macrophages).

• #27 A new era for giant cell arteritis | Eye

  https://www.nature.com/articles/s41433-019-0608-7

  In some patients, IFN- promotes the differentiation and fusion of highly activated macrophages to form multinucleated giant cells. These giant cells also secrete cytokines and growth factors. […] The injured arterial cells respond to damage through dysfunctional repair. This leads to media thickening, luminal occlusion, ischaemia and eventually end organ damage.

• #28 Giant Cell Arteritis | Encyclopedia MDPI

  https://encyclopedia.pub/entry/54742

  Anti-inflammatory M2-type macrophages, on the other hand, tend to localize at the border between the media and vascular intima. […] It should be noted that in GCA, macrophages tend to form special multinucleated cells after fusion of activated cells, so-called giant cells, which are the hallmark of this vasculitis. […] Neutrophils also play an important role in the pathogenesis of GCA. […] Neutrophil activation after stimulation by danger signals results in the local release of pro-inflammatory cytokines, including IL-6 and IL-17A. […] A crucial role in the pathogenesis of GCA is played by dendritic cells (DCs) that reside in the space between the media and adventitia of the arterial wall. […] Once activated, DCs can induce the activation of macrophages with subsequent amplification of the inflammatory cascade.

• #29 Giant Cell Arteritis | Encyclopedia MDPI

  https://encyclopedia.pub/entry/54742

  More recently, based on further experimental evidence, it has been proposed that failure of peripheral tolerance, breakdown of tissue barriers, and granuloma formation constitute successive stages of a single process proceeding from PMR to GCA. […] An international committee recently recommended that the close temporal and pathogenetic correlation between GCA and PMR should be closely considered in a treat-to-target approach. […] Macrophages have been found to infiltrate the arterial wall of patients with GCA. […] These cells of the innate immune system are one of the main cell types involved in granuloma formation and are recruited into the vessel wall by DCs and T cells. […] M1-type macrophages, characterized by high proinflammatory activity, tend to localize between the media and adventitia, amplifying damage to the vascular wall through the production of cytokines IL-1 and IL-6 and of reactive oxygen species (ROS).

• #30 Pathogenesis of giant cell arteritis – UpToDate

  https://www.uptodate.com/contents/pathogenesis-of-giant-cell-arteritis

  Pathogenesis of giant cell arteritis […] Histopathology and immunopathology studies reveal inflammation of the artery wall with predominance of CD4+ T lymphocytes and macrophages, which frequently undergo granulomatous organization with formation of giant cells. […] There is a remarkable loss of vascular smooth muscle cells (VSMC) and elastic fibers that may eventually facilitate aneurysm formation. Inflammation-induced vascular remodeling leads to intimal hyperplasia and lumen occlusion, the source of the ischemic complications of the disease. […] The pathogenesis of GCA is incompletely understood. The current pathogenic model has been largely built on immunopathology and molecular studies performed with temporal artery biopsies. […] The role of particular cells, molecules, or pathways has been investigated in temporal artery biopsy xenografts into severe combined immunodeficiency (SCID) mice or in ex vivo cultured arteries. […] Clinical trials with targeted therapies are providing proof of concept about the relevance of specific pathways in the pathogenesis of vascular inflammation. […] Epidemiologic studies demonstrate predominance in older adults, females, and individuals of Northern European ancestry. Occasional family clustering has been reported. These data strongly suggest that senescence, sex, and genetic background all contribute to the pathogenesis of giant cell arteritis (GCA).

• #31 A new era for giant cell arteritis | Eye

  https://www.nature.com/articles/s41433-019-0608-7

  GCA mainly affects the medium and large arteries of the external cranial branches of the aorta. The pathological process occurring in GCA is summarised below. […] Proceeding from an unknown trigger, there is abnormal maturation of vascular dendritic cells (DC) in the adventitia of the large-vessel walls. These activated DC recruit and activate cluster differentiation (CD) 4+ nave T cells. […] Nave CD4+ cells are activated and differentiate to T helper (Th) 1 cells, Th17 and T regulatory (Treg) cells. […] Macrophages within the tunica adventitia of the vessel wall produce IL-6 and IL-1. Within the tunica media, macrophages secrete metalloproteinases, which degrade the internal elastic lamina and other connective tissue. Reactive oxygen species and secreted IL-6 contribute to inflammation, local vascular damage. Vascular damage and macrophage-derived growth factors such as VEGF and platelet derived growth factor cause intimal hyperplasia and subsequent vascular stenosis and occlusion.

