Materiały źródłowe

• #1 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.

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

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10855045/

  Giant cell arteritis (GCA) is a noninfectious granulomatous vasculitis of unknown etiology affecting individuals older than 50 years. […] A key role in the pathogenesis of GCA is played by cells of both the innate and adaptive immune systems, which contribute to the formation of granulomas that may include giant cells, a hallmark of the disease, and arterial tertiary follicular organs. […] Cells of the vessel wall cells, including vascular smooth muscle cells (VSMCs) and endothelial cells, actively contribute to vascular remodeling responsible for vascular stenosis and ischemic complications. […] The purpose of this review is to summarize the current evidence on the molecular and cellular mechanisms of GCA, emphasizing both the genetic and epigenetic factors and the immunological and non-immunologic mechanisms responsible for the inflammatory process and vascular remodeling.

• #3 Pathogenesis of giant cell arteritis – UpToDate

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

  Pathogenesis of giant cell arteritis […] Giant cell arteritis (GCA) is a chronic inflammatory disease involving large- and medium-sized arteries and affecting individuals older than 50 years. Involvement of the cranial branches of the carotid arteries is very common and, due to its easy access, biopsy of the superficial temporal artery is frequently performed to obtain histopathologic confirmation of GCA. […] 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.

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

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

  Giant cell arteritis (GCA) is a noninfectious granulomatous vasculitis of unknown etiology affecting individuals older than 50 years. […] A key role in the pathogenesis of GCA is played by cells of both the innate and adaptive immune systems, which contribute to the formation of granulomas that may include giant cells, a hallmark of the disease, and arterial tertiary follicular organs. […] This review will discuss new insights into the molecular and cellular pathogenetic mechanisms of GCA, as well as the implications of these findings for the development of new diagnostic biomarkers and targeted drugs that could hopefully replace glucocorticoids (GCs), still the backbone of therapy for this vasculitis. […] The purpose of this review is to summarize the current evidence on the molecular and cellular mechanisms of GCA, emphasizing both the genetic and epigenetic factors and the immunological and non-immunologic mechanisms responsible for the inflammatory process and vascular remodeling.

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

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

  Early studies on the genetic predisposition to develop GCA focused on the association with the presence of particular HLA alleles. […] New associations between genetic mutations and GCA have also been described. […] In genome-wide association studies (GWAS), genes encoding for plasminogen (PLG) and the alpha 2 subunit of prolyl 4-hydroxylase (P4HA2) have been identified as other genetic factors responsible for susceptibility to GCA. […] Regarding epigenetic modifications that have been shown to be involved in the onset of GCA, hypomethylation of loci of genes encoding for proteins involved in T-cell receptor (TCR) activation, especially after interaction with the co-stimulatory molecule CD28 and of genes involved in the calcineurin-mediated intracellular pathway, which is critical for the induction of the nuclear transcription factor of activated T cells (NFAT), was observed in the arterial wall of GCA patients.

• #6 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 wide array of potentially involved cellular pathways associated with GCA susceptibility underscores the polygenic nature and complex immunopathogenesis employing both the innate and adaptive immune response in this condition. […] 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.

• #7 Pathogenesis of giant cell arteritis – UpToDate

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

  Pathogenesis of giant cell arteritis 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. These data strongly suggest that senescence, sex, and genetic background all contribute to the pathogenesis of giant cell arteritis (GCA).

• #8 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.

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

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

  Early studies on the genetic predisposition to develop GCA focused on the association with the presence of particular HLA alleles. […] New associations between genetic mutations and GCA have also been described. […] In genome-wide association studies (GWAS), genes encoding for plasminogen (PLG) and the alpha 2 subunit of prolyl 4-hydroxylase (P4HA2) have been identified as other genetic factors responsible for susceptibility to GCA. […] Regarding epigenetic modifications that have been shown to be involved in the onset of GCA, hypomethylation of loci of genes encoding for proteins involved in T-cell receptor (TCR) activation, especially after interaction with the co-stimulatory molecule CD28 and of genes involved in the calcineurin-mediated intracellular pathway, which is critical for the induction of the nuclear transcription factor of activated T cells (NFAT), was observed in the arterial wall of GCA patients.

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

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

  On the basis of its familial, ethnic, and geographic distribution, temporal arteritis appears to have a genetic predisposition. Studies have shown familial clustering and monozygotic twin concordance. 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.

• #11 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. […] The combination of these reactants under the systemic inflammatory reaction leads to the general signs of inflammation seen in GCA such as fevers, chills, sweats, myalgias, anorexia, and weight loss. In comparison, the antigen-specific immune response damages the arterial walls and results in the focal ischemic complications seen in GCA.

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

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

  Early studies on the genetic predisposition to develop GCA focused on the association with the presence of particular HLA alleles. […] New associations between genetic mutations and GCA have also been described. […] In genome-wide association studies (GWAS), genes encoding for plasminogen (PLG) and the alpha 2 subunit of prolyl 4-hydroxylase (P4HA2) have been identified as other genetic factors responsible for susceptibility to GCA. […] Regarding epigenetic modifications that have been shown to be involved in the onset of GCA, hypomethylation of loci of genes encoding for proteins involved in T-cell receptor (TCR) activation, especially after interaction with the co-stimulatory molecule CD28 and of genes involved in the calcineurin-mediated intracellular pathway, which is critical for the induction of the nuclear transcription factor of activated T cells (NFAT), was observed in the arterial wall of GCA patients.

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

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10855045/

  Early studies on the genetic predisposition to develop GCA focused on the association with the presence of particular HLA alleles. […] New associations between genetic mutations and GCA have also been described. […] Hypomethylation of loci of genes encoding for proteins involved in T-cell receptor (TCR) activation, especially after interaction with the co-stimulatory molecule CD28 and of genes involved in the calcineurin-mediated intracellular pathway, which is critical for the induction of the nuclear transcription factor of activated T cells (NFAT), was observed in the arterial wall of GCA patients. […] A relatively new line of research is the role of microRNAs (miRNAs) in GCA pathogenesis. […] In addition, IFN- secreted by Th1 cells activates VSMCs to produce other important factors involved in vascular remodeling.

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

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

  A relatively new line of research is the role of microRNAs (miRNAs) in GCA pathogenesis. […] In particular, miR-146, miR-155, and miR-21 have been found to be overexpressed in the arterial wall of patients with CGA. […] 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. […] Dendritic cells (DCs) that reside in the space between the media and adventitia of the arterial wall play a crucial role in the pathogenesis of GCA. […] Once activated, DCs can induce the activation of macrophages with subsequent amplification of the inflammatory cascade. […] Th1 and Th17 cells are believed to play different roles in the pathogenesis of GCA.

