Materiały źródłowe

• #1 Systemic Vasculitis | AAFP

  https://www.aafp.org/pubs/afp/issues/2011/0301/p556.html

  The pathogenesis of vasculitides is poorly understood. Three possible mechanisms of vascular damage are immune complex deposition, ANCAs (humoral response), and T-lymphocyte response with granuloma formation (cell-mediated). The end result of these various pathways is endothelial cell activation, with subsequent vessel obstruction and ischemia of dependent tissue. This may cause hemorrhage in the surrounding tissues and, in some cases, weakening of the vessel wall, which leads to the formation of aneurysms. For almost all forms of vasculitis, the triggering event initiating and driving this inflammatory response is unknown. Many small vessel vasculitides have a paucity of vascular immune deposits and, therefore, other mechanisms have been sought for these so-called pauci-immune vasculitides.

• #2 Immunologic Mechanisms of Vasculitis – Clinical Tree

  https://clinicalpub.com/immunologic-mechanisms-of-vasculitis/

  The kidneys are among the organs most commonly affected by systemic vasculitis. This chapter reviews the etiology and pathogenesis of forms of vasculitis that most often affect the kidneys. A broad spectrum of cellular and humoral inflammatory mediator systems are involved in the pathophysiology of vasculitis. The two most common pathways to renal vasculitis are immunoglobulin-rich immune complex-mediated vasculitis and immunoglobulin-poor pauci-immune antineutrophil cytoplasmic autoantibody (ANCA)-mediated vasculitis. Immune complexes in vessel walls cause inflammation by activating humoral and cellular inflammatory mediator systems in the blood, including the complement, kinin, and coagulation systems. ANCA cause vasculitis by activating cytokine-primed neutrophils by both Fc and Fab2 binding, resulting in the release of destructive oxygen radicals and lytic enzymes that injure tissue. This inflammation is amplified by activation of the alternative complement system with generation of C5a, which is a pivotal factor in mediating intense necrotizing inflammation.

• #2 The pathogenesis of vasculitis | Arthritis Research & Therapy | Full Text

  https://arthritis-research.biomedcentral.com/articles/10.1186/ar164

  In the secondary vasculitides, associated with infectious disorders, connective tissue diseases and other conditions, immune complexes play a major immunopathogenic role. […] T-cells are, probably, involved in the large vessel vasculitides, particularly giant cell arteritis, whereas the small vessel vasculitides are associated with anti-neutrophil cytoplasmic autoantibodies (ANCA). […] Clinical observations, in vitro experimental findings, and in vivo data from animal experiments suggest that ANCA in those diseases, which are directed to proteinase 3 (PR3) or myeloperoxidase (MPO), are involved in their pathogenesis. […] ANCA appear to activate integrin-mediated adhesion of neutrophils and adhesion-dependent degranulation. […] Data from clinical and experimental studies suggest that ANCA alone are not sufficient to induce disease. Exogenous factors, in particular carriage of Staphylococcus aureus and silica exposure, may be involved as well. […] Taken together, the interplay between genetic and exogenous factors may induce autoimmunity to myeloid enzymes which, in concert, lead to the clinical expression of the ANCA-associated vasculitides.

• #3 Vasculitis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK545186/

  Vasculitis is a heterogeneous group of pathologies characterized by inflammation of vessels. They share common links of clinical, laboratory, and pathophysiologic features. The clinical and pathological features are variable and depend on the site and type of blood vessels affected. […] The endothelium is an active player in inflammatory processes and pathogenesis of vasculitis. Cytokine-mediated changes in the expression and function of adhesion molecules coupled with inappropriate activation of leukocytes and endothelial cells are the primary factors influencing the degree and location of vessel damage in vasculitis syndromes. Few mechanisms studied include pathogenic immune complex formation and deposition (mixed cryoglobulinemia, PAN), production of antineutrophilic cytoplasmic antibodies (in GPA, MPA, and Churg-Strauss syndrome), and pathogenic T lymphocyte responses and granuloma formation.

• #3 Systemic Vasculitis | AAFP

  https://www.aafp.org/pubs/afp/issues/2011/0301/p556.html

  The pathogenesis of vasculitides is poorly understood. Three possible mechanisms of vascular damage are immune complex deposition, ANCAs (humoral response), and T-lymphocyte response with granuloma formation (cell-mediated). The end result of these various pathways is endothelial cell activation, with subsequent vessel obstruction and ischemia of dependent tissue. This may cause hemorrhage in the surrounding tissues and, in some cases, weakening of the vessel wall, which leads to the formation of aneurysms. For almost all forms of vasculitis, the triggering event initiating and driving this inflammatory response is unknown. Many small vessel vasculitides have a paucity of vascular immune deposits and, therefore, other mechanisms have been sought for these so-called pauci-immune vasculitides.

• #4 Systemic Vasculitis | AAFP

  https://www.aafp.org/pubs/afp/issues/2011/0301/p556.html

  The pathogenesis of vasculitides is poorly understood. Three possible mechanisms of vascular damage are immune complex deposition, ANCAs (humoral response), and T-lymphocyte response with granuloma formation (cell-mediated). The end result of these various pathways is endothelial cell activation, with subsequent vessel obstruction and ischemia of dependent tissue. This may cause hemorrhage in the surrounding tissues and, in some cases, weakening of the vessel wall, which leads to the formation of aneurysms. For almost all forms of vasculitis, the triggering event initiating and driving this inflammatory response is unknown. Many small vessel vasculitides have a paucity of vascular immune deposits and, therefore, other mechanisms have been sought for these so-called pauci-immune vasculitides.

• #4 The pathogenesis of vasculitis | Arthritis Research & Therapy | Full Text

  https://arthritis-research.biomedcentral.com/articles/10.1186/ar164

  In the secondary vasculitides, associated with infectious disorders, connective tissue diseases and other conditions, immune complexes play a major immunopathogenic role. […] T-cells are, probably, involved in the large vessel vasculitides, particularly giant cell arteritis, whereas the small vessel vasculitides are associated with anti-neutrophil cytoplasmic autoantibodies (ANCA). […] Clinical observations, in vitro experimental findings, and in vivo data from animal experiments suggest that ANCA in those diseases, which are directed to proteinase 3 (PR3) or myeloperoxidase (MPO), are involved in their pathogenesis. […] ANCA appear to activate integrin-mediated adhesion of neutrophils and adhesion-dependent degranulation. […] Data from clinical and experimental studies suggest that ANCA alone are not sufficient to induce disease. Exogenous factors, in particular carriage of Staphylococcus aureus and silica exposure, may be involved as well. […] Taken together, the interplay between genetic and exogenous factors may induce autoimmunity to myeloid enzymes which, in concert, lead to the clinical expression of the ANCA-associated vasculitides.

• #5 Vasculitis: mechanisms involved and clinical manifestations | Arthritis Research & Therapy | Full Text

  https://arthritis-research.biomedcentral.com/articles/10.1186/ar2193

  Systemic vasculitis, an inflammatory necrotizing disease of the blood vessel walls, can occur secondary to autoimmune diseases, including connective tissue diseases. Various pathogenic mechanisms have been implicated in the induction of vasculitis, including cell-mediated inflammation, immune complex-mediated inflammation and autoantibody-mediated inflammation. […] Progress in the classification of the systemic vasculitides has facilitated better understanding of the pathogenesis underlying these inflammatory conditions, which can involve cell-mediated inflammation, immune complex (IC)-mediated inflammation, and ANCA-mediated inflammation. Of central importance is that many data have accumulated demonstrating that various inflammatory pathways lead to endothelial cell activation, which may induce complications such as vessel occlusion and tissue destruction in a predisposed host, and longstanding disease.

• #5 Vasculitis: mechanisms involved and clinical manifestations | Arthritis Research & Therapy | Full Text

  https://arthritis-research.biomedcentral.com/articles/10.1186/ar2193

  In GCA, for example, vasculitis is essentially a T-cell driven process that is triggered by exposure to antigens, most probably infectious agents. […] In contrast to GCA, which appears to be an antigen-driven disease with local T cell and macrophage activation in the vessel wall, IC formation is usually considered to be the major pathological event in polyarteritis nodosa, cryoglobulinaemia and Henoch-Schnlein purpura. […] Autoantibodies play a central role in the ANCA-related vasculitis that is characteristic of Wegener’s granulomatosis, Churg-Strauss syndrome, microscopic polyangiitis and necrotizing glomerulonephritis. […] IC formation and binding to the endothelial cell surface leading to endothelial cell activation plays an important role in the pathogenesis of vasculitis and is a feature of vasculitis in both RA and SLE. […] Binding of autoantibodies and ICs to the surface of endothelial cells results, among other things, in enhanced ET-1 release. […] There is evidence, albeit limited, suggesting that ET-1 plays a role in some clinical manifestations of vasculitis.