• #32 Giant Cell Arteritis (Temporal Arteritis): Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/332483-overview

  Systemic manifestations are likely related to the inflammatory process and cytokine elaboration. End-organ involvement relates to hyperplasia and occlusion of the arteries serving those organs. […] Concentric intimal hyperplasia is an important underlying pathologic lesion in GCA. Intimal hyperplasia presumably occurs as a repair mechanism in response to injury of the blood vessel wall. […] Platelet-derived growth factor (PDGF) is important in stimulating intimal hyperplasia. In GCA, PDGF derives from macrophages and giant cells, and this distinguishes GCA from other vasculopathies. […] Intimal macrophages also produce vascular endothelial growth factor (VEGF), which promotes intimal proliferation. Medial macrophages generate metalloproteinases, leading to the destruction of vascular elements, including the internal elastic lamina.

• #33 Giant Cell Arteritis (Temporal Arteritis): Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/332483-overview

  Systemic manifestations are likely related to the inflammatory process and cytokine elaboration. End-organ involvement relates to hyperplasia and occlusion of the arteries serving those organs. […] Concentric intimal hyperplasia is an important underlying pathologic lesion in GCA. Intimal hyperplasia presumably occurs as a repair mechanism in response to injury of the blood vessel wall. […] Platelet-derived growth factor (PDGF) is important in stimulating intimal hyperplasia. In GCA, PDGF derives from macrophages and giant cells, and this distinguishes GCA from other vasculopathies. […] Intimal macrophages also produce vascular endothelial growth factor (VEGF), which promotes intimal proliferation. Medial macrophages generate metalloproteinases, leading to the destruction of vascular elements, including the internal elastic lamina.

• #34 Giant Cell Arteritis (Temporal Arteritis): Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/332483-overview

  Systemic manifestations are likely related to the inflammatory process and cytokine elaboration. End-organ involvement relates to hyperplasia and occlusion of the arteries serving those organs. […] Concentric intimal hyperplasia is an important underlying pathologic lesion in GCA. Intimal hyperplasia presumably occurs as a repair mechanism in response to injury of the blood vessel wall. […] Platelet-derived growth factor (PDGF) is important in stimulating intimal hyperplasia. In GCA, PDGF derives from macrophages and giant cells, and this distinguishes GCA from other vasculopathies. […] Intimal macrophages also produce vascular endothelial growth factor (VEGF), which promotes intimal proliferation. Medial macrophages generate metalloproteinases, leading to the destruction of vascular elements, including the internal elastic lamina.

• #35 Giant Cell Arteritis (Temporal Arteritis): Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/332483-overview

  Systemic manifestations are likely related to the inflammatory process and cytokine elaboration. End-organ involvement relates to hyperplasia and occlusion of the arteries serving those organs. […] Concentric intimal hyperplasia is an important underlying pathologic lesion in GCA. Intimal hyperplasia presumably occurs as a repair mechanism in response to injury of the blood vessel wall. […] Platelet-derived growth factor (PDGF) is important in stimulating intimal hyperplasia. In GCA, PDGF derives from macrophages and giant cells, and this distinguishes GCA from other vasculopathies. […] Intimal macrophages also produce vascular endothelial growth factor (VEGF), which promotes intimal proliferation. Medial macrophages generate metalloproteinases, leading to the destruction of vascular elements, including the internal elastic lamina.

• #36 New Insights into the Pathogenesis of Giant Cell Arteritis: Mechanisms Involved in Maintaining Vascular Inflammation

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9143803/

  Step 3: IFN- induces the activation of vascular smooth muscle cells (VSMC) in the media and enables them to produce chemokines (CCL2, CXCL9, CXCL10, CXCL11), which trigger the recruitment of additional T cells (CD4+ and CD8+) and monocytes. […] Step 4: vascular remodeling is characterized by the destruction of the internal elastic lamina and the proliferation and migration of VSMC into the intima. […] Macrophages play a key role in this process through the release of several factors such as Platelet-Derived Growth Factor (PDGF), reactive oxygen species (ROS), Matrix metalloproteinase-9 (MMP-9), IL-6, IL-1, Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) and TNF-, which contribute to tissue damage and intimal hyperplasia. […] Current knowledge also suggests that IFN-, which is produced by Th1 cells, is the main lymphocytic cytokine inducing vascular remodeling.

• #37 New Insights into the Pathogenesis of Giant Cell Arteritis: Mechanisms Involved in Maintaining Vascular Inflammation

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9143803/

  IFN–activated macrophages, giant cells or injured VSMCs produce growth factors, essentially platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF). […] PDGF is implicated in the activation and proliferation of VSMCs and their migration toward the intima, thus resulting in intimal hyperplasia. […] In GCA, VSMCs are injured by mediators released by mononuclear cells, which have accumulated in the media, and acquire pro-inflammatory properties. […] The blockade of the PDGF receptor with imatinib results in a significant decrease in the proliferation of VSMCs from ex vivo cultured temporal arteries. […] ET-1 has also been shown to be implicated in vascular remodeling during GCA. […] The blockade of ET-1 receptors (A and/or B) decreases the migration and proliferation of VSMCs, thus demonstrating that the ET-1 pathway is also implicated in remodeling processes leading to vascular occlusion.