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

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

  New Insights into the Pathogenesis of Giant Cell Arteritis: Mechanisms Involved in Maintaining Vascular Inflammation […] 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-γ) and interleukin-17 (IL-17), respectively. IFN-γ triggers the production of chemokines by vascular smooth muscle cells, which leads to the recruitment of additional CD4 and CD8 T cells and also monocytes that differentiate into macrophages. Recent data have shown that IL-17, IFN-γ 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. 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 aging process has been associated with modifications to multiple cells implicated in the immune response and vascular remodeling, such as dendritic cells (DC), T cells, endothelial cells and vascular smooth muscle cells (VSMC). In particular, aging triggers a decrease in the number of naive T cells, increase in memory and effector T cells, decrease in the diversity of the T-cell repertoire and enrichment in CD4+CD28− and CD8+CD28− senescent T cells. Immune aging also alters the regulation of immune cells, for instance, by impacting CD8+ Treg, thus leading to the production of pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) by senescent DCs, macrophages, endothelial cells and fibroblasts. […] The role of DC in the pathogenesis of GCA suggests a relationship between a potential infection and the initiation of GCA. It is generally assumed that an infectious agent can activate adventitial DC and trigger immunologic processes leading to the development of vasculitis. However, this hypothesis has never been fully resolved, mainly because no specific pathogen triggering GCA has been identified. […] The immunopathological model of GCA can be divided into four main phases. Phase 1: Loss of Tolerance and Activation of Resident Dendritic Cells of the Adventitia. Immature myeloid DCs are physiologically localized in the adventitia where they are involved in immune surveillance. These cells can trigger adaptive immunity after detecting danger signals through pattern recognition receptors (PPRs) such as TLR. By contrast, they induce tolerance in the absence of a danger signal. The detection of a danger signal via TLR of adventitial DCs induces their activation, followed by phenotypic modifications and the production of cytokines and chemokines responsible for the recruitment of CD4+ T cells in the arterial wall. […] CD4+ T cells, which are physiologically absent from the walls of healthy arteries, play a major role in the pathogenesis of GCA, as highlighted by the fact that their depletion in immunocompromised mice engrafted with GCA arteries strongly decreases vasculitis lesions. […] The strong infiltration of Th1 and Th17 cells into the arterial wall is responsible for the production of large amounts of IFN-γ and IL-17, respectively. IFN-γ induces the production of several chemokines by VSMCs. […] Macrophages play a major role in vascular remodeling through their ability to produce enzymes, growth factors and other mediators. […] Current knowledge also suggests that IFN-γ, which is produced by Th1 cells, is the main lymphocytic cytokine inducing vascular remodeling. IFN-γ-activated macrophages, giant cells or injured VSMCs produce growth factors, essentially platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF). […] The major role of IL-6 in the GCA pathogenesis is demonstrated by the dramatic efficacy of tocilizumab for the treatment of GCA. Furthermore, the Th17/Treg imbalance observed in GCA is controlled by IL-6, which increases Th17 polarization and decreases Treg differentiation.

• #16 The role of immune aging in giant cell arteritis | Harkins | Aging Pathobiology and Therapeutics

  http://www.antpublisher.com/index.php/APT/article/view/675/770

  GCA is characterized by a granulomatous inflammation, that typically affects all three layers of the vessel wall, which can culminate not only in the classic ischemic symptoms, but also in dissection and aneurysm formation with subsequent rupture. […] Tissue-resident dendritic cells, residing in the adventitia of the arterial wall, are of utmost importance in the initiation of GCA pathogenesis. When activated, these dendritic cells trigger an inflammatory cascade involving macrophages and T cells. […] What exactly causes activation of the dendritic cell and the subsequent development of GCA remains unknown. Whilst multiple different risk factors have been implicated, the strongest risk factor is most certainly increasing chronological age. […] There is considerable overlap in the molecular and cellular pathways between the immune dysregulation, and indeed local vascular tissue abnormalities observed in those with GCA, and those seen in immune aging. Whether these changes are accelerated in those with GCA and contribute to disease pathogenesis has yet to be conclusively addressed. […] The immune system is a complex interactive network, whose essential role is defence of the host against infectious, neoplastic and other deleterious agents, whilst also maintaining tissue repair and regeneration.

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

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

  New Insights into the Pathogenesis of Giant Cell Arteritis: Mechanisms Involved in Maintaining Vascular Inflammation […] 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-γ) and interleukin-17 (IL-17), respectively. IFN-γ triggers the production of chemokines by vascular smooth muscle cells, which leads to the recruitment of additional CD4 and CD8 T cells and also monocytes that differentiate into macrophages. Recent data have shown that IL-17, IFN-γ 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. 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 aging process has been associated with modifications to multiple cells implicated in the immune response and vascular remodeling, such as dendritic cells (DC), T cells, endothelial cells and vascular smooth muscle cells (VSMC). In particular, aging triggers a decrease in the number of naive T cells, increase in memory and effector T cells, decrease in the diversity of the T-cell repertoire and enrichment in CD4+CD28− and CD8+CD28− senescent T cells. Immune aging also alters the regulation of immune cells, for instance, by impacting CD8+ Treg, thus leading to the production of pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) by senescent DCs, macrophages, endothelial cells and fibroblasts. […] The role of DC in the pathogenesis of GCA suggests a relationship between a potential infection and the initiation of GCA. It is generally assumed that an infectious agent can activate adventitial DC and trigger immunologic processes leading to the development of vasculitis. However, this hypothesis has never been fully resolved, mainly because no specific pathogen triggering GCA has been identified. […] The immunopathological model of GCA can be divided into four main phases. Phase 1: Loss of Tolerance and Activation of Resident Dendritic Cells of the Adventitia. Immature myeloid DCs are physiologically localized in the adventitia where they are involved in immune surveillance. These cells can trigger adaptive immunity after detecting danger signals through pattern recognition receptors (PPRs) such as TLR. By contrast, they induce tolerance in the absence of a danger signal. The detection of a danger signal via TLR of adventitial DCs induces their activation, followed by phenotypic modifications and the production of cytokines and chemokines responsible for the recruitment of CD4+ T cells in the arterial wall. […] CD4+ T cells, which are physiologically absent from the walls of healthy arteries, play a major role in the pathogenesis of GCA, as highlighted by the fact that their depletion in immunocompromised mice engrafted with GCA arteries strongly decreases vasculitis lesions. […] The strong infiltration of Th1 and Th17 cells into the arterial wall is responsible for the production of large amounts of IFN-γ and IL-17, respectively. IFN-γ induces the production of several chemokines by VSMCs. […] Macrophages play a major role in vascular remodeling through their ability to produce enzymes, growth factors and other mediators. […] Current knowledge also suggests that IFN-γ, which is produced by Th1 cells, is the main lymphocytic cytokine inducing vascular remodeling. IFN-γ-activated macrophages, giant cells or injured VSMCs produce growth factors, essentially platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF). […] The major role of IL-6 in the GCA pathogenesis is demonstrated by the dramatic efficacy of tocilizumab for the treatment of GCA. Furthermore, the Th17/Treg imbalance observed in GCA is controlled by IL-6, which increases Th17 polarization and decreases Treg differentiation.

• #18 The role of immune aging in giant cell arteritis | Harkins | Aging Pathobiology and Therapeutics

  http://www.antpublisher.com/index.php/APT/article/view/675/770

  Age impacts both the innate and adaptive immune systems, as evidenced by marked changes in the distribution and competence of immune cells. […] The term inflammaging, was first coined in 2000, and refers to the chronic low-level pro-inflammatory response observed in the absence of overt stimuli (sterile inflammation) that is associated with advancing age. […] Characteristically, it is associated with an increase in the circulating levels of acute phase proteins, such as C-reactive protein (CRP), in addition to a number of pro-inflammatory cytokines, notably interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-). […] In GCA, macrophages, specifically multinucleated giant cells are the principal constituent of the granulomatous lesion reflecting their integral role in GCA pathobiology. […] There are a number of shared similarities between the myeloid cell dysfunction observed in GCA patients and that seen with immune aging. […] With advancing age, changes also occur in the extracellular matrix (ECM) that alters its functions. Under normal physiological conditions, the vessel wall is inaccessible to inflammatory cells, a concept often referred to as immune privilege.

• #19 The role of immune aging in giant cell arteritis | Harkins | Aging Pathobiology and Therapeutics

  http://www.antpublisher.com/index.php/APT/article/view/675/770

  Age impacts both the innate and adaptive immune systems, as evidenced by marked changes in the distribution and competence of immune cells. […] The term inflammaging, was first coined in 2000, and refers to the chronic low-level pro-inflammatory response observed in the absence of overt stimuli (sterile inflammation) that is associated with advancing age. […] Characteristically, it is associated with an increase in the circulating levels of acute phase proteins, such as C-reactive protein (CRP), in addition to a number of pro-inflammatory cytokines, notably interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-). […] In GCA, macrophages, specifically multinucleated giant cells are the principal constituent of the granulomatous lesion reflecting their integral role in GCA pathobiology. […] There are a number of shared similarities between the myeloid cell dysfunction observed in GCA patients and that seen with immune aging. […] With advancing age, changes also occur in the extracellular matrix (ECM) that alters its functions. Under normal physiological conditions, the vessel wall is inaccessible to inflammatory cells, a concept often referred to as immune privilege.