• #6 Vasculitis: mechanisms involved and clinical manifestations | Arthritis Research & Therapy | Full Text

  https://arthritis-research.biomedcentral.com/articles/10.1186/ar2193

  In GCA, for example, vasculitis is essentially a T-cell driven process that is triggered by exposure to antigens, most probably infectious agents. […] In contrast to GCA, which appears to be an antigen-driven disease with local T cell and macrophage activation in the vessel wall, IC formation is usually considered to be the major pathological event in polyarteritis nodosa, cryoglobulinaemia and Henoch-Schnlein purpura. […] Autoantibodies play a central role in the ANCA-related vasculitis that is characteristic of Wegener’s granulomatosis, Churg-Strauss syndrome, microscopic polyangiitis and necrotizing glomerulonephritis. […] IC formation and binding to the endothelial cell surface leading to endothelial cell activation plays an important role in the pathogenesis of vasculitis and is a feature of vasculitis in both RA and SLE. […] Binding of autoantibodies and ICs to the surface of endothelial cells results, among other things, in enhanced ET-1 release. […] There is evidence, albeit limited, suggesting that ET-1 plays a role in some clinical manifestations of vasculitis.

• #7 Vasculitis: mechanisms involved and clinical manifestations | Arthritis Research & Therapy | Full Text

  https://arthritis-research.biomedcentral.com/articles/10.1186/ar2193

  In GCA, for example, vasculitis is essentially a T-cell driven process that is triggered by exposure to antigens, most probably infectious agents. […] In contrast to GCA, which appears to be an antigen-driven disease with local T cell and macrophage activation in the vessel wall, IC formation is usually considered to be the major pathological event in polyarteritis nodosa, cryoglobulinaemia and Henoch-Schnlein purpura. […] Autoantibodies play a central role in the ANCA-related vasculitis that is characteristic of Wegener’s granulomatosis, Churg-Strauss syndrome, microscopic polyangiitis and necrotizing glomerulonephritis. […] IC formation and binding to the endothelial cell surface leading to endothelial cell activation plays an important role in the pathogenesis of vasculitis and is a feature of vasculitis in both RA and SLE. […] Binding of autoantibodies and ICs to the surface of endothelial cells results, among other things, in enhanced ET-1 release. […] There is evidence, albeit limited, suggesting that ET-1 plays a role in some clinical manifestations of vasculitis.

• #8 IgA Vasculitis (Henoch-Schonlein Purpura): Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/984105-overview

  IgA clearly plays a critical role in the immunopathogenesis of IgAV, as evidenced by increased serum IgA concentrations, IgA-containing circulating immune complexes, and IgA deposition in vessel walls of affected organs and in the kidney mesangium. Deposition of IgA aggregates or IgA complexes in target organs occurs with activation of the alternative complement pathway (with deposition of C3). This results in elaboration of inflammatory mediators, including vascular prostaglandins such as prostacyclin, that may play a central role in the pathogenesis of IgAV and its organ-specific clinical manifestations. […] IgA is found in the serum and mucosal secretions and is a major class of immunoglobulins that plays an important role in mucosal immunity. IgAV is almost exclusively associated with abnormalities involving IgA1, rather than IgA2. IgA1 is phylogenetically younger and differs from IgA2 by the insertion of a 13-17 amino acid sequence in the hinge region of the IgA1 molecule.

• #9 IgA Vasculitis (Henoch-Schonlein Purpura): Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/984105-overview

  IgA clearly plays a critical role in the immunopathogenesis of IgAV, as evidenced by increased serum IgA concentrations, IgA-containing circulating immune complexes, and IgA deposition in vessel walls of affected organs and in the kidney mesangium. Deposition of IgA aggregates or IgA complexes in target organs occurs with activation of the alternative complement pathway (with deposition of C3). This results in elaboration of inflammatory mediators, including vascular prostaglandins such as prostacyclin, that may play a central role in the pathogenesis of IgAV and its organ-specific clinical manifestations. […] IgA is found in the serum and mucosal secretions and is a major class of immunoglobulins that plays an important role in mucosal immunity. IgAV is almost exclusively associated with abnormalities involving IgA1, rather than IgA2. IgA1 is phylogenetically younger and differs from IgA2 by the insertion of a 13-17 amino acid sequence in the hinge region of the IgA1 molecule.

• #10 IgA Vasculitis (Henoch-Schonlein Purpura): Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/984105-overview

  IgA clearly plays a critical role in the immunopathogenesis of IgAV, as evidenced by increased serum IgA concentrations, IgA-containing circulating immune complexes, and IgA deposition in vessel walls of affected organs and in the kidney mesangium. Deposition of IgA aggregates or IgA complexes in target organs occurs with activation of the alternative complement pathway (with deposition of C3). This results in elaboration of inflammatory mediators, including vascular prostaglandins such as prostacyclin, that may play a central role in the pathogenesis of IgAV and its organ-specific clinical manifestations. […] IgA is found in the serum and mucosal secretions and is a major class of immunoglobulins that plays an important role in mucosal immunity. IgAV is almost exclusively associated with abnormalities involving IgA1, rather than IgA2. IgA1 is phylogenetically younger and differs from IgA2 by the insertion of a 13-17 amino acid sequence in the hinge region of the IgA1 molecule.

• #11 IgA Vasculitis (Henoch-Schonlein Purpura): Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/984105-overview

  The predominance of IgA1 in IgAV may be a consequence of abnormal glycosylation of O-linked oligosaccharides unique to the IgA1 hinge region. Patients with IgAV and IgA nephritis express inherited galactose-deficient glycosylation of IgA1 molecules. […] IgAV-associated nephritis is characterized by an abnormal IgA1 glycosylation pattern with reduced galactosylation. […] The lack of terminal 1,3-galactosyl residues in the hinge region of IgA might be due to the reduced activity of 1,3-galactosyltransferase in IgA1-producing peripheral B cells. This reduction of galactosylation results in the exposure of GalNAc residues in the IgA1 surface, forming a novel antigen and inducing a humoral IgG autoimmune response. […] Circulating complexes of mixed IgG and galactose-deficient IgA1 are detected in patients with IgAV, and also in the serum of patients with mucosal infections.

• #12 Pathogenesis and therapeutic interventions for ANCA-associated vasculitis | Nature Reviews Rheumatology

  https://www.nature.com/articles/s41584-018-0145-y

  Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) affects systemic small vessels and is accompanied by the presence of ANCAs in the serum. […] The mechanism by which ANCAs cause vasculitis involves ANCA-mediated excessive activation of neutrophils that subsequently release inflammatory cytokines, reactive oxygen species and lytic enzymes. […] Moreover, NETs are involved not only in ANCA-mediated vascular injury but also in the production of ANCAs themselves. Therefore, a vicious cycle of NET formation and ANCA production is considered to be involved in the pathogenesis of AAV. […] ANCAs have a central role in the pathogenesis of AAV because they induce excessive activation of neutrophils, which results in injury to small vessels. […] Elucidation of the aetiology and pathogenesis of AAV is needed to develop new biomarkers as well as novel targeted therapeutic agents.

• #13 Pathophysiology of Vasculitis | Thoracic Key

  https://thoracickey.com/pathophysiology-of-vasculitis/

  The principal antigens recognized by ANCA are the neutrophil enzymes myeloperoxidase (MPO) and proteinase-3 (PR3). […] Binding of ANCAs to cell surfaceassociated MPO and PR3 on intact neutrophils leads to further activation of these leukocytes. […] These events together aggravate the local inflammatory response. […] Not all patients with small-vessel vasculitis have ANCA-positive serology, indicating that some small-vessel vasculitides may involve other mechanisms or have low titer antibodies. […] Antineutrophil cytoplasmic antibodies have proven unequivocally pathogenic in mice. […] Antineutrophil cytoplasmic antibodies may provoke vasculitis in several ways. […] Production of pathogenic amounts of ANCA requires loss of tolerance. […] Multiple environmental and genetic factors modulate each pathogenic step from onset to outcome.

• #14

  https://link.springer.com/article/10.1007/s00467-017-3597-4

  Better understanding of the pathogenesis and treatment of primary systemic vasculitides (PSV) has led to the development of many potentially clinically relevant biomarkers. […] A considerable body of evidence supports the concept that ANCAs are directly involved in the pathogenesis of small vessel vasculitis. […] The most accepted model of pathogenesis proposes that ANCAs activate cytokine-primed neutrophils, leading to bystander damage of endothelial cells and an escalation of inflammation with recruitment of mononuclear cells. […] Thus, it is clear that ANCAs are directly pathogenic, but why do patients make ANCAs in the first instance? […] In recent years, the genetic factors predisposing to ANCA development are better understood. […] This study thus confirmed that the pathogenesis of ANCA-associated vasculitis has a genetic component, shows genetic distinctions between GPA and MPA in terms of the ANCA serotype, but not the phenotype of AAV per se.