• #38 New Insights into the Pathogenesis of Giant Cell Arteritis: Mechanisms Involved in Maintaining Vascular Inflammation

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9143803/

  IFN–activated macrophages, giant cells or injured VSMCs produce growth factors, essentially platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF). […] PDGF is implicated in the activation and proliferation of VSMCs and their migration toward the intima, thus resulting in intimal hyperplasia. […] In GCA, VSMCs are injured by mediators released by mononuclear cells, which have accumulated in the media, and acquire pro-inflammatory properties. […] The blockade of the PDGF receptor with imatinib results in a significant decrease in the proliferation of VSMCs from ex vivo cultured temporal arteries. […] ET-1 has also been shown to be implicated in vascular remodeling during GCA. […] The blockade of ET-1 receptors (A and/or B) decreases the migration and proliferation of VSMCs, thus demonstrating that the ET-1 pathway is also implicated in remodeling processes leading to vascular occlusion.

• #39 New Insights into the Pathogenesis of Giant Cell Arteritis: Mechanisms Involved in Maintaining Vascular Inflammation

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9143803/

  IFN–activated macrophages, giant cells or injured VSMCs produce growth factors, essentially platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF). […] PDGF is implicated in the activation and proliferation of VSMCs and their migration toward the intima, thus resulting in intimal hyperplasia. […] In GCA, VSMCs are injured by mediators released by mononuclear cells, which have accumulated in the media, and acquire pro-inflammatory properties. […] The blockade of the PDGF receptor with imatinib results in a significant decrease in the proliferation of VSMCs from ex vivo cultured temporal arteries. […] ET-1 has also been shown to be implicated in vascular remodeling during GCA. […] The blockade of ET-1 receptors (A and/or B) decreases the migration and proliferation of VSMCs, thus demonstrating that the ET-1 pathway is also implicated in remodeling processes leading to vascular occlusion.

• #40 New Insights into the Pathogenesis of Giant Cell Arteritis: Mechanisms Involved in Maintaining Vascular Inflammation

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9143803/

  IFN–activated macrophages, giant cells or injured VSMCs produce growth factors, essentially platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF). […] PDGF is implicated in the activation and proliferation of VSMCs and their migration toward the intima, thus resulting in intimal hyperplasia. […] In GCA, VSMCs are injured by mediators released by mononuclear cells, which have accumulated in the media, and acquire pro-inflammatory properties. […] The blockade of the PDGF receptor with imatinib results in a significant decrease in the proliferation of VSMCs from ex vivo cultured temporal arteries. […] ET-1 has also been shown to be implicated in vascular remodeling during GCA. […] The blockade of ET-1 receptors (A and/or B) decreases the migration and proliferation of VSMCs, thus demonstrating that the ET-1 pathway is also implicated in remodeling processes leading to vascular occlusion.

• #41 New Insights into the Pathogenesis of Giant Cell Arteritis: Mechanisms Involved in Maintaining Vascular Inflammation

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9143803/

  IFN–activated macrophages, giant cells or injured VSMCs produce growth factors, essentially platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF). […] PDGF is implicated in the activation and proliferation of VSMCs and their migration toward the intima, thus resulting in intimal hyperplasia. […] In GCA, VSMCs are injured by mediators released by mononuclear cells, which have accumulated in the media, and acquire pro-inflammatory properties. […] The blockade of the PDGF receptor with imatinib results in a significant decrease in the proliferation of VSMCs from ex vivo cultured temporal arteries. […] ET-1 has also been shown to be implicated in vascular remodeling during GCA. […] The blockade of ET-1 receptors (A and/or B) decreases the migration and proliferation of VSMCs, thus demonstrating that the ET-1 pathway is also implicated in remodeling processes leading to vascular occlusion.

• #42 New Insights into the Pathogenesis of Giant Cell Arteritis: Mechanisms Involved in Maintaining Vascular Inflammation

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9143803/

  IFN–activated macrophages, giant cells or injured VSMCs produce growth factors, essentially platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF). […] PDGF is implicated in the activation and proliferation of VSMCs and their migration toward the intima, thus resulting in intimal hyperplasia. […] In GCA, VSMCs are injured by mediators released by mononuclear cells, which have accumulated in the media, and acquire pro-inflammatory properties. […] The blockade of the PDGF receptor with imatinib results in a significant decrease in the proliferation of VSMCs from ex vivo cultured temporal arteries. […] ET-1 has also been shown to be implicated in vascular remodeling during GCA. […] The blockade of ET-1 receptors (A and/or B) decreases the migration and proliferation of VSMCs, thus demonstrating that the ET-1 pathway is also implicated in remodeling processes leading to vascular occlusion.