• #20 The role of immune aging in giant cell arteritis | Harkins | Aging Pathobiology and Therapeutics

  http://www.antpublisher.com/index.php/APT/article/view/675/770

  Age impacts both the innate and adaptive immune systems, as evidenced by marked changes in the distribution and competence of immune cells. […] The term inflammaging, was first coined in 2000, and refers to the chronic low-level pro-inflammatory response observed in the absence of overt stimuli (sterile inflammation) that is associated with advancing age. […] Characteristically, it is associated with an increase in the circulating levels of acute phase proteins, such as C-reactive protein (CRP), in addition to a number of pro-inflammatory cytokines, notably interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-). […] In GCA, macrophages, specifically multinucleated giant cells are the principal constituent of the granulomatous lesion reflecting their integral role in GCA pathobiology. […] There are a number of shared similarities between the myeloid cell dysfunction observed in GCA patients and that seen with immune aging. […] With advancing age, changes also occur in the extracellular matrix (ECM) that alters its functions. Under normal physiological conditions, the vessel wall is inaccessible to inflammatory cells, a concept often referred to as immune privilege.

• #21 The role of immune aging in giant cell arteritis | Harkins | Aging Pathobiology and Therapeutics

  http://www.antpublisher.com/index.php/APT/article/view/675/770

  However, in those with GCA, a critical determinant of vasculitis is the ability of immune cells to enter the vascular tissue microenvironment. […] MMP-9, also known as type IV collagenase, plays an integral role in ECM remodeling, neoangiogenesis, and serves as a critical checkpoint in the pathogenesis of GCA by controlling the migration of both monocytes and T cells into the protected tissue niche of the vessel wall. […] The aging process results in a number of changes in T cell structure and function that culminate in a reduced specificity of the immune response, with an associated dysregulation in the balance between host protection and the tolerance of self-antigens. […] Such age-related changes in the T cell compartment have been summarized as the T cell aging associated phenotype (TASP). […] Moreover, regulatory T cells reduce, with resultant unopposed effector responses.

• #22 The role of immune aging in giant cell arteritis | Harkins | Aging Pathobiology and Therapeutics

  http://www.antpublisher.com/index.php/APT/article/view/675/770

  However, in those with GCA, a critical determinant of vasculitis is the ability of immune cells to enter the vascular tissue microenvironment. […] MMP-9, also known as type IV collagenase, plays an integral role in ECM remodeling, neoangiogenesis, and serves as a critical checkpoint in the pathogenesis of GCA by controlling the migration of both monocytes and T cells into the protected tissue niche of the vessel wall. […] The aging process results in a number of changes in T cell structure and function that culminate in a reduced specificity of the immune response, with an associated dysregulation in the balance between host protection and the tolerance of self-antigens. […] Such age-related changes in the T cell compartment have been summarized as the T cell aging associated phenotype (TASP). […] Moreover, regulatory T cells reduce, with resultant unopposed effector responses.

• #23 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. […] 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. […] 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. MMP-9 production allows T cells to pass through collagen IVcontaining basement membrane.

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

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

  New Insights into the Pathogenesis of Giant Cell Arteritis: Mechanisms Involved in Maintaining Vascular Inflammation […] 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-γ) and interleukin-17 (IL-17), respectively. IFN-γ triggers the production of chemokines by vascular smooth muscle cells, which leads to the recruitment of additional CD4 and CD8 T cells and also monocytes that differentiate into macrophages. Recent data have shown that IL-17, IFN-γ 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. 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 aging process has been associated with modifications to multiple cells implicated in the immune response and vascular remodeling, such as dendritic cells (DC), T cells, endothelial cells and vascular smooth muscle cells (VSMC). In particular, aging triggers a decrease in the number of naive T cells, increase in memory and effector T cells, decrease in the diversity of the T-cell repertoire and enrichment in CD4+CD28− and CD8+CD28− senescent T cells. Immune aging also alters the regulation of immune cells, for instance, by impacting CD8+ Treg, thus leading to the production of pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) by senescent DCs, macrophages, endothelial cells and fibroblasts. […] The role of DC in the pathogenesis of GCA suggests a relationship between a potential infection and the initiation of GCA. It is generally assumed that an infectious agent can activate adventitial DC and trigger immunologic processes leading to the development of vasculitis. However, this hypothesis has never been fully resolved, mainly because no specific pathogen triggering GCA has been identified. […] The immunopathological model of GCA can be divided into four main phases. Phase 1: Loss of Tolerance and Activation of Resident Dendritic Cells of the Adventitia. Immature myeloid DCs are physiologically localized in the adventitia where they are involved in immune surveillance. These cells can trigger adaptive immunity after detecting danger signals through pattern recognition receptors (PPRs) such as TLR. By contrast, they induce tolerance in the absence of a danger signal. The detection of a danger signal via TLR of adventitial DCs induces their activation, followed by phenotypic modifications and the production of cytokines and chemokines responsible for the recruitment of CD4+ T cells in the arterial wall. […] CD4+ T cells, which are physiologically absent from the walls of healthy arteries, play a major role in the pathogenesis of GCA, as highlighted by the fact that their depletion in immunocompromised mice engrafted with GCA arteries strongly decreases vasculitis lesions. […] The strong infiltration of Th1 and Th17 cells into the arterial wall is responsible for the production of large amounts of IFN-γ and IL-17, respectively. IFN-γ induces the production of several chemokines by VSMCs. […] Macrophages play a major role in vascular remodeling through their ability to produce enzymes, growth factors and other mediators. […] Current knowledge also suggests that IFN-γ, which is produced by Th1 cells, is the main lymphocytic cytokine inducing vascular remodeling. IFN-γ-activated macrophages, giant cells or injured VSMCs produce growth factors, essentially platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF). […] The major role of IL-6 in the GCA pathogenesis is demonstrated by the dramatic efficacy of tocilizumab for the treatment of GCA. Furthermore, the Th17/Treg imbalance observed in GCA is controlled by IL-6, which increases Th17 polarization and decreases Treg differentiation.

• #25 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.

• #26 Giant Cell Arteritis | Encyclopedia MDPI

  https://encyclopedia.pub/entry/54742

  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. […] 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. Dendritic cells express toll-like receptors (TLRs) on their surface, which can recognize specific pathogen-associated molecular patterns (PAMPs) derived from components of microorganisms and/or damage-associated molecular patterns (DAMPs) that recognize various proteins, including fragments of necrotic self-cells.

• #27 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.

• #28 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 adventitia is the likely site of initial immunologic injury and is considered the immunological center of the disorder, while the intima and media are the histological center. […] 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.

• #29 Giant Cell Arteritis | Encyclopedia MDPI

  https://encyclopedia.pub/entry/54742

  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. […] 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. Dendritic cells express toll-like receptors (TLRs) on their surface, which can recognize specific pathogen-associated molecular patterns (PAMPs) derived from components of microorganisms and/or damage-associated molecular patterns (DAMPs) that recognize various proteins, including fragments of necrotic self-cells.