• #15

  https://link.springer.com/article/10.1007/s00467-017-3597-4

  Better understanding of the pathogenesis and treatment of primary systemic vasculitides (PSV) has led to the development of many potentially clinically relevant biomarkers. […] A considerable body of evidence supports the concept that ANCAs are directly involved in the pathogenesis of small vessel vasculitis. […] The most accepted model of pathogenesis proposes that ANCAs activate cytokine-primed neutrophils, leading to bystander damage of endothelial cells and an escalation of inflammation with recruitment of mononuclear cells. […] Thus, it is clear that ANCAs are directly pathogenic, but why do patients make ANCAs in the first instance? […] In recent years, the genetic factors predisposing to ANCA development are better understood. […] This study thus confirmed that the pathogenesis of ANCA-associated vasculitis has a genetic component, shows genetic distinctions between GPA and MPA in terms of the ANCA serotype, but not the phenotype of AAV per se.

• #16 Pathogenesis and therapeutic interventions for ANCA-associated vasculitis | Nature Reviews Rheumatology

  https://www.nature.com/articles/s41584-018-0145-y

  Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) affects systemic small vessels and is accompanied by the presence of ANCAs in the serum. […] The mechanism by which ANCAs cause vasculitis involves ANCA-mediated excessive activation of neutrophils that subsequently release inflammatory cytokines, reactive oxygen species and lytic enzymes. […] Moreover, NETs are involved not only in ANCA-mediated vascular injury but also in the production of ANCAs themselves. Therefore, a vicious cycle of NET formation and ANCA production is considered to be involved in the pathogenesis of AAV. […] ANCAs have a central role in the pathogenesis of AAV because they induce excessive activation of neutrophils, which results in injury to small vessels. […] Elucidation of the aetiology and pathogenesis of AAV is needed to develop new biomarkers as well as novel targeted therapeutic agents.

• #17 What is ANCA? – Vasculitis UK

  https://www.vasculitis.org.uk/about-vasculitis/what-is-anca

  ANCA are not only a measurable blood marker in patients with ANCA-associated vasculitis but they are harmful autoantibodies that are directly involved in small blood vessel damage. The binding of ANCA to neutrophils in the blood, results in: 1 the release of toxic substances from neutrophils causing damage to small blood vessel walls, 2 neutrophil migration through blood vessel walls causing inflammation in surrounding tissues, 3 release of signalling factors that attract more neutrophils, perpetuating the inflammation and destruction of small blood vessels. […] ANCA-induced activation of neutrophils […] There is evidence that both genetic susceptibility and environmental exposures contribute to the aetiology of AAV. However, the actual mechanism by which ANCA arise in different people at different ages is poorly understood. Infections are one possible trigger; 63% of patients with granulomatosis with polyangiitis (GPA, Wegeners) chronically carry the common bacteria, Staphylococcus aureus in their noses, and nasal inflammation is common in GPA. Another proposed mechanism is molecular mimicry between bacterial and self-antigens, when similarities between foreign and self-antigens may be sufficient to activate immune cells. Alternatively ANCA may result from defective neutrophil cell death, resulting in abnormal exposure of internal neutrophil fragments.

• #18 Immunopathogenesis of ANCA-Associated Vasculitis

  https://www.mdpi.com/1422-0067/21/19/7319

  The initial mechanisms of ANCA generation are not well understood. […] The exposed autoantigens interact with ANCA which results in excessive activation of neutrophils adhering to endothelial cells. […] Thus, neutrophils, ANCA elevation, disruption of plasma and T cell tolerance, and overproduction and persistence of NETs together contribute to the pathogenesis of PR3-and MPO-ANCA vasculitis. […] One of the key steps in the pathogenesis of ANCA-associated vasculitis is priming of neutrophils, which in turn leads to expression of ANCA on the cell membrane. […] As Kessenbrock et al. demonstrated, NETs released by ANCA-stimulated neutrophils play a critical role in pathways leading to vascular damage and further ANCA production.

• #19 What is ANCA? – Vasculitis UK

  https://www.vasculitis.org.uk/about-vasculitis/what-is-anca

  ANCA are not only a measurable blood marker in patients with ANCA-associated vasculitis but they are harmful autoantibodies that are directly involved in small blood vessel damage. The binding of ANCA to neutrophils in the blood, results in: 1 the release of toxic substances from neutrophils causing damage to small blood vessel walls, 2 neutrophil migration through blood vessel walls causing inflammation in surrounding tissues, 3 release of signalling factors that attract more neutrophils, perpetuating the inflammation and destruction of small blood vessels. […] ANCA-induced activation of neutrophils […] There is evidence that both genetic susceptibility and environmental exposures contribute to the aetiology of AAV. However, the actual mechanism by which ANCA arise in different people at different ages is poorly understood. Infections are one possible trigger; 63% of patients with granulomatosis with polyangiitis (GPA, Wegeners) chronically carry the common bacteria, Staphylococcus aureus in their noses, and nasal inflammation is common in GPA. Another proposed mechanism is molecular mimicry between bacterial and self-antigens, when similarities between foreign and self-antigens may be sufficient to activate immune cells. Alternatively ANCA may result from defective neutrophil cell death, resulting in abnormal exposure of internal neutrophil fragments.

• #20 Pathophysiology of Vasculitis | Thoracic Key

  https://thoracickey.com/pathophysiology-of-vasculitis/

  In resting polymorphonuclear (PMN) leukocytes, antigens such as myeloperoxidase (MPO) or proteinase-3 (PR3) remain localized within cells in millimolar quantities and hidden from the immune system. […] Activated PMN leukocytes can undergo an oxidative burst, producing high levels of reactive oxygen species (ROS) such as superoxide anion or hypochlorous acid (HOCl), which can injure ECs.

• #21 Immunopathogenesis of ANCA-Associated Vasculitis

  https://www.mdpi.com/1422-0067/21/19/7319

  Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis is an autoimmune disorder which affects small- and, to a lesser degree, medium-sized vessels. […] ANCA play an important role in the pathogenesis of ANCA-associated vasculitis, which is summarized in Figure 1. […] A variety of different factors have been identified for their implication in the pathogenesis of ANCA-associated vasculitis, including the environment, genetics, and infections. […] Evidence suggests that both genetic and epigenetic factors are involved in the complex pathogenesis of ANCA-associated vasculitis. […] Kessenbrock et al. showed that neutrophil extracellular traps (NETs) are released by ANCA-stimulated neutrophils and contain the respective target antigens PR3 and MPO. […] Neutrophils are the most important effector cells in the pathogenesis of ANCA-associated vasculitis.

• #22 Pathogenesis and therapeutic interventions for ANCA-associated vasculitis | Nature Reviews Rheumatology

  https://www.nature.com/articles/s41584-018-0145-y

  Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) affects systemic small vessels and is accompanied by the presence of ANCAs in the serum. […] The mechanism by which ANCAs cause vasculitis involves ANCA-mediated excessive activation of neutrophils that subsequently release inflammatory cytokines, reactive oxygen species and lytic enzymes. […] Moreover, NETs are involved not only in ANCA-mediated vascular injury but also in the production of ANCAs themselves. Therefore, a vicious cycle of NET formation and ANCA production is considered to be involved in the pathogenesis of AAV. […] ANCAs have a central role in the pathogenesis of AAV because they induce excessive activation of neutrophils, which results in injury to small vessels. […] Elucidation of the aetiology and pathogenesis of AAV is needed to develop new biomarkers as well as novel targeted therapeutic agents.

• #23 Immunopathogenesis of ANCA-Associated Vasculitis

  https://www.mdpi.com/1422-0067/21/19/7319

  The initial mechanisms of ANCA generation are not well understood. […] The exposed autoantigens interact with ANCA which results in excessive activation of neutrophils adhering to endothelial cells. […] Thus, neutrophils, ANCA elevation, disruption of plasma and T cell tolerance, and overproduction and persistence of NETs together contribute to the pathogenesis of PR3-and MPO-ANCA vasculitis. […] One of the key steps in the pathogenesis of ANCA-associated vasculitis is priming of neutrophils, which in turn leads to expression of ANCA on the cell membrane. […] As Kessenbrock et al. demonstrated, NETs released by ANCA-stimulated neutrophils play a critical role in pathways leading to vascular damage and further ANCA production.

• #24 Immunopathogenesis of ANCA-Associated Vasculitis

  https://www.mdpi.com/1422-0067/21/19/7319

  Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis is an autoimmune disorder which affects small- and, to a lesser degree, medium-sized vessels. […] ANCA play an important role in the pathogenesis of ANCA-associated vasculitis, which is summarized in Figure 1. […] A variety of different factors have been identified for their implication in the pathogenesis of ANCA-associated vasculitis, including the environment, genetics, and infections. […] Evidence suggests that both genetic and epigenetic factors are involved in the complex pathogenesis of ANCA-associated vasculitis. […] Kessenbrock et al. showed that neutrophil extracellular traps (NETs) are released by ANCA-stimulated neutrophils and contain the respective target antigens PR3 and MPO. […] Neutrophils are the most important effector cells in the pathogenesis of ANCA-associated vasculitis.