• #43 Temporal Arteritis Pathology: Definition, Epidemiology, Etiology

  https://emedicine.medscape.com/article/1612591-overview

  Activated CD4+ T helper cells develop into two distinct T cell lineages Th1 and Th17 that produce various pro-inflammatory cytokines. […] The access of monocytes and T cells to the vascular wall is controlled by matrix metalloproteinase (MMP)-9, a type IV collagenase that is produced in the vasculitic lesions of giant cell arteritis. […] Adventitia-based macrophages produce interleukin-6 (IL-6), which further augments the inflammatory cascade. […] The net effect of these events is arteritis with local vascular destruction and intimal hyperplasia leading to luminal stenosis, occlusion, impaired blood flow, and tissue ischemia. […] Endothelial cells also contribute to this maladaptive vascular wall-remodeling process and are involved in both neovascularization and angiogenesis. […] The exuberant release of cytokines associated with this process may be responsible for the constitutional symptoms frequently encountered with the disease.

• #44 Giant Cell Arteritis (Temporal Arteritis): Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/332483-overview

  Cell adhesion molecules influence the pathogenesis, and endothelial cells play a pivotal role. Inflammation is an important process that influences the endothelium and causes neovascularization. […] A cellular immune reaction to elastin has been implicated in the pathogenesis of GCA. […] In support of the hypothesis that elastin is the inciting antigen, disease severity has been shown to correlate with the amount of elastic tissue within the vessels. […] This hypothesis also is supported by histopathologic findings of a disrupted, fragmented internal elastic lamina in affected vessels and the presence of characteristic giant cells, which may contain elastic fiber fragments, close to the internal elastic lamina. […] Finally, numerous studies now suggest that GCA consists of various clinical subsets rather than one uniform disease. Variable expression of different cytokine profiles likely determines the clinical manifestations. Tumor necrosis factor (TNF) and, more recently, interleukin 6, have been recognized to play a major role in the pathophysiology of temporal arteritis.

• #45 New Insights into the Pathogenesis of Giant Cell Arteritis: Mechanisms Involved in Maintaining Vascular Inflammation

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9143803/

  In addition, several defects in the immune regulatory mechanisms probably contribute to chronic vascular inflammation in GCA: a defect in the PD-1/PD-L1 pathway, a quantitative and qualitative Treg deficiency, the implication of resident cells, the role of GM-CSF and IL-6, the implication of the NOTCH pathway and the role of mucosal-associated invariant T cells and tissue-resident memory T cells. […] The immunopathological model of GCA can be divided into four main phases. […] Step 1: an undefined danger signal activates vascular dendritic cells (DC) that then acquire a mature phenotype (CD83+CD80/86+CCR7+MHC-IIhigh) and produce chemokines (CCL18, CCL19, CCL20 and CCL21), leading to the recruitment of CCR6+CD161+CD4+ T cells. […] Step 2: CD4+ T cells are activated by DCs and polarize into Th1 and Th17 cells through the effect of IL-12, IL-23, IL-6 and IL-1, which are produced by activated DC.

• #46 New Insights into the Pathogenesis of Giant Cell Arteritis: Mechanisms Involved in Maintaining Vascular Inflammation

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9143803/

  In addition, several defects in the immune regulatory mechanisms probably contribute to chronic vascular inflammation in GCA: a defect in the PD-1/PD-L1 pathway, a quantitative and qualitative Treg deficiency, the implication of resident cells, the role of GM-CSF and IL-6, the implication of the NOTCH pathway and the role of mucosal-associated invariant T cells and tissue-resident memory T cells. […] The immunopathological model of GCA can be divided into four main phases. […] Step 1: an undefined danger signal activates vascular dendritic cells (DC) that then acquire a mature phenotype (CD83+CD80/86+CCR7+MHC-IIhigh) and produce chemokines (CCL18, CCL19, CCL20 and CCL21), leading to the recruitment of CCR6+CD161+CD4+ T cells. […] Step 2: CD4+ T cells are activated by DCs and polarize into Th1 and Th17 cells through the effect of IL-12, IL-23, IL-6 and IL-1, which are produced by activated DC.

• #47 New Insights into the Pathogenesis of Giant Cell Arteritis: Mechanisms Involved in Maintaining Vascular Inflammation

  https://www.mdpi.com/2077-0383/11/10/2905

  In addition, several defects in the immune regulatory mechanisms probably contribute to chronic vascular inflammation in GCA: a defect in the PD-1/PD-L1 pathway, a quantitative and qualitative Treg deficiency, the implication of resident cells, the role of GM-CSF and IL-6, the implication of the NOTCH pathway and the role of mucosal-associated invariant T cells and tissue-resident memory T cells.