• #30 Clinical Manifestations of Giant Cell Arteritis | IntechOpen

  https://www.intechopen.com/chapters/75468

  GCA is primarily an immune-mediated disease due to a maladaptive response to endothelial injury, occurring in susceptible individuals and triggered by factors that have not been identified with certainty. […] The pathophysiology of GCA is complex and not fully understood. Histopathology 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. […] The initial inflammatory response involves the activation of dendritic cells, present in the adventitia of normal arteries, through pathogen- or damage-sensing receptors, such as toll-like receptors, producing chemokines able to attract and retain dendritic cells as well as lymphocytes and macrophages. […] Once activated, both T helper (Th)1 and Th17 differentiation pathways contribute to the development of vascular inflammation. Interleukin (IL)-12 and IL-18 produced by dendritic cells stimulate Th1 differentiation and production of interferon (IFN)-gamma which is noticeably expressed in GCA-involved arteries.

• #31 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.

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

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

  New Insights into the Pathogenesis of Giant Cell Arteritis: Mechanisms Involved in Maintaining Vascular Inflammation […] 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-γ) and interleukin-17 (IL-17), respectively. IFN-γ triggers the production of chemokines by vascular smooth muscle cells, which leads to the recruitment of additional CD4 and CD8 T cells and also monocytes that differentiate into macrophages. Recent data have shown that IL-17, IFN-γ 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. 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 aging process has been associated with modifications to multiple cells implicated in the immune response and vascular remodeling, such as dendritic cells (DC), T cells, endothelial cells and vascular smooth muscle cells (VSMC). In particular, aging triggers a decrease in the number of naive T cells, increase in memory and effector T cells, decrease in the diversity of the T-cell repertoire and enrichment in CD4+CD28− and CD8+CD28− senescent T cells. Immune aging also alters the regulation of immune cells, for instance, by impacting CD8+ Treg, thus leading to the production of pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) by senescent DCs, macrophages, endothelial cells and fibroblasts. […] The role of DC in the pathogenesis of GCA suggests a relationship between a potential infection and the initiation of GCA. It is generally assumed that an infectious agent can activate adventitial DC and trigger immunologic processes leading to the development of vasculitis. However, this hypothesis has never been fully resolved, mainly because no specific pathogen triggering GCA has been identified. […] The immunopathological model of GCA can be divided into four main phases. Phase 1: Loss of Tolerance and Activation of Resident Dendritic Cells of the Adventitia. Immature myeloid DCs are physiologically localized in the adventitia where they are involved in immune surveillance. These cells can trigger adaptive immunity after detecting danger signals through pattern recognition receptors (PPRs) such as TLR. By contrast, they induce tolerance in the absence of a danger signal. The detection of a danger signal via TLR of adventitial DCs induces their activation, followed by phenotypic modifications and the production of cytokines and chemokines responsible for the recruitment of CD4+ T cells in the arterial wall. […] CD4+ T cells, which are physiologically absent from the walls of healthy arteries, play a major role in the pathogenesis of GCA, as highlighted by the fact that their depletion in immunocompromised mice engrafted with GCA arteries strongly decreases vasculitis lesions. […] The strong infiltration of Th1 and Th17 cells into the arterial wall is responsible for the production of large amounts of IFN-γ and IL-17, respectively. IFN-γ induces the production of several chemokines by VSMCs. […] Macrophages play a major role in vascular remodeling through their ability to produce enzymes, growth factors and other mediators. […] Current knowledge also suggests that IFN-γ, which is produced by Th1 cells, is the main lymphocytic cytokine inducing vascular remodeling. IFN-γ-activated macrophages, giant cells or injured VSMCs produce growth factors, essentially platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF). […] The major role of IL-6 in the GCA pathogenesis is demonstrated by the dramatic efficacy of tocilizumab for the treatment of GCA. Furthermore, the Th17/Treg imbalance observed in GCA is controlled by IL-6, which increases Th17 polarization and decreases Treg differentiation.

• #33 Giant Cell Arteritis | Encyclopedia MDPI

  https://encyclopedia.pub/entry/54742

  The first clue suggesting the involvement of T cells in GCA was the finding that the immunohistology lesions in the wall of vessels affected by this vasculitis are granulomatous in nature. Granulomas are known to consist of both cells of the innate system, such as macrophages, and cells of the adaptive system, including T cells that aggregate to form well-ordered structures in the course of inflammation. […] Th1 and Th17 cells are believed to play different roles in the pathogenesis of GCA. Th1 cells are characterized by the production of IFN-γ, and their differentiation is controlled by IL12/IFN-γ axis. […] An important role in the pathogenesis of GCA is played by Treg. As mentioned above, these cells are known to be able to differentiate into Th17 cells and vice versa. […] It should be further emphasized that the differentiation of T cell precursors into the various T cell subpopulations depends critically on soluble factors produced by cells of the innate immune system, and in particular, DCs.

• #34 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 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. […] 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 rapid decline in these cytokines upon GC initiation contributes to the prompt decrease of systemic inflammatory features. […] 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.

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

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

  New Insights into the Pathogenesis of Giant Cell Arteritis: Mechanisms Involved in Maintaining Vascular Inflammation […] 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-γ) and interleukin-17 (IL-17), respectively. IFN-γ triggers the production of chemokines by vascular smooth muscle cells, which leads to the recruitment of additional CD4 and CD8 T cells and also monocytes that differentiate into macrophages. Recent data have shown that IL-17, IFN-γ 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. 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 aging process has been associated with modifications to multiple cells implicated in the immune response and vascular remodeling, such as dendritic cells (DC), T cells, endothelial cells and vascular smooth muscle cells (VSMC). In particular, aging triggers a decrease in the number of naive T cells, increase in memory and effector T cells, decrease in the diversity of the T-cell repertoire and enrichment in CD4+CD28− and CD8+CD28− senescent T cells. Immune aging also alters the regulation of immune cells, for instance, by impacting CD8+ Treg, thus leading to the production of pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) by senescent DCs, macrophages, endothelial cells and fibroblasts. […] The role of DC in the pathogenesis of GCA suggests a relationship between a potential infection and the initiation of GCA. It is generally assumed that an infectious agent can activate adventitial DC and trigger immunologic processes leading to the development of vasculitis. However, this hypothesis has never been fully resolved, mainly because no specific pathogen triggering GCA has been identified. […] The immunopathological model of GCA can be divided into four main phases. Phase 1: Loss of Tolerance and Activation of Resident Dendritic Cells of the Adventitia. Immature myeloid DCs are physiologically localized in the adventitia where they are involved in immune surveillance. These cells can trigger adaptive immunity after detecting danger signals through pattern recognition receptors (PPRs) such as TLR. By contrast, they induce tolerance in the absence of a danger signal. The detection of a danger signal via TLR of adventitial DCs induces their activation, followed by phenotypic modifications and the production of cytokines and chemokines responsible for the recruitment of CD4+ T cells in the arterial wall. […] CD4+ T cells, which are physiologically absent from the walls of healthy arteries, play a major role in the pathogenesis of GCA, as highlighted by the fact that their depletion in immunocompromised mice engrafted with GCA arteries strongly decreases vasculitis lesions. […] The strong infiltration of Th1 and Th17 cells into the arterial wall is responsible for the production of large amounts of IFN-γ and IL-17, respectively. IFN-γ induces the production of several chemokines by VSMCs. […] Macrophages play a major role in vascular remodeling through their ability to produce enzymes, growth factors and other mediators. […] Current knowledge also suggests that IFN-γ, which is produced by Th1 cells, is the main lymphocytic cytokine inducing vascular remodeling. IFN-γ-activated macrophages, giant cells or injured VSMCs produce growth factors, essentially platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF). […] The major role of IL-6 in the GCA pathogenesis is demonstrated by the dramatic efficacy of tocilizumab for the treatment of GCA. Furthermore, the Th17/Treg imbalance observed in GCA is controlled by IL-6, which increases Th17 polarization and decreases Treg differentiation.