• #25

  https://link.springer.com/article/10.1007/s00467-017-3597-4

  A study by Hong et al. revealed insights into the pathogenesis of AAV by studying ANCA-neutrophil interactions. […] It is increasingly apparent that NETs may also be involved in various other autoimmune diseases, including systemic lupus erythematosus (SLE), and thus may offer insight into the pathogenesis of autoimmunity more generally, and possibly even a novel therapeutic target. […] The endothelial injury and repair concept provides a framework for studies that provide insight into the pathogenesis of systemic vasculitis and its sequelae.

• #26

  https://link.springer.com/article/10.1007/s00467-017-3597-4

  A study by Hong et al. revealed insights into the pathogenesis of AAV by studying ANCA-neutrophil interactions. […] It is increasingly apparent that NETs may also be involved in various other autoimmune diseases, including systemic lupus erythematosus (SLE), and thus may offer insight into the pathogenesis of autoimmunity more generally, and possibly even a novel therapeutic target. […] The endothelial injury and repair concept provides a framework for studies that provide insight into the pathogenesis of systemic vasculitis and its sequelae.

• #27 New Insights into Pathogenesis and Treatment of ANCA-Associated Vasculitis: Autoantibodies and Beyond

  https://www.mdpi.com/2073-4468/12/1/25

  Neutrophils play a central role in mediating and amplifying tissue damage. […] In genetically predisposed individuals and with the contribution of environmental factors, proinflammatory cytokines induce neutrophils to express MPO and PR3 antigens on their cell surface making them visible to autoreactive cells of the adaptive immune system. […] The pathogenic role of ANCAs is also supported by clinical data. […] It has also been reported that regulatory B cells (Breg) induce the trans-differentiation of effector T cells into regulatory T cells (Treg), contributing to reduced ANCA production by B cells. […] AAV is considered a pauci-immune disease because immunoglobulin and complement deposits are absent or greatly reduced in patients with AAV. […] However, recent experimental and clinical studies suggest that the complement system is actively involved in the pathogenesis of AAV, particularly through the alternative pathway. […] Eosinophils are responsible for most tissue damage. […] The success of therapy based on blocking IL-5 by monoclonal antibodies underscores the importance of Th2 cells and eosinophils in disease pathogenesis.

• #28 New Insights into Pathogenesis and Treatment of ANCA-Associated Vasculitis: Autoantibodies and Beyond

  https://www.mdpi.com/2073-4468/12/1/25

  Neutrophils play a central role in mediating and amplifying tissue damage. […] In genetically predisposed individuals and with the contribution of environmental factors, proinflammatory cytokines induce neutrophils to express MPO and PR3 antigens on their cell surface making them visible to autoreactive cells of the adaptive immune system. […] The pathogenic role of ANCAs is also supported by clinical data. […] It has also been reported that regulatory B cells (Breg) induce the trans-differentiation of effector T cells into regulatory T cells (Treg), contributing to reduced ANCA production by B cells. […] AAV is considered a pauci-immune disease because immunoglobulin and complement deposits are absent or greatly reduced in patients with AAV. […] However, recent experimental and clinical studies suggest that the complement system is actively involved in the pathogenesis of AAV, particularly through the alternative pathway. […] Eosinophils are responsible for most tissue damage. […] The success of therapy based on blocking IL-5 by monoclonal antibodies underscores the importance of Th2 cells and eosinophils in disease pathogenesis.

• #29 Vasculitis and Thrombophlebitis: Practice Essentials, Classification Guidelines, The EULAR and PRES Classification of Childhood Vasculitis

  https://emedicine.medscape.com/article/1008239-overview

  ANCA antibodies are directed towards cytoplasmic proteins within neutrophils and monocytes (eg, PR3, MPO), which may also be expressed at the cell surface, particularly on stimulated cells. In vitro studies have shown that ANCA IgGs can directly activate neutrophils and monocytes by both Fc receptor engagement and direct Fab2 binding to antigen. These activated cells interact with endothelial cells via adhesion molecules and release inflammatory mediators, such as toxic granule enzymes and reactive oxygen metabolites that cause apoptosis and necrosis. In addition, anti-MPO IgG may activate MPO itself triggering an oxidative burst and resulting in severe endothelial damage. ANCA-activated neutrophils may release factors that activate the alternative complement pathway, which initiates an amplification loop that mediates the severe necrotizing inflammation of ANCA disease.

• #30 Vasculitis and Thrombophlebitis: Practice Essentials, Classification Guidelines, The EULAR and PRES Classification of Childhood Vasculitis

  https://emedicine.medscape.com/article/1008239-overview

  In vivo studies also support this pathogenesis; for example, injection of mice with anti-MPO antibodies results in the development of necrotizing and crescentic glomerulonephritis and pulmonary capillaritis. […] Henoch-Schnlein purpura is generally characterized by the deposition of IgA antibodies in affected tissues. Histopathologically, the typical finding on skin biopsy is leukocytoclastic vasculitis, with perivascular accumulation of neutrophils and mononuclear cells. Immunofluorescence demonstrates IgA, C3, and fibrin in the walls of affected vessels, including the postcapillary venules within the dermis, and the endothelial and mesangial cells of the kidney. Elevated serum IgA and circulating IgA-containing immune complexes may be present in some patients. One study showed that galactose deficiency of O-linked glycans in the hinge region of IgA1 has been associated with Henoch-Schnlein purpura.

• #31 The pathogenesis of vasculitis | Arthritis Research & Therapy | Full Text

  https://arthritis-research.biomedcentral.com/articles/10.1186/ar164

  In the secondary vasculitides, associated with infectious disorders, connective tissue diseases and other conditions, immune complexes play a major immunopathogenic role. […] T-cells are, probably, involved in the large vessel vasculitides, particularly giant cell arteritis, whereas the small vessel vasculitides are associated with anti-neutrophil cytoplasmic autoantibodies (ANCA). […] Clinical observations, in vitro experimental findings, and in vivo data from animal experiments suggest that ANCA in those diseases, which are directed to proteinase 3 (PR3) or myeloperoxidase (MPO), are involved in their pathogenesis. […] ANCA appear to activate integrin-mediated adhesion of neutrophils and adhesion-dependent degranulation. […] Data from clinical and experimental studies suggest that ANCA alone are not sufficient to induce disease. Exogenous factors, in particular carriage of Staphylococcus aureus and silica exposure, may be involved as well. […] Taken together, the interplay between genetic and exogenous factors may induce autoimmunity to myeloid enzymes which, in concert, lead to the clinical expression of the ANCA-associated vasculitides.

• #32 Vasculitis: mechanisms involved and clinical manifestations | Arthritis Research & Therapy | Full Text

  https://arthritis-research.biomedcentral.com/articles/10.1186/ar2193

  In GCA, for example, vasculitis is essentially a T-cell driven process that is triggered by exposure to antigens, most probably infectious agents. […] In contrast to GCA, which appears to be an antigen-driven disease with local T cell and macrophage activation in the vessel wall, IC formation is usually considered to be the major pathological event in polyarteritis nodosa, cryoglobulinaemia and Henoch-Schnlein purpura. […] Autoantibodies play a central role in the ANCA-related vasculitis that is characteristic of Wegener’s granulomatosis, Churg-Strauss syndrome, microscopic polyangiitis and necrotizing glomerulonephritis. […] IC formation and binding to the endothelial cell surface leading to endothelial cell activation plays an important role in the pathogenesis of vasculitis and is a feature of vasculitis in both RA and SLE. […] Binding of autoantibodies and ICs to the surface of endothelial cells results, among other things, in enhanced ET-1 release. […] There is evidence, albeit limited, suggesting that ET-1 plays a role in some clinical manifestations of vasculitis.

• #33 Vasculitis and Thrombophlebitis: Practice Essentials, Classification Guidelines, The EULAR and PRES Classification of Childhood Vasculitis

  https://emedicine.medscape.com/article/1008239-overview

  Vessel inflammation occurs by various mechanisms in this heterogenous group of diseases. The histopathological pattern of inflammation is a characteristic feature of the vasculitis subtypes. […] Takayasu arteritis and temporal arteritis (in adults) both involve large elastic arteries and share a similar histopathology. This form of vasculitis is T-cell dependent, and CD4+ T cells are the main players in the process. Dendritic cells within the arterial adventitia recruit and stimulate the CD4+ cells, which then activate the monocytes and macrophages that mediate oxidative injury of the vessel wall. Vascular lesions are characterized by a panarteritis with mononuclear infiltration of all layers of the arterial wall. Typically, activated T cells and macrophages are arranged in granulomas, and multinucleated giant cells are present. Often, the intimal layer is hyperplastic, leading to concentric occlusion of the lumen. Also, the end stage of giant-cell aortitis may be complicated by the formation and rupture of aneurysms.