• #48 Giant Cell Arteritis: Advances in Understanding Pathogenesis and Implications for Clinical Practice

  https://www.mdpi.com/2073-4409/13/3/267

  Th1 and Th17 cells are believed to play different roles in the pathogenesis of GCA. […] An important role in the pathogenesis of GCA is played by Treg. […] It has been shown that Treg present at the level of the vessel wall in GCA are unable to perform their regulatory function. […] A significant role in the pathogenesis of GCA is played by the cells of the arterial wall itself. […] The role of many of these factors in vascular wall remodeling has been indirectly demonstrated in experimental models using PDGF or endothelin-1 inhibitors that resulted in the blockade of VSMC migration and proliferation. […] The new knowledge about the pathogenesis of GCA is not only of interest to bench scientists but also has an important impact on the management of this vasculitis at the bedside.

• #49 Giant Cell Arteritis | Encyclopedia MDPI

  https://encyclopedia.pub/entry/54742

  It has been shown that Treg present at the level of the vessel wall in GCA are unable to perform their regulatory function. […] The presence of IL-23 in the microenvironment produced by cells of the innate system further inhibits the expression of the transcription factor forkhead box P3 (FOXP3) necessary for Treg differentiation. […] The potential role of B cells in the pathogenesis of GCA is also suggested by the description of two cases that significantly improved following therapy with the anti-CD20 antibody rituximab that depletes B cells.

• #50 Giant Cell Arteritis | Encyclopedia MDPI

  https://encyclopedia.pub/entry/54742

  It has been shown that Treg present at the level of the vessel wall in GCA are unable to perform their regulatory function. […] The presence of IL-23 in the microenvironment produced by cells of the innate system further inhibits the expression of the transcription factor forkhead box P3 (FOXP3) necessary for Treg differentiation. […] The potential role of B cells in the pathogenesis of GCA is also suggested by the description of two cases that significantly improved following therapy with the anti-CD20 antibody rituximab that depletes B cells.

• #51 Giant cell arteritis: pathogenic mechanisms and new potential therapeutic targets | BMC Rheumatology | Full Text

  https://bmcrheumatol.biomedcentral.com/articles/10.1186/s41927-017-0004-5

  Despite the effective reduction of the Th17 pathway, a Th1 cell response persists, both in blood samples and arterial specimens from patients treated with high-dose GC. […] The receptor molecule PD-1 provides inhibitory signals by binding to programmed cell death ligand 1 and 2 (PD-L1 and PD-L2), resulting in T cell anergy, apoptosis, or polarization to Tregs. […] Recent transcriptome analysis of temporal arteries positive for GCA has demonstrated an inefficiency of the PD-1/PD-L1 checkpoint. […] The Janus kinasesignal transducers and activators of transcription (JAK-STAT) signalling pathway is involved in cellular regulation and has been implicated in the pathogenesis of several inflammatory and autoimmune conditions, including rheumatoid arthritis, inflammatory bowel disease, and psoriasis.

• #52 Giant cell arteritis: pathogenic mechanisms and new potential therapeutic targets | BMC Rheumatology | Full Text

  https://bmcrheumatol.biomedcentral.com/articles/10.1186/s41927-017-0004-5

  JAK-STAT signalling has been identified as having a potential role in sustaining vascular inflammation. […] The Notch signalling pathway is critical for regulating cellular proliferation, differentiation, apoptosis, and homeostasis. […] Dysregulation of this highly preserved pathway has been associated with several malignancies and autoimmune conditions. […] The complex interaction of genetics, vascular factors and immunologic pathways in this disease is responsible for the variability in both the clinical presentation and response to immunosuppressive therapy.

• #53 Giant cell arteritis: pathogenic mechanisms and new potential therapeutic targets | BMC Rheumatology | Full Text

  https://bmcrheumatol.biomedcentral.com/articles/10.1186/s41927-017-0004-5

  JAK-STAT signalling has been identified as having a potential role in sustaining vascular inflammation. […] The Notch signalling pathway is critical for regulating cellular proliferation, differentiation, apoptosis, and homeostasis. […] Dysregulation of this highly preserved pathway has been associated with several malignancies and autoimmune conditions. […] The complex interaction of genetics, vascular factors and immunologic pathways in this disease is responsible for the variability in both the clinical presentation and response to immunosuppressive therapy.