• #36 Giant Cell Arteritis | Encyclopedia MDPI

  https://encyclopedia.pub/entry/54742

  The first clue suggesting the involvement of T cells in GCA was the finding that the immunohistology lesions in the wall of vessels affected by this vasculitis are granulomatous in nature. Granulomas are known to consist of both cells of the innate system, such as macrophages, and cells of the adaptive system, including T cells that aggregate to form well-ordered structures in the course of inflammation. […] Th1 and Th17 cells are believed to play different roles in the pathogenesis of GCA. Th1 cells are characterized by the production of IFN-γ, and their differentiation is controlled by IL12/IFN-γ axis. […] An important role in the pathogenesis of GCA is played by Treg. As mentioned above, these cells are known to be able to differentiate into Th17 cells and vice versa. […] It should be further emphasized that the differentiation of T cell precursors into the various T cell subpopulations depends critically on soluble factors produced by cells of the innate immune system, and in particular, DCs.

• #37 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 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. […] 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 rapid decline in these cytokines upon GC initiation contributes to the prompt decrease of systemic inflammatory features. […] 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.

• #38 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 adventitia is the likely site of initial immunologic injury and is considered the immunological center of the disorder, while the intima and media are the histological center. […] 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.

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

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

  It has been shown that Treg present at the level of the vessel wall in GCA are unable to perform their regulatory function. […] An important role in the pathogenesis of GCA is played by Treg. […] 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. […] A significant role in the pathogenesis of GCA is played by the cells of the arterial wall itself. […] A key role of macrophages has been identified in this process. […] The tunica media is progressively destroyed, while the intima undergoes thickening due to myofibroblast proliferation and protein deposition in the extracellular matrix, leading to vessel occlusion. […] 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.

• #40 Giant Cell Arteritis | Encyclopedia MDPI

  https://encyclopedia.pub/entry/54742

  The first clue suggesting the involvement of T cells in GCA was the finding that the immunohistology lesions in the wall of vessels affected by this vasculitis are granulomatous in nature. Granulomas are known to consist of both cells of the innate system, such as macrophages, and cells of the adaptive system, including T cells that aggregate to form well-ordered structures in the course of inflammation. […] Th1 and Th17 cells are believed to play different roles in the pathogenesis of GCA. Th1 cells are characterized by the production of IFN-γ, and their differentiation is controlled by IL12/IFN-γ axis. […] An important role in the pathogenesis of GCA is played by Treg. As mentioned above, these cells are known to be able to differentiate into Th17 cells and vice versa. […] It should be further emphasized that the differentiation of T cell precursors into the various T cell subpopulations depends critically on soluble factors produced by cells of the innate immune system, and in particular, DCs.

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

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

  It has been shown that Treg present at the level of the vessel wall in GCA are unable to perform their regulatory function. […] An important role in the pathogenesis of GCA is played by Treg. […] 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. […] A significant role in the pathogenesis of GCA is played by the cells of the arterial wall itself. […] A key role of macrophages has been identified in this process. […] The tunica media is progressively destroyed, while the intima undergoes thickening due to myofibroblast proliferation and protein deposition in the extracellular matrix, leading to vessel occlusion. […] 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.

• #42 Giant Cell Arteritis | Encyclopedia MDPI

  https://encyclopedia.pub/entry/54742

  The first clue suggesting the involvement of T cells in GCA was the finding that the immunohistology lesions in the wall of vessels affected by this vasculitis are granulomatous in nature. Granulomas are known to consist of both cells of the innate system, such as macrophages, and cells of the adaptive system, including T cells that aggregate to form well-ordered structures in the course of inflammation. […] Th1 and Th17 cells are believed to play different roles in the pathogenesis of GCA. Th1 cells are characterized by the production of IFN-γ, and their differentiation is controlled by IL12/IFN-γ axis. […] An important role in the pathogenesis of GCA is played by Treg. As mentioned above, these cells are known to be able to differentiate into Th17 cells and vice versa. […] It should be further emphasized that the differentiation of T cell precursors into the various T cell subpopulations depends critically on soluble factors produced by cells of the innate immune system, and in particular, DCs.

• #43 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 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. […] 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 rapid decline in these cytokines upon GC initiation contributes to the prompt decrease of systemic inflammatory features. […] 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.

• #44 The role of immune aging in giant cell arteritis | Harkins | Aging Pathobiology and Therapeutics

  http://www.antpublisher.com/index.php/APT/article/view/675/770

  Treg cells are immune-inhibitory, and function in both lymphoid and peripheral tissue sites to mediate effector T cell functions and maintain immunological self-tolerance. […] Altered Treg cell homeostasis has also been implicated in GCA immunopathogenesis. […] Interestingly, treatment with the IL-6 receptor antagonist tocilizumab resulted in a complete correction of the aforementioned abnormalities observed in the Treg cells of those with active GCA. […] Our understanding of the immunopathogenesis of GCA is continually increasing, and with it the role of aging in its pathogenesis is becoming more appreciated. […] We have discussed how advancing age is associated with significant restructuring of both the innate and adaptive immune systems, rendering the host more susceptible to autoimmunity and disease pathogenesis.

• #45 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.

• #46 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 adventitia is the likely site of initial immunologic injury and is considered the immunological center of the disorder, while the intima and media are the histological center. […] 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.

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

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

  A relatively new line of research is the role of microRNAs (miRNAs) in GCA pathogenesis. […] In particular, miR-146, miR-155, and miR-21 have been found to be overexpressed in the arterial wall of patients with CGA. […] 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. […] Dendritic cells (DCs) that reside in the space between the media and adventitia of the arterial wall play a crucial role in the pathogenesis of GCA. […] Once activated, DCs can induce the activation of macrophages with subsequent amplification of the inflammatory cascade. […] Th1 and Th17 cells are believed to play different roles in the pathogenesis of GCA.

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

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

  Adventitial macrophages produce interleukin-6, augmenting the inflammatory response. This results in inflammation with local vascular damage and intimal hyperplasia, leading to stenosis and occlusion. […] 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.

• #49 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.

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

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

  New Insights into the Pathogenesis of Giant Cell Arteritis: Mechanisms Involved in Maintaining Vascular Inflammation […] 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-γ) and interleukin-17 (IL-17), respectively. IFN-γ triggers the production of chemokines by vascular smooth muscle cells, which leads to the recruitment of additional CD4 and CD8 T cells and also monocytes that differentiate into macrophages. Recent data have shown that IL-17, IFN-γ 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. 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 aging process has been associated with modifications to multiple cells implicated in the immune response and vascular remodeling, such as dendritic cells (DC), T cells, endothelial cells and vascular smooth muscle cells (VSMC). In particular, aging triggers a decrease in the number of naive T cells, increase in memory and effector T cells, decrease in the diversity of the T-cell repertoire and enrichment in CD4+CD28− and CD8+CD28− senescent T cells. Immune aging also alters the regulation of immune cells, for instance, by impacting CD8+ Treg, thus leading to the production of pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) by senescent DCs, macrophages, endothelial cells and fibroblasts. […] The role of DC in the pathogenesis of GCA suggests a relationship between a potential infection and the initiation of GCA. It is generally assumed that an infectious agent can activate adventitial DC and trigger immunologic processes leading to the development of vasculitis. However, this hypothesis has never been fully resolved, mainly because no specific pathogen triggering GCA has been identified. […] The immunopathological model of GCA can be divided into four main phases. Phase 1: Loss of Tolerance and Activation of Resident Dendritic Cells of the Adventitia. Immature myeloid DCs are physiologically localized in the adventitia where they are involved in immune surveillance. These cells can trigger adaptive immunity after detecting danger signals through pattern recognition receptors (PPRs) such as TLR. By contrast, they induce tolerance in the absence of a danger signal. The detection of a danger signal via TLR of adventitial DCs induces their activation, followed by phenotypic modifications and the production of cytokines and chemokines responsible for the recruitment of CD4+ T cells in the arterial wall. […] CD4+ T cells, which are physiologically absent from the walls of healthy arteries, play a major role in the pathogenesis of GCA, as highlighted by the fact that their depletion in immunocompromised mice engrafted with GCA arteries strongly decreases vasculitis lesions. […] The strong infiltration of Th1 and Th17 cells into the arterial wall is responsible for the production of large amounts of IFN-γ and IL-17, respectively. IFN-γ induces the production of several chemokines by VSMCs. […] Macrophages play a major role in vascular remodeling through their ability to produce enzymes, growth factors and other mediators. […] Current knowledge also suggests that IFN-γ, which is produced by Th1 cells, is the main lymphocytic cytokine inducing vascular remodeling. IFN-γ-activated macrophages, giant cells or injured VSMCs produce growth factors, essentially platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF). […] The major role of IL-6 in the GCA pathogenesis is demonstrated by the dramatic efficacy of tocilizumab for the treatment of GCA. Furthermore, the Th17/Treg imbalance observed in GCA is controlled by IL-6, which increases Th17 polarization and decreases Treg differentiation.