• #34 Vasculitis and Thrombophlebitis: Practice Essentials, Classification Guidelines, The EULAR and PRES Classification of Childhood Vasculitis

  https://emedicine.medscape.com/article/1008239-overview

  Vessel inflammation occurs by various mechanisms in this heterogenous group of diseases. The histopathological pattern of inflammation is a characteristic feature of the vasculitis subtypes. […] Takayasu arteritis and temporal arteritis (in adults) both involve large elastic arteries and share a similar histopathology. This form of vasculitis is T-cell dependent, and CD4+ T cells are the main players in the process. Dendritic cells within the arterial adventitia recruit and stimulate the CD4+ cells, which then activate the monocytes and macrophages that mediate oxidative injury of the vessel wall. Vascular lesions are characterized by a panarteritis with mononuclear infiltration of all layers of the arterial wall. Typically, activated T cells and macrophages are arranged in granulomas, and multinucleated giant cells are present. Often, the intimal layer is hyperplastic, leading to concentric occlusion of the lumen. Also, the end stage of giant-cell aortitis may be complicated by the formation and rupture of aneurysms.

• #35 Vasculitis and Thrombophlebitis: Practice Essentials, Classification Guidelines, The EULAR and PRES Classification of Childhood Vasculitis

  https://emedicine.medscape.com/article/1008239-overview

  Vessel inflammation occurs by various mechanisms in this heterogenous group of diseases. The histopathological pattern of inflammation is a characteristic feature of the vasculitis subtypes. […] Takayasu arteritis and temporal arteritis (in adults) both involve large elastic arteries and share a similar histopathology. This form of vasculitis is T-cell dependent, and CD4+ T cells are the main players in the process. Dendritic cells within the arterial adventitia recruit and stimulate the CD4+ cells, which then activate the monocytes and macrophages that mediate oxidative injury of the vessel wall. Vascular lesions are characterized by a panarteritis with mononuclear infiltration of all layers of the arterial wall. Typically, activated T cells and macrophages are arranged in granulomas, and multinucleated giant cells are present. Often, the intimal layer is hyperplastic, leading to concentric occlusion of the lumen. Also, the end stage of giant-cell aortitis may be complicated by the formation and rupture of aneurysms.

• #36 Vasculitis and Thrombophlebitis: Practice Essentials, Classification Guidelines, The EULAR and PRES Classification of Childhood Vasculitis

  https://emedicine.medscape.com/article/1008239-overview

  Kawasaki disease and polyarteritis nodosa are examples of necrotizing vasculitis. Possible etiologies in the case of Kawasaki disease include infectious agents and/or superantigen-mediated activation of lymphocytes. The inciting factors in polyarteritis nodosa are less well understood; however, in developing countries, it has been associated with hepatitis B or C. Pathologically, segmental transmural inflammation of muscular arteries is noted. Nodule (vascular narrowing) and aneurysm formation result from panmural fibrinoid necrosis. Note that aneurysmal dilatation of the arterial wall is a common feature of necrotizing vasculitis. Typically, immunofluorescence for immunoglobulin or complement deposition is negative. […] A review by Jennette and Falk discusses the scientific evidence showing that ANCA immunoglobulin Gs (IgGs) are involved in the pathogenesis of small vessel vasculitides such as GPA and MPA.

• #37 Immunopathogenesis of ANCA-Associated Vasculitis

  https://www.mdpi.com/1422-0067/21/19/7319

  Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis is an autoimmune disorder which affects small- and, to a lesser degree, medium-sized vessels. […] ANCA play an important role in the pathogenesis of ANCA-associated vasculitis, which is summarized in Figure 1. […] A variety of different factors have been identified for their implication in the pathogenesis of ANCA-associated vasculitis, including the environment, genetics, and infections. […] Evidence suggests that both genetic and epigenetic factors are involved in the complex pathogenesis of ANCA-associated vasculitis. […] Kessenbrock et al. showed that neutrophil extracellular traps (NETs) are released by ANCA-stimulated neutrophils and contain the respective target antigens PR3 and MPO. […] Neutrophils are the most important effector cells in the pathogenesis of ANCA-associated vasculitis.

• #38 Immunopathogenesis of ANCA-Associated Vasculitis

  https://www.mdpi.com/1422-0067/21/19/7319

  Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis is an autoimmune disorder which affects small- and, to a lesser degree, medium-sized vessels. […] ANCA play an important role in the pathogenesis of ANCA-associated vasculitis, which is summarized in Figure 1. […] A variety of different factors have been identified for their implication in the pathogenesis of ANCA-associated vasculitis, including the environment, genetics, and infections. […] Evidence suggests that both genetic and epigenetic factors are involved in the complex pathogenesis of ANCA-associated vasculitis. […] Kessenbrock et al. showed that neutrophil extracellular traps (NETs) are released by ANCA-stimulated neutrophils and contain the respective target antigens PR3 and MPO. […] Neutrophils are the most important effector cells in the pathogenesis of ANCA-associated vasculitis.

• #39

  https://discovery.ucl.ac.uk/id/eprint/1570099/

  Better understanding of the pathogenesis and treatment of primary systemic vasculitides (PSV) has led to the development of many potentially clinically relevant biomarkers. […] Genome-wide association studies have highlighted that MHC class II polymorphisms may influence the development of particular anti-neutrophil cytoplasmic antibody (ANCA) serotypes, but not the clinical phenotype of ANCA-associated vasculitis (AAV). […] Although ANCAs are overall poor biomarkers of disease activity, they may be useful for the prediction of flares of renal and/or pulmonary vasculitis. […] Moreover, patients with proteinase 3 (PR3)-AAV may respond better to rituximab than cyclophosphamide. […] Newer biomarkers of renal vasculitis in AAV include urinary soluble CD163, and may in the future reduce the requirement for renal biopsy.

• #40 Pathogens in Vasculitis: Is It Really Idiopathic? | JMA Journal

  https://www.jmaj.jp/detail.php?id=10.31662%2Fjmaj.2021-0021

  However, an increasing number of human and animal studies suggest that vasculitis is not only caused by a few infectious agents but also, in fact, associated with various pathogenic agents, including viruses, bacteria, fungi, and parasites. […] Comparable to other autoimmune conditions, an aberrantly activated host immune response to the pathogen is considered to play a central role in vasculitis. […] In this review, we summarize previous reports on animal vasculitis models and human vasculitis cases associated with infectious agents and discuss the potential approach for investigating the pathogenesis of vasculitis, which is often considered an idiopathic disease. […] A deeper understanding of the mechanism by which pathogens induce vasculitis could help develop novel therapeutic targets and prevention strategies for vasculitis.

• #41 Pathogens in Vasculitis: Is It Really Idiopathic? | JMA Journal

  https://www.jmaj.jp/detail.php?id=10.31662%2Fjmaj.2021-0021

  However, an increasing number of human and animal studies suggest that vasculitis is not only caused by a few infectious agents but also, in fact, associated with various pathogenic agents, including viruses, bacteria, fungi, and parasites. […] Comparable to other autoimmune conditions, an aberrantly activated host immune response to the pathogen is considered to play a central role in vasculitis. […] In this review, we summarize previous reports on animal vasculitis models and human vasculitis cases associated with infectious agents and discuss the potential approach for investigating the pathogenesis of vasculitis, which is often considered an idiopathic disease. […] A deeper understanding of the mechanism by which pathogens induce vasculitis could help develop novel therapeutic targets and prevention strategies for vasculitis.

• #42 Telomere dysfunction promotes small vessel vasculitis via the LL37-NETs-dependent mechanism

  https://atm.amegroups.org/article/view/39167/html

  Small vessel vasculitis (SVV) is a group of systemic autoimmune diseases that are mediated by neutrophil extracellular traps (NETs) in response to cathelicidin LL37, an aging molecular marker, which could be induced by telomere dysfunction. Therefore, in this study, we evaluated the hypothesis that telomere dysfunction in neutrophils may promote SVV via an LL37-NETs-dependent mechanism. […] We found that NETs were over-induced by telomere dysfunction and DNA damage in mice, which may be associated with a marked increase in LL37. For patients with SVV, telomeres in neutrophils were significantly shortened, which was also associated with higher levels of LL37 and NETs. Inhibition of LL37 reduced the NETs released from neutrophils. […] Taken together, the results of these studies suggest that dysfunction of telomeres may promote SVV through the mechanism of LL37-dependent NETs. Thus, targeting the LL37-NETs may be a novel therapy for SVV.