• #54 Giant cell arteritis: pathogenic mechanisms and new potential therapeutic targets | BMC Rheumatology | Full Text

  https://bmcrheumatol.biomedcentral.com/articles/10.1186/s41927-017-0004-5

  JAK-STAT signalling has been identified as having a potential role in sustaining vascular inflammation. […] The Notch signalling pathway is critical for regulating cellular proliferation, differentiation, apoptosis, and homeostasis. […] Dysregulation of this highly preserved pathway has been associated with several malignancies and autoimmune conditions. […] The complex interaction of genetics, vascular factors and immunologic pathways in this disease is responsible for the variability in both the clinical presentation and response to immunosuppressive therapy.

• #55 Pathogenesis of giant cell arteritis with focus on cellular populations.

  https://www.repository.cam.ac.uk/items/642db986-7285-46ae-b8c5-5aca72629d7d

  Giant cell arteritis (GCA), the most common non-infectious vasculitis, mainly affects elderly individuals. […] The pathogenesis of the GCA is complex and includes a dysregulated immune response that affects both the innate and the adaptive immunity. […] Toll-like receptor signaling and interactions through the VEGF-Notch-Jagged1 pathway are emerging as crucial events of the aberrant inflammatory response, facilitating among others the migration of inflammatory cells to the inflamed arteries and their interactions with the local stromal milieu. […] The increased use of checkpoint inhibitors in cancer immunotherapy and their immune-related adverse events has fed interest in the role of checkpoint dysfunction in GCA, and recent studies suggest a dysregulated check point system which is unable to suppress the inflammation in the previously immune-privileged arteries, leading to vasculitis.

• #56 Giant Cell Arteritis (Temporal Arteritis): Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/332483-overview

  Systemic manifestations are likely related to the inflammatory process and cytokine elaboration. End-organ involvement relates to hyperplasia and occlusion of the arteries serving those organs. […] Concentric intimal hyperplasia is an important underlying pathologic lesion in GCA. Intimal hyperplasia presumably occurs as a repair mechanism in response to injury of the blood vessel wall. […] Platelet-derived growth factor (PDGF) is important in stimulating intimal hyperplasia. In GCA, PDGF derives from macrophages and giant cells, and this distinguishes GCA from other vasculopathies. […] Intimal macrophages also produce vascular endothelial growth factor (VEGF), which promotes intimal proliferation. Medial macrophages generate metalloproteinases, leading to the destruction of vascular elements, including the internal elastic lamina.

• #57 Temporal Arteritis Pathology: Definition, Epidemiology, Etiology

  https://emedicine.medscape.com/article/1612591-overview

  Activated CD4+ T helper cells develop into two distinct T cell lineages Th1 and Th17 that produce various pro-inflammatory cytokines. […] The access of monocytes and T cells to the vascular wall is controlled by matrix metalloproteinase (MMP)-9, a type IV collagenase that is produced in the vasculitic lesions of giant cell arteritis. […] Adventitia-based macrophages produce interleukin-6 (IL-6), which further augments the inflammatory cascade. […] The net effect of these events is arteritis with local vascular destruction and intimal hyperplasia leading to luminal stenosis, occlusion, impaired blood flow, and tissue ischemia. […] Endothelial cells also contribute to this maladaptive vascular wall-remodeling process and are involved in both neovascularization and angiogenesis. […] The exuberant release of cytokines associated with this process may be responsible for the constitutional symptoms frequently encountered with the disease.

• #58 Temporal Arteritis Pathology: Definition, Epidemiology, Etiology

  https://emedicine.medscape.com/article/1612591-overview

  Proinflammatory cytokine IL-6, responsible for the exaggerated acute phase of the immune response, is implicated in high levels of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). […] On the basis of its familial, ethnic, and geographic distribution, temporal arteritis appears to have a genetic predisposition. […] Most genetic factors center on the human leukocyte antigen (HLA) genes. […] It is likely that various HLA alleles predispose to temporal arteritis and mediate its severity. […] The precise role of genetic susceptibility in the pathogenesis of temporal arteritis remains unclear and requires further investigation.

• #59 Giant Cell Arteritis (Temporal Arteritis): Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/332483-overview

  Systemic manifestations are likely related to the inflammatory process and cytokine elaboration. End-organ involvement relates to hyperplasia and occlusion of the arteries serving those organs. […] Concentric intimal hyperplasia is an important underlying pathologic lesion in GCA. Intimal hyperplasia presumably occurs as a repair mechanism in response to injury of the blood vessel wall. […] Platelet-derived growth factor (PDGF) is important in stimulating intimal hyperplasia. In GCA, PDGF derives from macrophages and giant cells, and this distinguishes GCA from other vasculopathies. […] Intimal macrophages also produce vascular endothelial growth factor (VEGF), which promotes intimal proliferation. Medial macrophages generate metalloproteinases, leading to the destruction of vascular elements, including the internal elastic lamina.