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

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

  In GCA, VSMCs are injured by mediators released by mononuclear cells, which have accumulated in the media, and acquire pro-inflammatory properties. […] Activated macrophages and VSMCs themselves produce several growth factors (PDGF, TGF-, endothelin-1 [ET-1], NGF and BDNF neutrophins), thus inducing the migration of VSMCs into the intima and their differentiation into myofibroblasts, which synthesize matrix proteins.

• #52 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.

• #53 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.

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

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

  Giant cell arteritis (GCA) has replaced temporal arteritis (TA) as the preferred term due to the multiple vessels involved. […] 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).

• #55 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.

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

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10855045/

  The tunica media is progressively destroyed, while the intima undergoes thickening due to myofibroblast proliferation and protein deposition in the extracellular matrix, leading to vessel occlusion. […] A key role of macrophages has been identified in this process. […] 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. […] Given the role of B lymphocytes in the pathogenesis of GCA, autoantibodies that could facilitate diagnosis were also sought.

• #57 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.

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

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

  New Insights into the Pathogenesis of Giant Cell Arteritis: Mechanisms Involved in Maintaining Vascular Inflammation […] 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-γ) and interleukin-17 (IL-17), respectively. IFN-γ triggers the production of chemokines by vascular smooth muscle cells, which leads to the recruitment of additional CD4 and CD8 T cells and also monocytes that differentiate into macrophages. Recent data have shown that IL-17, IFN-γ 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. 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 aging process has been associated with modifications to multiple cells implicated in the immune response and vascular remodeling, such as dendritic cells (DC), T cells, endothelial cells and vascular smooth muscle cells (VSMC). In particular, aging triggers a decrease in the number of naive T cells, increase in memory and effector T cells, decrease in the diversity of the T-cell repertoire and enrichment in CD4+CD28− and CD8+CD28− senescent T cells. Immune aging also alters the regulation of immune cells, for instance, by impacting CD8+ Treg, thus leading to the production of pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) by senescent DCs, macrophages, endothelial cells and fibroblasts. […] The role of DC in the pathogenesis of GCA suggests a relationship between a potential infection and the initiation of GCA. It is generally assumed that an infectious agent can activate adventitial DC and trigger immunologic processes leading to the development of vasculitis. However, this hypothesis has never been fully resolved, mainly because no specific pathogen triggering GCA has been identified. […] The immunopathological model of GCA can be divided into four main phases. Phase 1: Loss of Tolerance and Activation of Resident Dendritic Cells of the Adventitia. Immature myeloid DCs are physiologically localized in the adventitia where they are involved in immune surveillance. These cells can trigger adaptive immunity after detecting danger signals through pattern recognition receptors (PPRs) such as TLR. By contrast, they induce tolerance in the absence of a danger signal. The detection of a danger signal via TLR of adventitial DCs induces their activation, followed by phenotypic modifications and the production of cytokines and chemokines responsible for the recruitment of CD4+ T cells in the arterial wall. […] CD4+ T cells, which are physiologically absent from the walls of healthy arteries, play a major role in the pathogenesis of GCA, as highlighted by the fact that their depletion in immunocompromised mice engrafted with GCA arteries strongly decreases vasculitis lesions. […] The strong infiltration of Th1 and Th17 cells into the arterial wall is responsible for the production of large amounts of IFN-γ and IL-17, respectively. IFN-γ induces the production of several chemokines by VSMCs. […] Macrophages play a major role in vascular remodeling through their ability to produce enzymes, growth factors and other mediators. […] Current knowledge also suggests that IFN-γ, which is produced by Th1 cells, is the main lymphocytic cytokine inducing vascular remodeling. IFN-γ-activated macrophages, giant cells or injured VSMCs produce growth factors, essentially platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF). […] The major role of IL-6 in the GCA pathogenesis is demonstrated by the dramatic efficacy of tocilizumab for the treatment of GCA. Furthermore, the Th17/Treg imbalance observed in GCA is controlled by IL-6, which increases Th17 polarization and decreases Treg differentiation.

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

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

  New Insights into the Pathogenesis of Giant Cell Arteritis: Mechanisms Involved in Maintaining Vascular Inflammation […] 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-γ) and interleukin-17 (IL-17), respectively. IFN-γ triggers the production of chemokines by vascular smooth muscle cells, which leads to the recruitment of additional CD4 and CD8 T cells and also monocytes that differentiate into macrophages. Recent data have shown that IL-17, IFN-γ 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. 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 aging process has been associated with modifications to multiple cells implicated in the immune response and vascular remodeling, such as dendritic cells (DC), T cells, endothelial cells and vascular smooth muscle cells (VSMC). In particular, aging triggers a decrease in the number of naive T cells, increase in memory and effector T cells, decrease in the diversity of the T-cell repertoire and enrichment in CD4+CD28− and CD8+CD28− senescent T cells. Immune aging also alters the regulation of immune cells, for instance, by impacting CD8+ Treg, thus leading to the production of pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) by senescent DCs, macrophages, endothelial cells and fibroblasts. […] The role of DC in the pathogenesis of GCA suggests a relationship between a potential infection and the initiation of GCA. It is generally assumed that an infectious agent can activate adventitial DC and trigger immunologic processes leading to the development of vasculitis. However, this hypothesis has never been fully resolved, mainly because no specific pathogen triggering GCA has been identified. […] The immunopathological model of GCA can be divided into four main phases. Phase 1: Loss of Tolerance and Activation of Resident Dendritic Cells of the Adventitia. Immature myeloid DCs are physiologically localized in the adventitia where they are involved in immune surveillance. These cells can trigger adaptive immunity after detecting danger signals through pattern recognition receptors (PPRs) such as TLR. By contrast, they induce tolerance in the absence of a danger signal. The detection of a danger signal via TLR of adventitial DCs induces their activation, followed by phenotypic modifications and the production of cytokines and chemokines responsible for the recruitment of CD4+ T cells in the arterial wall. […] CD4+ T cells, which are physiologically absent from the walls of healthy arteries, play a major role in the pathogenesis of GCA, as highlighted by the fact that their depletion in immunocompromised mice engrafted with GCA arteries strongly decreases vasculitis lesions. […] The strong infiltration of Th1 and Th17 cells into the arterial wall is responsible for the production of large amounts of IFN-γ and IL-17, respectively. IFN-γ induces the production of several chemokines by VSMCs. […] Macrophages play a major role in vascular remodeling through their ability to produce enzymes, growth factors and other mediators. […] Current knowledge also suggests that IFN-γ, which is produced by Th1 cells, is the main lymphocytic cytokine inducing vascular remodeling. IFN-γ-activated macrophages, giant cells or injured VSMCs produce growth factors, essentially platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF). […] The major role of IL-6 in the GCA pathogenesis is demonstrated by the dramatic efficacy of tocilizumab for the treatment of GCA. Furthermore, the Th17/Treg imbalance observed in GCA is controlled by IL-6, which increases Th17 polarization and decreases Treg differentiation.