• #43 Telomere dysfunction promotes small vessel vasculitis via the LL37-NETs-dependent mechanism

  https://atm.amegroups.org/article/view/39167/html

  Small vessel vasculitis (SVV) is a group of systemic autoimmune diseases that are mediated by neutrophil extracellular traps (NETs) in response to cathelicidin LL37, an aging molecular marker, which could be induced by telomere dysfunction. Therefore, in this study, we evaluated the hypothesis that telomere dysfunction in neutrophils may promote SVV via an LL37-NETs-dependent mechanism. […] We found that NETs were over-induced by telomere dysfunction and DNA damage in mice, which may be associated with a marked increase in LL37. For patients with SVV, telomeres in neutrophils were significantly shortened, which was also associated with higher levels of LL37 and NETs. Inhibition of LL37 reduced the NETs released from neutrophils. […] Taken together, the results of these studies suggest that dysfunction of telomeres may promote SVV through the mechanism of LL37-dependent NETs. Thus, targeting the LL37-NETs may be a novel therapy for SVV.

• #44 Certain Cytokines Linked to ANCA-Associated Vasculitis Pathogenesis, Activity – Rheumatology Advisor

  https://www.rheumatologyadvisor.com/news/certain-cytokines-linked-to-anca-associated-vasculitis-pathogenesis-activity/

  Investigators have identified cytokines they believe are involved in the pathogenesis of ANCA-associated vasculitis (AAV), according to a recent report in Frontiers in Immunology. […] We found some cytokines that together constituted a complex interaction system and played a crucial role in the pathogenesis of AAV.

• #45 Certain Cytokines Linked to ANCA-Associated Vasculitis Pathogenesis, Activity – Renal and Urology News

  https://www.renalandurologynews.com/news/certain-cytokines-linked-to-anca-associated-vasculitis-pathogenesis-activity/

  Investigators have identified cytokines they believe are involved in the pathogenesis of ANCA-associated vasculitis (AAV), according to a recent report in Frontiers in Immunology. […] Findings also demonstrated that 9 cytokines can distinguish between disease relapse and remission: PTX3, IL34, IL2RA, CCL23, VEGFA, TNFSF13, Granzyme A, CSF3, and IL1A. […] They concluded that their study proved the validity of previous research results from different perspectives. We found some cytokines that together constituted a complex interaction system and played a crucial role in the pathogenesis of AAV.

• #46 Certain Cytokines Linked to ANCA-Associated Vasculitis Pathogenesis, Activity – Renal and Urology News

  https://www.renalandurologynews.com/news/certain-cytokines-linked-to-anca-associated-vasculitis-pathogenesis-activity/

  Investigators have identified cytokines they believe are involved in the pathogenesis of ANCA-associated vasculitis (AAV), according to a recent report in Frontiers in Immunology. […] Findings also demonstrated that 9 cytokines can distinguish between disease relapse and remission: PTX3, IL34, IL2RA, CCL23, VEGFA, TNFSF13, Granzyme A, CSF3, and IL1A. […] They concluded that their study proved the validity of previous research results from different perspectives. We found some cytokines that together constituted a complex interaction system and played a crucial role in the pathogenesis of AAV.

• #47

  https://link.springer.com/article/10.1007/s11926-012-0286-y

  Antineutrophil cytoplasmic autoantibodies (ANCA)-associated vasculitides (AAV) are a group of systemic vasculitis syndromes characterized by inflammation and necrosis of blood vessel walls. Genetic, epigenetic, and environmental factors contribute to the etiology and pathogenesis of AAV. On the basis of currently available clinical and experimental evidence, it is reasonable to believe that, in predisposed patients, different triggers can lead to the production of autoantibodies (ANCA) that, in the context of an inflammatory environment, can cause tissue inflammation and vascular injury. Several different pathways and mechanisms in the pathogenesis of AAV are described in this contemporary review. […] T cells producing IL-17 (Th17) have been implicated in the pathogenesis of several autoimmune diseases and this study identified that serum IL-17 levels and autoantigen-specific Th17 cells were elevated in patients with active AAV as compared to healthy individuals.

• #48 Eosinophils in vasculitis: characteristics and roles in pathogenesis | Nature Reviews Rheumatology

  https://www.nature.com/articles/nrrheum.2014.98

  Eosinophils are granulocytic cells that secrete a wide variety of cytokines, chemokines and other mediators that probably have direct and indirect roles in the pathogenesis of eosinophilic granulomatosis with polyangiitis (EGPA) […] Although data is scarce, eosinophils seem to have a central role in disease pathogenesis in all three clinical stages of EGPA […] Clinical trials using novel therapeutic strategies that specifically target eosinophils are helping define the role of eosinophils in the pathogenesis of EGPA […] the precise role of eosinophils in disease pathogenesis has been difficult to ascertain owing to the complexity of the disease process […] results of clinical trials using novel agents that specifically target eosinophils are providing the first direct evidence of a central role of eosinophils in EGPA.

• #49 Eosinophils in vasculitis: characteristics and roles in pathogenesis | Nature Reviews Rheumatology

  https://www.nature.com/articles/nrrheum.2014.98

  Eosinophils are granulocytic cells that secrete a wide variety of cytokines, chemokines and other mediators that probably have direct and indirect roles in the pathogenesis of eosinophilic granulomatosis with polyangiitis (EGPA) […] Although data is scarce, eosinophils seem to have a central role in disease pathogenesis in all three clinical stages of EGPA […] Clinical trials using novel therapeutic strategies that specifically target eosinophils are helping define the role of eosinophils in the pathogenesis of EGPA […] the precise role of eosinophils in disease pathogenesis has been difficult to ascertain owing to the complexity of the disease process […] results of clinical trials using novel agents that specifically target eosinophils are providing the first direct evidence of a central role of eosinophils in EGPA.

• #50 Eosinophils in vasculitis: characteristics and roles in pathogenesis | Nature Reviews Rheumatology

  https://www.nature.com/articles/nrrheum.2014.98

  Eosinophils are granulocytic cells that secrete a wide variety of cytokines, chemokines and other mediators that probably have direct and indirect roles in the pathogenesis of eosinophilic granulomatosis with polyangiitis (EGPA) […] Although data is scarce, eosinophils seem to have a central role in disease pathogenesis in all three clinical stages of EGPA […] Clinical trials using novel therapeutic strategies that specifically target eosinophils are helping define the role of eosinophils in the pathogenesis of EGPA […] the precise role of eosinophils in disease pathogenesis has been difficult to ascertain owing to the complexity of the disease process […] results of clinical trials using novel agents that specifically target eosinophils are providing the first direct evidence of a central role of eosinophils in EGPA.

• #51 New Insights into Pathogenesis and Treatment of ANCA-Associated Vasculitis: Autoantibodies and Beyond

  https://www.mdpi.com/2073-4468/12/1/25

  Neutrophils play a central role in mediating and amplifying tissue damage. […] In genetically predisposed individuals and with the contribution of environmental factors, proinflammatory cytokines induce neutrophils to express MPO and PR3 antigens on their cell surface making them visible to autoreactive cells of the adaptive immune system. […] The pathogenic role of ANCAs is also supported by clinical data. […] It has also been reported that regulatory B cells (Breg) induce the trans-differentiation of effector T cells into regulatory T cells (Treg), contributing to reduced ANCA production by B cells. […] AAV is considered a pauci-immune disease because immunoglobulin and complement deposits are absent or greatly reduced in patients with AAV. […] However, recent experimental and clinical studies suggest that the complement system is actively involved in the pathogenesis of AAV, particularly through the alternative pathway. […] Eosinophils are responsible for most tissue damage. […] The success of therapy based on blocking IL-5 by monoclonal antibodies underscores the importance of Th2 cells and eosinophils in disease pathogenesis.

• #52 Mechanism discovered that leads to ANCA-associated vasculitis

  https://medicalxpress.com/news/2022-08-mechanism-anca-associated-vasculitis.html

  Mechanism discovered that leads to ANCA-associated vasculitis […] Researchers at the University of Bonn, together with colleagues from Germany, the Netherlands, Switzerland and England, have deciphered a mechanism in mice and patients that leads to the severe disease. […] Together with colleagues from Germany, the Netherlands, Switzerland and the United Kingdom, the scientists have now discovered a mechanism responsible for the development of the disease in the form of the cGAS/STING/IFN-I signaling pathway. […] From the results in the mice, the researchers conclude that it is indeed an overactivation of cGAS/STING by DNA misplaced in the cell that leads to the severe disease. […] Elevated blood levels of IFN-I and cGAMP in the patients studied suggest that the out-of-control DNA guardian in the cells is responsible for disease progression. […] By better understanding the molecular processes of severe ANCA vasculitis, we have been able to identify potential drug targets in the preclinical model that are already approved for other diseases.