• #60 Pathogenesis of giant cell arteritis – UpToDate

  https://www.uptodate.com/contents/pathogenesis-of-giant-cell-arteritis

  Pathogenesis of giant cell arteritis […] Histopathology and immunopathology studies reveal inflammation of the artery wall with predominance of CD4+ T lymphocytes and macrophages, which frequently undergo granulomatous organization with formation of giant cells. […] There is a remarkable loss of vascular smooth muscle cells (VSMC) and elastic fibers that may eventually facilitate aneurysm formation. Inflammation-induced vascular remodeling leads to intimal hyperplasia and lumen occlusion, the source of the ischemic complications of the disease. […] The pathogenesis of GCA is incompletely understood. The current pathogenic model has been largely built on immunopathology and molecular studies performed with temporal artery biopsies. […] The role of particular cells, molecules, or pathways has been investigated in temporal artery biopsy xenografts into severe combined immunodeficiency (SCID) mice or in ex vivo cultured arteries. […] Clinical trials with targeted therapies are providing proof of concept about the relevance of specific pathways in the pathogenesis of vascular inflammation. […] Epidemiologic studies demonstrate predominance in older adults, females, and individuals of Northern European ancestry. Occasional family clustering has been reported. These data strongly suggest that senescence, sex, and genetic background all contribute to the pathogenesis of giant cell arteritis (GCA).

• #61 A new era for giant cell arteritis | Eye

  https://www.nature.com/articles/s41433-019-0608-7

  In some patients, IFN- promotes the differentiation and fusion of highly activated macrophages to form multinucleated giant cells. These giant cells also secrete cytokines and growth factors. […] The injured arterial cells respond to damage through dysfunctional repair. This leads to media thickening, luminal occlusion, ischaemia and eventually end organ damage.

• #62 Giant Cell Arteritis: Advances in Understanding Pathogenesis and Implications for Clinical Practice

  https://www.mdpi.com/2073-4409/13/3/267

  Th1 and Th17 cells are believed to play different roles in the pathogenesis of GCA. […] An important role in the pathogenesis of GCA is played by Treg. […] It has been shown that Treg present at the level of the vessel wall in GCA are unable to perform their regulatory function. […] A significant role in the pathogenesis of GCA is played by the cells of the arterial wall itself. […] The role of many of these factors in vascular wall remodeling has been indirectly demonstrated in experimental models using PDGF or endothelin-1 inhibitors that resulted in the blockade of VSMC migration and proliferation. […] The new knowledge about the pathogenesis of GCA is not only of interest to bench scientists but also has an important impact on the management of this vasculitis at the bedside.

• #63 Pathogenesis of giant cell arteritis – UpToDate

  https://www.uptodate.com/contents/pathogenesis-of-giant-cell-arteritis

  Pathogenesis of giant cell arteritis […] Histopathology and immunopathology studies reveal inflammation of the artery wall with predominance of CD4+ T lymphocytes and macrophages, which frequently undergo granulomatous organization with formation of giant cells. […] There is a remarkable loss of vascular smooth muscle cells (VSMC) and elastic fibers that may eventually facilitate aneurysm formation. Inflammation-induced vascular remodeling leads to intimal hyperplasia and lumen occlusion, the source of the ischemic complications of the disease. […] The pathogenesis of GCA is incompletely understood. The current pathogenic model has been largely built on immunopathology and molecular studies performed with temporal artery biopsies. […] The role of particular cells, molecules, or pathways has been investigated in temporal artery biopsy xenografts into severe combined immunodeficiency (SCID) mice or in ex vivo cultured arteries. […] Clinical trials with targeted therapies are providing proof of concept about the relevance of specific pathways in the pathogenesis of vascular inflammation. […] Epidemiologic studies demonstrate predominance in older adults, females, and individuals of Northern European ancestry. Occasional family clustering has been reported. These data strongly suggest that senescence, sex, and genetic background all contribute to the pathogenesis of giant cell arteritis (GCA).

• #64 Giant Cell Arteritis – Rheumatology Advisor

  https://www.rheumatologyadvisor.com/ddi/giant-cell-arteritis/

  Tocilizumab is a humanized recombinant anti-IL-6 receptor antibody that inhibits the binding of IL-6 to membrane-bound and soluble IL-6 receptors in a competitive manner. IL-6 supports the shift from acute to chronic inflammation and stimulates the release of CRP from hepatocytes. Its excessive production adds to giant cell arteritis pathogenesis. Drugs that block IL-6 should be able to stop the inflammatory cascade.