• #60 Giant Cell Arteritis – Musculoskeletal and Connective Tissue Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/musculoskeletal-and-connective-tissue-disorders/vasculitis/giant-cell-arteritis

  If the diagnosis of giant cell arteritis is suspected, biopsy of an artery is recommended. Because inflamed segments often alternate with normal segments, a segment that appears abnormal should be sampled if possible. […] Tocilizumab, an interleukin (IL)-6 receptor antagonist, should be considered when treatment with corticosteroids is initiated, which allows for an accelerated corticosteroid tapering regimen. Tocilizumab has been shown to reduce exposure to corticosteroids.

• #61 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.

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

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

  In GCA, VSMCs are injured by mediators released by mononuclear cells, which have accumulated in the media, and acquire pro-inflammatory properties. […] Activated macrophages and VSMCs themselves produce several growth factors (PDGF, TGF-, endothelin-1 [ET-1], NGF and BDNF neutrophins), thus inducing the migration of VSMCs into the intima and their differentiation into myofibroblasts, which synthesize matrix proteins.

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

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

  It has been shown that Treg present at the level of the vessel wall in GCA are unable to perform their regulatory function. […] An important role in the pathogenesis of GCA is played by Treg. […] 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. […] A significant role in the pathogenesis of GCA is played by the cells of the arterial wall itself. […] A key role of macrophages has been identified in this process. […] The tunica media is progressively destroyed, while the intima undergoes thickening due to myofibroblast proliferation and protein deposition in the extracellular matrix, leading to vessel occlusion. […] 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.

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

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10855045/

  The tunica media is progressively destroyed, while the intima undergoes thickening due to myofibroblast proliferation and protein deposition in the extracellular matrix, leading to vessel occlusion. […] A key role of macrophages has been identified in this process. […] 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. […] Given the role of B lymphocytes in the pathogenesis of GCA, autoantibodies that could facilitate diagnosis were also sought.

• #65 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.

• #66 Giant Cell Arteritis – EyeWiki

  https://eyewiki.org/Giant_Cell_Arteritis

  Metalloproteinases and reactive oxygen intermediates expressed by macrophages ultimately cause destruction within the blood vessel wall. […] After this initial immune response, the vessel undergoes a healing response to injury, which includes intimal thickening, myofibroblast proliferation, and extracellular matrix deposition all of which contribute to vascular stenosis and occlusion. […] This vascular stenosis and occlusion ultimately cause a variable set of signs and symptoms, depending on the territory supplied by the affected vessel. […] The pathology of the disease was further explained by Gilmoure in 1941 when he described the presence of giant cells as part of the disease. […] The most common vessels affected are the superficial temporal artery, the ophthalmic artery, the posterior ciliary arteries, and the vertebral arteries.

• #67 Pathogenesis of giant cell arteritis – UpToDate

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

  Pathogenesis of giant cell arteritis […] Giant cell arteritis (GCA) is a chronic inflammatory disease involving large- and medium-sized arteries and affecting individuals older than 50 years. Involvement of the cranial branches of the carotid arteries is very common and, due to its easy access, biopsy of the superficial temporal artery is frequently performed to obtain histopathologic confirmation of GCA. […] 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.

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

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

  Adventitia-based macrophages produce interleukin-6 (IL-6), which further augments the inflammatory cascade. Interferon-activated macrophages within the media release chemokines (such as CXCL9, CXCL10, and CXCL11), produce reactive oxygen, growth factors (such as fibroblast growth factor), and metalloproteases (MMP-2, MMP-9), which degrade the arterial wall and fragment the elastic lamina. […] 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. […] The exuberant release of cytokines associated with this process may be responsible for the constitutional symptoms frequently encountered with the disease. […] 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).

• #69 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 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. […] 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.

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

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10855045/

  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 role played by type-I interferon in GCA, particularly IFN-, the interferon signature, that is, the activation of those genes specifically induced by the action of this cytokine at the level of aortic tissue, was studied. […] The JAK/STAT signaling pathway appears to be up-regulated in patients with this vasculitis.

• #71 Biologic Therapies for Giant Cell Arteritis | BTT

  https://www.dovepress.com/biologic-therapies-for-giant-cell-arteritis-peer-reviewed-fulltext-article-BTT

  The importance of the JAK/STAT pathway in the pathophysiology of GCA has more recently garnered attention. It is postulated that JAK-1 and JAK-2 inhibition can downregulate both the Th-17 and Th-1 pathways, notably suppressing the effects of IFN-, IL-12 and IL-23 (the targets of ustekinumab) and IL-6 (the target of tocilizumab). As a result, JAK inhibitors are currently under investigation in clinical trials for GCA treatment.

• #72 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 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. […] 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.

• #73 Giant Cell Arteritis versus Takayasu Arteritis: An Update | MJR – Mediterranean Journal of Rheumatology

  http://www.mjrheum.org/june-2020/showreferences792/1/showfulltext792/1/newsid792/240

  The above-mentioned HLA-class II genetic associations and the presence of clonal T-cells in different arterial sites suggest that GCA is an immune mediated disease. In large and medium sized arteries with vasa vasorum (diameter 2000m), reside in the adventitia media border vascular dendritic cells (vas DCs). These vas DCs in healthy individuals are tolerogenic, sparing the host of the devastating consequences of inflammation in the arterial tissue. Several studies have shown that these vas DCs are impaired in GCA. In predisposed for GCA individuals, impaired vas DCs (eg, with polymorphisms in their Toll-like receptors) may be activated by the presence of danger signals, gaining T stimulatory capacity. This activation causes the migration of these DCs in the media where DCs produce chemotactic factors, which, in turn, cause the migration and activation of T-cells and macrophages. The subsequent inflammatory cascade orchestrated, mainly, by Th1-cell mediated and Th17-cell mediated responses contribute to the granulomatous infiltrate seen in GCA. There are also emerging data regarding possible immunostromal interactions (between T-cells, vascular smooth cells and endothelial cell, eg, Notch-Notch ligand interactions) and immunoinhibitory signals such as PD1-PDL1 pathway.

• #74 Giant Cell Arteritis | Encyclopedia MDPI

  https://encyclopedia.pub/entry/54742

  Initial studies had suggested a possible role of autoantibodies produced by B cells in the pathogenesis of GCA. These findings, however, have not subsequently been confirmed. In more recent studies, B cells and plasma cells have been identified in high numbers in the temporal artery of patients with this form of GCA.

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

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10855045/

  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 role played by type-I interferon in GCA, particularly IFN-, the interferon signature, that is, the activation of those genes specifically induced by the action of this cytokine at the level of aortic tissue, was studied. […] The JAK/STAT signaling pathway appears to be up-regulated in patients with this vasculitis.

• #76 Giant Cell Arteritis | Encyclopedia MDPI

  https://encyclopedia.pub/entry/54742

  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. […] 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. Dendritic cells express toll-like receptors (TLRs) on their surface, which can recognize specific pathogen-associated molecular patterns (PAMPs) derived from components of microorganisms and/or damage-associated molecular patterns (DAMPs) that recognize various proteins, including fragments of necrotic self-cells.

• #77

  https://insight.jci.org/articles/view/139163

  Giant cell arteritis (GCA) is a common form of primary systemic vasculitis in adults, with no reliable indicators of prognosis or treatment responses. […] Immature neutrophils were resistant to apoptosis, remained in the vasculature for a prolonged period of time, interacted with platelets, and extravasated into the tissue surrounding the temporal arteries of patients with GCA. […] We discovered that immature neutrophils generated high levels of extracellular reactive oxygen species, leading to enhanced protein oxidation and permeability of endothelial barrier in an in vitro coculture system. […] These findings link functions of immature neutrophils to disease pathogenesis, establishing a clinical cellular signature of GCA and suggesting different therapeutic approaches in systemic vascular inflammation.