• #53 Mechanism discovered that leads to ANCA-associated vasculitis

  https://medicalxpress.com/news/2022-08-mechanism-anca-associated-vasculitis.html

  Mechanism discovered that leads to ANCA-associated vasculitis […] Researchers at the University of Bonn, together with colleagues from Germany, the Netherlands, Switzerland and England, have deciphered a mechanism in mice and patients that leads to the severe disease. […] Together with colleagues from Germany, the Netherlands, Switzerland and the United Kingdom, the scientists have now discovered a mechanism responsible for the development of the disease in the form of the cGAS/STING/IFN-I signaling pathway. […] From the results in the mice, the researchers conclude that it is indeed an overactivation of cGAS/STING by DNA misplaced in the cell that leads to the severe disease. […] Elevated blood levels of IFN-I and cGAMP in the patients studied suggest that the out-of-control DNA guardian in the cells is responsible for disease progression. […] By better understanding the molecular processes of severe ANCA vasculitis, we have been able to identify potential drug targets in the preclinical model that are already approved for other diseases.

• #54 Mechanism discovered that leads to ANCA-associated vasculitis

  https://medicalxpress.com/news/2022-08-mechanism-anca-associated-vasculitis.html

  Mechanism discovered that leads to ANCA-associated vasculitis […] Researchers at the University of Bonn, together with colleagues from Germany, the Netherlands, Switzerland and England, have deciphered a mechanism in mice and patients that leads to the severe disease. […] Together with colleagues from Germany, the Netherlands, Switzerland and the United Kingdom, the scientists have now discovered a mechanism responsible for the development of the disease in the form of the cGAS/STING/IFN-I signaling pathway. […] From the results in the mice, the researchers conclude that it is indeed an overactivation of cGAS/STING by DNA misplaced in the cell that leads to the severe disease. […] Elevated blood levels of IFN-I and cGAMP in the patients studied suggest that the out-of-control DNA guardian in the cells is responsible for disease progression. […] By better understanding the molecular processes of severe ANCA vasculitis, we have been able to identify potential drug targets in the preclinical model that are already approved for other diseases.

• #55 Mechanism discovered that leads to ANCA-associated vasculitis

  https://medicalxpress.com/news/2022-08-mechanism-anca-associated-vasculitis.html

  Mechanism discovered that leads to ANCA-associated vasculitis […] Researchers at the University of Bonn, together with colleagues from Germany, the Netherlands, Switzerland and England, have deciphered a mechanism in mice and patients that leads to the severe disease. […] Together with colleagues from Germany, the Netherlands, Switzerland and the United Kingdom, the scientists have now discovered a mechanism responsible for the development of the disease in the form of the cGAS/STING/IFN-I signaling pathway. […] From the results in the mice, the researchers conclude that it is indeed an overactivation of cGAS/STING by DNA misplaced in the cell that leads to the severe disease. […] Elevated blood levels of IFN-I and cGAMP in the patients studied suggest that the out-of-control DNA guardian in the cells is responsible for disease progression. […] By better understanding the molecular processes of severe ANCA vasculitis, we have been able to identify potential drug targets in the preclinical model that are already approved for other diseases.

• #56 Distinguishing VEXAS Syndrome From Primary Vasculitis Disorders – Renal and Urology News

  https://www.renalandurologynews.com/news/vasculitis-vexas-syndrome-primary-disorders-treatment-risk/

  VEXAS syndrome is known to be a mimicker of ANCA-associated vasculitis, making it a challenge to distinguish between the disorders. […] VEXAS syndrome is a newly identified disease that can manifest as vasculitis (commonly, small-vessel vasculitis), making it a challenge to distinguish from primary vasculitic disorders such as antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), according to a study published in Clinical and Experimental Rheumatology. […] They found that vasculitis was a common manifestation of VEXAS syndrome. […] The most common form of vasculitis seen in VEXAS syndrome is cutaneous vasculitis. In up to 40% of patients, small-vessel vasculitis is observed. […] Hence, the presence of inflammatory cutaneous lesions with leukocytoclasia absent overt vasculitis should arouse clinical suspicions of VEXAS syndrome.

• #57 Distinguishing VEXAS Syndrome From Primary Vasculitis Disorders – Renal and Urology News

  https://www.renalandurologynews.com/news/vasculitis-vexas-syndrome-primary-disorders-treatment-risk/

  VEXAS syndrome is known to be a mimicker of ANCA-associated vasculitis, making it a challenge to distinguish between the disorders. […] VEXAS syndrome is a newly identified disease that can manifest as vasculitis (commonly, small-vessel vasculitis), making it a challenge to distinguish from primary vasculitic disorders such as antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), according to a study published in Clinical and Experimental Rheumatology. […] They found that vasculitis was a common manifestation of VEXAS syndrome. […] The most common form of vasculitis seen in VEXAS syndrome is cutaneous vasculitis. In up to 40% of patients, small-vessel vasculitis is observed. […] Hence, the presence of inflammatory cutaneous lesions with leukocytoclasia absent overt vasculitis should arouse clinical suspicions of VEXAS syndrome.

• #58 Distinguishing VEXAS Syndrome From Primary Vasculitis Disorders – Renal and Urology News

  https://www.renalandurologynews.com/news/vasculitis-vexas-syndrome-primary-disorders-treatment-risk/

  In addition, VEXAS syndrome is known to mimic AAV. […] Studies indicate that most patients who were initially diagnosed with AAV but had their diagnosis revised to VEXAS syndrome were typically ANCA-negative. […] In the interim, male patients with recurrent, relapsing, recalcitrant, or chronic inflammation associated with 1 or more cytopenia or hematologic disturbance, and for whom traditional standard of care therapies are considered ineffective resulting in chronic steroid dependency should strongly trigger suspicion for VEXAS.

• #59 UNC Researchers Uncover Molecular Mechanism Behind Hydralazine-Induced ANCA Vasculitis | Newswise

  https://www.newswise.com/articles/unc-researchers-uncover-molecular-mechanism-behind-hydralazine-induced-anca-vasculitis

  For the first time, investigators are gaining a clearer understanding of what causes drug-induced antineutrophil cytoplasmic autoantibody (ANCA) vasculitis. […] These changes may trigger the autoimmune response seen in ANCA vasculitis. […] More specifically, the study found that the addition of a carbonyl group to MPO allows hydralazine to bind and form hydrazone adducts. These structural changes in MPO appear to set off an immune reaction. […] Hydralazine has long been associated with drug-induced ANCA vasculitis, but the exact mechanism behind that link wasn’t well understood, until now. […] A commentary, published in the same issue, details how the study sheds light on the mechanisms by which hydralazine induces vasculitis. […] Since drug-induced autoimmunity can act like a natural experiment, uncovering its mechanisms may also shed light on how other autoimmune diseases, especially those with no known cause, develop.

• #60 UNC Researchers Uncover Molecular Mechanism Behind Hydralazine-Induced ANCA Vasculitis | Newswise

  https://www.newswise.com/articles/unc-researchers-uncover-molecular-mechanism-behind-hydralazine-induced-anca-vasculitis

  For the first time, investigators are gaining a clearer understanding of what causes drug-induced antineutrophil cytoplasmic autoantibody (ANCA) vasculitis. […] These changes may trigger the autoimmune response seen in ANCA vasculitis. […] More specifically, the study found that the addition of a carbonyl group to MPO allows hydralazine to bind and form hydrazone adducts. These structural changes in MPO appear to set off an immune reaction. […] Hydralazine has long been associated with drug-induced ANCA vasculitis, but the exact mechanism behind that link wasn’t well understood, until now. […] A commentary, published in the same issue, details how the study sheds light on the mechanisms by which hydralazine induces vasculitis. […] Since drug-induced autoimmunity can act like a natural experiment, uncovering its mechanisms may also shed light on how other autoimmune diseases, especially those with no known cause, develop.

• #61 UNC Researchers Uncover Molecular Mechanism Behind Hydralazine-Induced ANCA Vasculitis | Newswise

  https://www.newswise.com/articles/unc-researchers-uncover-molecular-mechanism-behind-hydralazine-induced-anca-vasculitis

  For the first time, investigators are gaining a clearer understanding of what causes drug-induced antineutrophil cytoplasmic autoantibody (ANCA) vasculitis. […] These changes may trigger the autoimmune response seen in ANCA vasculitis. […] More specifically, the study found that the addition of a carbonyl group to MPO allows hydralazine to bind and form hydrazone adducts. These structural changes in MPO appear to set off an immune reaction. […] Hydralazine has long been associated with drug-induced ANCA vasculitis, but the exact mechanism behind that link wasn’t well understood, until now. […] A commentary, published in the same issue, details how the study sheds light on the mechanisms by which hydralazine induces vasculitis. […] Since drug-induced autoimmunity can act like a natural experiment, uncovering its mechanisms may also shed light on how other autoimmune diseases, especially those with no known cause, develop.