• #65 Giant Cell Arteritis – Rheumatology Advisor

  https://www.rheumatologyadvisor.com/ddi/giant-cell-arteritis/

  Tocilizumab is a humanized recombinant anti-IL-6 receptor antibody that inhibits the binding of IL-6 to membrane-bound and soluble IL-6 receptors in a competitive manner. IL-6 supports the shift from acute to chronic inflammation and stimulates the release of CRP from hepatocytes. Its excessive production adds to giant cell arteritis pathogenesis. Drugs that block IL-6 should be able to stop the inflammatory cascade.

• #66

  https://link.springer.com/article/10.1007/s11940-020-00660-2

  Giant cell arteritis (GCA), a medium and large vessel vasculitis occurring in the aged, remains a formidable disease, capable of taking both vision and life, through a multitude of vascular complications. […] Advances in our understanding of the immunological cascades underlying the disease have helped guide our search for steroid-sparing treatments for the GCA, the most important of which has been the IL-6 receptor antibody inhibitor tocilizumab, which has been shown to reduce cumulative steroid dose in a large multicenter, placebo-controlled prospective study. […] GCA is no longer a disease whose diagnosis is based exclusively on temporal artery biopsy and whose complications are prevented solely with the use of corticosteroids. […] The GiACTA trial was the first study to provide evidence for a steroid-sparing agent in the management of giant arteritis based on prospective, placebo-controlled design. It has revolutionized the way we treat giant cell arteritis, as the use of the IL-6 inhibitor tocilizumab could lead to a significant reduction of steroid usage (and side effects) in the disease.

• #67

  https://link.springer.com/article/10.1007/s11940-020-00660-2

  Giant cell arteritis (GCA), a medium and large vessel vasculitis occurring in the aged, remains a formidable disease, capable of taking both vision and life, through a multitude of vascular complications. […] Advances in our understanding of the immunological cascades underlying the disease have helped guide our search for steroid-sparing treatments for the GCA, the most important of which has been the IL-6 receptor antibody inhibitor tocilizumab, which has been shown to reduce cumulative steroid dose in a large multicenter, placebo-controlled prospective study. […] GCA is no longer a disease whose diagnosis is based exclusively on temporal artery biopsy and whose complications are prevented solely with the use of corticosteroids. […] The GiACTA trial was the first study to provide evidence for a steroid-sparing agent in the management of giant arteritis based on prospective, placebo-controlled design. It has revolutionized the way we treat giant cell arteritis, as the use of the IL-6 inhibitor tocilizumab could lead to a significant reduction of steroid usage (and side effects) in the disease.

• #68 Giant Cell Arteritis: Advances in Understanding Pathogenesis and Implications for Clinical Practice

  https://www.mdpi.com/2073-4409/13/3/267

  Given the role of B lymphocytes in the pathogenesis of GCA, autoantibodies that could facilitate diagnosis were also sought. […] The potential role of B cells in the pathogenesis of GCA is also suggested by the description of two cases that significantly improved following therapy with the anti-CD20 antibody rituximab that depletes B cells. […] The increased synthesis of these substances depends on the activation of pro-inflammatory cells involved in the pathogenetic mechanisms of GCA.

• #69 Giant Cell Arteritis: Advances in Understanding Pathogenesis and Implications for Clinical Practice

  https://www.mdpi.com/2073-4409/13/3/267

  Given the role of B lymphocytes in the pathogenesis of GCA, autoantibodies that could facilitate diagnosis were also sought. […] The potential role of B cells in the pathogenesis of GCA is also suggested by the description of two cases that significantly improved following therapy with the anti-CD20 antibody rituximab that depletes B cells. […] The increased synthesis of these substances depends on the activation of pro-inflammatory cells involved in the pathogenetic mechanisms of GCA.

• #70 Giant Cell Arteritis | Encyclopedia MDPI

  https://encyclopedia.pub/entry/54742

  It has been shown that Treg present at the level of the vessel wall in GCA are unable to perform their regulatory function. […] The presence of IL-23 in the microenvironment produced by cells of the innate system further inhibits the expression of the transcription factor forkhead box P3 (FOXP3) necessary for Treg differentiation. […] The potential role of B cells in the pathogenesis of GCA is also suggested by the description of two cases that significantly improved following therapy with the anti-CD20 antibody rituximab that depletes B cells.

• #71 Giant cell arteritis: pathogenic mechanisms and new potential therapeutic targets | BMC Rheumatology | Full Text

  https://bmcrheumatol.biomedcentral.com/articles/10.1186/s41927-017-0004-5

  JAK-STAT signalling has been identified as having a potential role in sustaining vascular inflammation. […] The Notch signalling pathway is critical for regulating cellular proliferation, differentiation, apoptosis, and homeostasis. […] Dysregulation of this highly preserved pathway has been associated with several malignancies and autoimmune conditions. […] The complex interaction of genetics, vascular factors and immunologic pathways in this disease is responsible for the variability in both the clinical presentation and response to immunosuppressive therapy.

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