• #78

  https://insight.jci.org/articles/view/139163

  In this study, we identified immature neutrophils as the cells that were characteristic of the patients with GCA, as well as GPA; remained in the vasculature for a prolonged time; interacted with platelets; extravasated into the tissue surrounding the temporal arteries; and generated high levels of extracellular ROS, affecting vascular barrier. […] These findings contribute to better understanding of GCA pathophysiology and lead to previously unrecognized therapeutic approaches to systemic vascular inflammation. […] Immature neutrophils extravasate into temporal artery walls of GCA patient biopsies. […] The potent release of extracellular ROS by immature CD10loCD64CD16hi LDNs was mirrored by an increase in permeability of the endothelial barrier in the neutrophil-endothelial coculture system.

• #79

  https://insight.jci.org/articles/view/139163

  Together, these data suggest that the immature neutrophil populations remained in the circulation of GCA patients for an extended period of time and were associated with clinical disease activity. […] We propose that immature neutrophils may play an active role in GCA pathogenesis. Through their extended life span and capabilities to cause vascular damage, immature neutrophils are the likely culprits to initiate blood vessel lesion, leading to local inflammation and gradually systemic vasculitis.

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

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10855045/

  The tunica media is progressively destroyed, while the intima undergoes thickening due to myofibroblast proliferation and protein deposition in the extracellular matrix, leading to vessel occlusion. […] A key role of macrophages has been identified in this process. […] 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. […] Given the role of B lymphocytes in the pathogenesis of GCA, autoantibodies that could facilitate diagnosis were also sought.

• #81 Giant Cell Arteritis Challenging to Diagnose, Manage – Page 6 of 6 – The Rheumatologist

  https://www.the-rheumatologist.org/article/giant-cell-arteritis-challenging-to-diagnose-manage/6/?singlepage=1

  GCA carries a substantial morbidity burden related not only to the disease itself but also to its therapy. […] The etiology of GCA remains elusive. However, research suggests that two distinct pathways driven by T helper (Th) 17 and Th1 lymphocytes, and a suppressed regulatory T-cell response contribute to disease pathogenesis. […] The IL-6 pathway, overexpressed in GCA, represents a potential target for therapy. IL-6 has diverse biological functions depending on its target cell. […] In GCA patients, the IL-6 gene is actively transcribed within inflamed arteries, and the IL-6 concentration is elevated in peripheral circulation. […] Therefore, IL-6 signaling inhibition may ameliorate large-vessel vasculitis in GCA through different mechanisms that include altering upstream differentiation of autoreactive lymphocytes, promoting the generation of regulatory T cells, and/or deamplifying downstream aspects of the innate inflammatory network. […] Although GCA is the most common form of primary vasculitis among adults in the U.S. and Europe, the cause of this disease is still unknown and its pathogenesis is poorly understood.

• #82 Giant Cell Arteritis Challenging to Diagnose, Manage – Page 6 of 6 – The Rheumatologist

  https://www.the-rheumatologist.org/article/giant-cell-arteritis-challenging-to-diagnose-manage/6/?singlepage=1

  GCA carries a substantial morbidity burden related not only to the disease itself but also to its therapy. […] The etiology of GCA remains elusive. However, research suggests that two distinct pathways driven by T helper (Th) 17 and Th1 lymphocytes, and a suppressed regulatory T-cell response contribute to disease pathogenesis. […] The IL-6 pathway, overexpressed in GCA, represents a potential target for therapy. IL-6 has diverse biological functions depending on its target cell. […] In GCA patients, the IL-6 gene is actively transcribed within inflamed arteries, and the IL-6 concentration is elevated in peripheral circulation. […] Therefore, IL-6 signaling inhibition may ameliorate large-vessel vasculitis in GCA through different mechanisms that include altering upstream differentiation of autoreactive lymphocytes, promoting the generation of regulatory T cells, and/or deamplifying downstream aspects of the innate inflammatory network. […] Although GCA is the most common form of primary vasculitis among adults in the U.S. and Europe, the cause of this disease is still unknown and its pathogenesis is poorly understood.

• #83 Giant Cell Arteritis – Rheumatology Advisor

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

  According to genome-wide association studies, HLA genes, such as HLA Br1*04 in the White population, are linked to GCA and increased risk of complications, including loss of vision and increased resistance to glucocorticoids. PTPN22, LRRC32, IL17A, and IL33 are examples of non-HLA genes linked to giant cell arteritis. The majority of the genes discovered are related to endothelial function, innate immunity, and cytokines and their receptors. […] 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.

• #84

  https://journals.lww.com/co-rheumatology/fulltext/2025/01000/giant_cell_arteritis__update_on_pathogenesis_and.11.aspx

  Giant cell arteritis (GCA) is an age-related autoimmune disease with a complex pathogenesis that involves several pathogenic mechanisms. This review provides recent critical insights into novel aspects of GCA pathogenesis. […] The use of novel approaches, including multiomic techniques, has uncovered notable findings that broaden the understanding of GCA pathogenesis. TCF1hiCD4+ T cells have been identified as stem-like T cells residing in tertiary lymphoid structures in the adventitia of GCA aortic tissues, which likely supply the pathogenic effector T cells present in vasculitic lesions. Studies have demonstrated that fibroblasts present in GCA-inflamed arteries are not innocent bystanders, but they contribute to arterial inflammation via maintenance of Th1 and Th17 polarisation, cytokine secretion (IL-6, IL-1B, IL-12, and IL-23) and antigen presentation. Additionally, deregulated cellular senescence programs are present in GCA as an accumulation of IL-6 and matrix metalloproteinase 9-producing senescent cells have been identified in vasculitic lesions.

• #85

  https://journals.lww.com/co-rheumatology/fulltext/2025/01000/giant_cell_arteritis__update_on_pathogenesis_and.11.aspx

  Giant cell arteritis (GCA) is an age-related autoimmune disease with a complex pathogenesis that involves several pathogenic mechanisms. This review provides recent critical insights into novel aspects of GCA pathogenesis. […] The use of novel approaches, including multiomic techniques, has uncovered notable findings that broaden the understanding of GCA pathogenesis. TCF1hiCD4+ T cells have been identified as stem-like T cells residing in tertiary lymphoid structures in the adventitia of GCA aortic tissues, which likely supply the pathogenic effector T cells present in vasculitic lesions. Studies have demonstrated that fibroblasts present in GCA-inflamed arteries are not innocent bystanders, but they contribute to arterial inflammation via maintenance of Th1 and Th17 polarisation, cytokine secretion (IL-6, IL-1B, IL-12, and IL-23) and antigen presentation. Additionally, deregulated cellular senescence programs are present in GCA as an accumulation of IL-6 and matrix metalloproteinase 9-producing senescent cells have been identified in vasculitic lesions.

• #86

  https://journals.lww.com/co-rheumatology/fulltext/2025/01000/giant_cell_arteritis__update_on_pathogenesis_and.11.aspx

  Recent studies have unravelled interesting findings with potentially significant clinical relevance. Stem-like T cells are likely key contributors to vascular disease persistence, and targeted depletion or modulation of these cells holds promise in GCA management. Fibroblast-targeting therapies and senotherapeutics are also exciting prospects in the treatment of GCA.

• #87 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.

• #88 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.

• #89 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.

• #90 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 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. […] 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.

• #91

  https://journals.lww.com/co-rheumatology/fulltext/2025/01000/giant_cell_arteritis__update_on_pathogenesis_and.11.aspx

  Recent studies have unravelled interesting findings with potentially significant clinical relevance. Stem-like T cells are likely key contributors to vascular disease persistence, and targeted depletion or modulation of these cells holds promise in GCA management. Fibroblast-targeting therapies and senotherapeutics are also exciting prospects in the treatment of GCA.

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