• #62 UNC Researchers Uncover Molecular Mechanism Behind Hydralazine-Induced ANCA Vasculitis | Newswise

  https://www.newswise.com/articles/unc-researchers-uncover-molecular-mechanism-behind-hydralazine-induced-anca-vasculitis

  For the first time, investigators are gaining a clearer understanding of what causes drug-induced antineutrophil cytoplasmic autoantibody (ANCA) vasculitis. […] These changes may trigger the autoimmune response seen in ANCA vasculitis. […] More specifically, the study found that the addition of a carbonyl group to MPO allows hydralazine to bind and form hydrazone adducts. These structural changes in MPO appear to set off an immune reaction. […] Hydralazine has long been associated with drug-induced ANCA vasculitis, but the exact mechanism behind that link wasn’t well understood, until now. […] A commentary, published in the same issue, details how the study sheds light on the mechanisms by which hydralazine induces vasculitis. […] Since drug-induced autoimmunity can act like a natural experiment, uncovering its mechanisms may also shed light on how other autoimmune diseases, especially those with no known cause, develop.

• #63

  https://link.springer.com/article/10.1007/s00467-017-3597-4

  Better understanding of the pathogenesis and treatment of primary systemic vasculitides (PSV) has led to the development of many potentially clinically relevant biomarkers. […] A considerable body of evidence supports the concept that ANCAs are directly involved in the pathogenesis of small vessel vasculitis. […] The most accepted model of pathogenesis proposes that ANCAs activate cytokine-primed neutrophils, leading to bystander damage of endothelial cells and an escalation of inflammation with recruitment of mononuclear cells. […] Thus, it is clear that ANCAs are directly pathogenic, but why do patients make ANCAs in the first instance? […] In recent years, the genetic factors predisposing to ANCA development are better understood. […] This study thus confirmed that the pathogenesis of ANCA-associated vasculitis has a genetic component, shows genetic distinctions between GPA and MPA in terms of the ANCA serotype, but not the phenotype of AAV per se.

• #64

  https://discovery.ucl.ac.uk/id/eprint/1570099/

  Better understanding of the pathogenesis and treatment of primary systemic vasculitides (PSV) has led to the development of many potentially clinically relevant biomarkers. […] Genome-wide association studies have highlighted that MHC class II polymorphisms may influence the development of particular anti-neutrophil cytoplasmic antibody (ANCA) serotypes, but not the clinical phenotype of ANCA-associated vasculitis (AAV). […] Although ANCAs are overall poor biomarkers of disease activity, they may be useful for the prediction of flares of renal and/or pulmonary vasculitis. […] Moreover, patients with proteinase 3 (PR3)-AAV may respond better to rituximab than cyclophosphamide. […] Newer biomarkers of renal vasculitis in AAV include urinary soluble CD163, and may in the future reduce the requirement for renal biopsy.

• #65

  https://discovery.ucl.ac.uk/id/eprint/1570099/

  Better understanding of the pathogenesis and treatment of primary systemic vasculitides (PSV) has led to the development of many potentially clinically relevant biomarkers. […] Genome-wide association studies have highlighted that MHC class II polymorphisms may influence the development of particular anti-neutrophil cytoplasmic antibody (ANCA) serotypes, but not the clinical phenotype of ANCA-associated vasculitis (AAV). […] Although ANCAs are overall poor biomarkers of disease activity, they may be useful for the prediction of flares of renal and/or pulmonary vasculitis. […] Moreover, patients with proteinase 3 (PR3)-AAV may respond better to rituximab than cyclophosphamide. […] Newer biomarkers of renal vasculitis in AAV include urinary soluble CD163, and may in the future reduce the requirement for renal biopsy.

• #66

  https://discovery.ucl.ac.uk/id/eprint/1570099/

  Better understanding of the pathogenesis and treatment of primary systemic vasculitides (PSV) has led to the development of many potentially clinically relevant biomarkers. […] Genome-wide association studies have highlighted that MHC class II polymorphisms may influence the development of particular anti-neutrophil cytoplasmic antibody (ANCA) serotypes, but not the clinical phenotype of ANCA-associated vasculitis (AAV). […] Although ANCAs are overall poor biomarkers of disease activity, they may be useful for the prediction of flares of renal and/or pulmonary vasculitis. […] Moreover, patients with proteinase 3 (PR3)-AAV may respond better to rituximab than cyclophosphamide. […] Newer biomarkers of renal vasculitis in AAV include urinary soluble CD163, and may in the future reduce the requirement for renal biopsy.

• #67

  https://discovery.ucl.ac.uk/id/eprint/1570099/

  Better understanding of the pathogenesis and treatment of primary systemic vasculitides (PSV) has led to the development of many potentially clinically relevant biomarkers. […] Genome-wide association studies have highlighted that MHC class II polymorphisms may influence the development of particular anti-neutrophil cytoplasmic antibody (ANCA) serotypes, but not the clinical phenotype of ANCA-associated vasculitis (AAV). […] Although ANCAs are overall poor biomarkers of disease activity, they may be useful for the prediction of flares of renal and/or pulmonary vasculitis. […] Moreover, patients with proteinase 3 (PR3)-AAV may respond better to rituximab than cyclophosphamide. […] Newer biomarkers of renal vasculitis in AAV include urinary soluble CD163, and may in the future reduce the requirement for renal biopsy.

• #68

  https://discovery.ucl.ac.uk/id/eprint/1570099/

  Better understanding of dysregulated neutrophil activation in AAV has led to the identification of novel biomarkers including circulating microparticles, and neutrophil extracellular traps (NETs), although their clinical utility has not yet been realised. […] Studies examining endothelial injury and repair responses have additionally revealed indices that may have utility as disease activity and/or prognostic biomarkers. […] Last, next-generation sequencing technologies are revealing monogenic forms of vasculitis, such as deficiency of adenosine deaminase type 2 (DADA2), and are profoundly influencing the approach to the diagnosis and treatment of vasculitis in the young.

• #69 ANCA-Associated Vasculitis Pathogenesis & Treatment Updates – The Rheumatologist

  https://www.the-rheumatologist.org/article/anca-associated-vasculitis-pathogenesis-treatment-updates/

  In the Philip Hench, MD, Memorial Lecture, J. Charles Jennette, MD, chair in pathology and laboratory medicine at the University of Carolina at Chapel Hill in Chapel Hill, N.C., said the pathogenesis of AAV involves a complex series of events that evolve over time, and the treatment approach is growing ever more sophisticated. […] Since then, the classification criteria for AAV has deepened, along with insights into its pathogenesis, now known to involve ANCA-induced activation of primed neutrophils resulting in acute inflammation and necrosis, and chronic inflammation and scarring. […] Today, Dr. Jennette said, treatment strategies have been influenced by the understanding of AAV pathogenesis. […] Therapy must also specifically interrupt the acute inflammatory amplification loop present in patients with active AAV, he said; that is, it must break the cycle in which the activation of neutrophils leads to activation of the alternative complement pathway, which leads to even more neutrophil activation. […] Treatment options continue to improve, Dr. Jennette said, with the introduction of novel therapies targeting specific components of the pathogenic process.

• #70 ANCA-Associated Vasculitis Pathogenesis & Treatment Updates – The Rheumatologist

  https://www.the-rheumatologist.org/article/anca-associated-vasculitis-pathogenesis-treatment-updates/

  In the Philip Hench, MD, Memorial Lecture, J. Charles Jennette, MD, chair in pathology and laboratory medicine at the University of Carolina at Chapel Hill in Chapel Hill, N.C., said the pathogenesis of AAV involves a complex series of events that evolve over time, and the treatment approach is growing ever more sophisticated. […] Since then, the classification criteria for AAV has deepened, along with insights into its pathogenesis, now known to involve ANCA-induced activation of primed neutrophils resulting in acute inflammation and necrosis, and chronic inflammation and scarring. […] Today, Dr. Jennette said, treatment strategies have been influenced by the understanding of AAV pathogenesis. […] Therapy must also specifically interrupt the acute inflammatory amplification loop present in patients with active AAV, he said; that is, it must break the cycle in which the activation of neutrophils leads to activation of the alternative complement pathway, which leads to even more neutrophil activation. […] Treatment options continue to improve, Dr. Jennette said, with the introduction of novel therapies targeting specific components of the pathogenic process.

• #71 Pathogens in Vasculitis: Is It Really Idiopathic? | JMA Journal

  https://www.jmaj.jp/detail.php?id=10.31662%2Fjmaj.2021-0021

  However, an increasing number of human and animal studies suggest that vasculitis is not only caused by a few infectious agents but also, in fact, associated with various pathogenic agents, including viruses, bacteria, fungi, and parasites. […] Comparable to other autoimmune conditions, an aberrantly activated host immune response to the pathogen is considered to play a central role in vasculitis. […] In this review, we summarize previous reports on animal vasculitis models and human vasculitis cases associated with infectious agents and discuss the potential approach for investigating the pathogenesis of vasculitis, which is often considered an idiopathic disease. […] A deeper understanding of the mechanism by which pathogens induce vasculitis could help develop novel therapeutic targets and prevention strategies for vasculitis.

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