Pathogenesis of Wegener's granulomatosis: current concepts

2005 ◽  
Vol 7 (8) ◽  
pp. 1-19 ◽  
Author(s):  
Pasha Sarraf ◽  
Michael C. Sneller
Keyword(s):  
Animal Models ◽  
Wegener’S Granulomatosis ◽  
Granulomatous Inflammation ◽  
Wegener's Granulomatosis ◽  
Small Vessel Vasculitis ◽  
Focused Attention ◽  
Pathogenic Role ◽  
Disease Pathogenesis ◽  
Autoimmune Syndrome

Wegener's granulomatosis (WG) is a complex autoimmune syndrome that is characterised by upper/lower respiratory necrotising granulomatosis, glomerulonephritis and small-vessel vasculitis. Since Wegener's 1936 description, considerable advances in recognition and treatment have changed this disease from a rapidly and uniformly fatal illness to a chronic disease characterised by remissions and relapses. The serendipitous discovery of anti-neutrophil cytoplasmic antibodies (ANCAs) as a marker associated with WG focused attention on the potential pathogenic role of these antibodies and has recently led to the development of novel animal models that might facilitate our understanding of the disease pathogenesis. Future animal models of this disease will have to account for the role of both ANCA-mediated pathology and granulomatous inflammation to enable us to understand the chronic and persistent features of WG in humans.

scholarly journals Wegener’s granulomatosis and retroperitoneal fibrosis: a case report and review of the literature

2019 ◽  
Vol 13 (2) ◽  
pp. 109-115
Author(s):  
Lia Salvati ◽  
Valeria Ludovici ◽  
Giuliana Properzi ◽  
Laura Natali ◽  
Angelo Viscido ◽  
...  
Keyword(s):  
Case Report ◽  
Wegener’S Granulomatosis ◽  
Retroperitoneal Fibrosis ◽  
Immunosuppressive Treatment ◽  
Granulomatous Inflammation ◽  
Wegener's Granulomatosis ◽  
Antineutrophil Cytoplasmic Antibodies ◽  
Small Vessel Vasculitis ◽  
Review Of The Literature ◽  
Vein Thrombosis

Granulomatosis with polyangiitis (GPA), also known as Wegener’s granulomatosis (WG), is a rare systemic auto-inflammatory disease characterized by necrotizing granulomatous inflammation and antineutrophil cytoplasmic antibodies-associated small vessel vasculitis. Retroperitoneal fibrosis (RPF) is an uncommon collagen vascular disease of unclear etiology, characterized by a chronic non-specific inflammation of the retroperitoneum, which can entrap and obstruct retroperitoneal structures, notably abdominal aorta, iliac arteries and ureters. RPF is mostly idiopathic, but an association with vasculitis has been shown. However, only few cases of retroperitoneal fibrosis with ureterohydronephrosis secondary to GPA have been described in literature. The outcome seems to be better when compared to the idiopathic form, and immunosuppressive treatment demonstrated to be effective, with low need in surgery. We provide the case report of a 57-year-old patient, affected by GPA, referred to our Division for massive vein thrombosis and ureteral stenosis secondary to retroperitoneal fibrosis. We also provide a review of the literature currently available on this topic.

scholarly journals Esophageal Involvement in Wegener’s Granulomatosis: A Case Report and Review of the Literature

2000 ◽  
Vol 14 (5) ◽  
pp. 449-451 ◽  
Author(s):  
Glen A Fallows ◽  
Sean F Hamilton ◽  
Douglas S Taylor ◽  
S Bharati Reddy
Keyword(s):  
Case Report ◽  
Gastrointestinal Tract ◽  
Disease Activity ◽  
Intestinal Perforation ◽  
Standard Therapy ◽  
Wegener’S Granulomatosis ◽  
Wegener's Granulomatosis ◽  
Small Vessel Vasculitis ◽  
Review Of The Literature ◽  
Systemic Symptoms

Wegener’s granulomatosis is characterized by a granulomatous arteritis involving the upper and lower respiratory tracts, progressive glomerulonephritis and systemic symptoms attributable to small vessel vasculitis. Although multisystemic manifestations are frequent, involvement of the gastrointestinal tract is uncommon. Cases have been reported of intestinal perforation, ulceration and hemorrhage. A patient whose initial presentation of Wegener’s granulomatosis was odynophagia secondary to esophageal vasculitis is described. Endoscopy revealed multiple punched out ulcerations in the esophagus, which resolved with standard therapy for systemic Wegener’s granulomatosis. There are only two previous reports of symptomatic esophageal vasculitis in patients with Wegener’s granulomatosis. These reports illustrate the need to consider odynophagia as a reflection of disease activity as opposed to complications of immunosuppressive therapy.

Th1 and Th2 CD4+ T cells and Tc1 and Tc2 CD8+ T cells of patients with Wegener’s granulomatosis

2002 ◽  
Vol 116 (8) ◽  
pp. 605-609 ◽  
Author(s):  
Nobuo Ohta ◽  
Shigeru Fukase ◽  
Takeo Fuse ◽  
Masaru Aoyagi
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Wegener’S Granulomatosis ◽  
Wegener's Granulomatosis ◽  
Th2 Cytokine ◽  
Cytokine Flow Cytometry ◽  
Th1 Cytokines ◽  
Cytokine Imbalance ◽  
Th1 And Th2

A Th1/Th2 cytokine imbalance with a predominance of Th1 cytokines has been suggested to be of pathogenic importance in Wegener’s granulomatosis. To evaluate the role of Th1/Th2 cytokines in Wegener’s granulomatosis, the subsets of Th1, Th2, Tc1 and Tc2 cells from patients with active Wegener’s granulomatosis were examined by intracellular cytokine flow cytometry. The population of Tc1 cells (72.0 ± 14.4 per cent) in Wegener’s granulomatosis was significantly increased compared with Tc1 cells (37.3 ± 14.6 per cent) in control (p<0.05). Th1, Th2 and Tc2 cells in Wegener’s granulomatosis were not significantly increased compared with the control cells. These results indicate that the predominance of Tc1 cells might contribute to the mechanism of the pathogenesis of Wegener’s granulomatosis.

Wegener's granulomatosis, subglottic stenosis and antineutrophil cytoplasm antibodies.

1989 ◽  
Vol 103 (12) ◽  
pp. 1187-1191 ◽  
Author(s):  
T. J. Hoare ◽  
D. Jayne ◽  
P. Rhys Evans ◽  
C. B. Croft ◽  
D. J. Howard
Keyword(s):  
Wegener’S Granulomatosis ◽  
Wegener's Granulomatosis ◽  
Subglottic Stenosis ◽  
The Past ◽  
The Future

AbstractWegener's granulomatosis is difficult to diagnose, especially when the presentation is unusual, restricted to an isolated region. We report four cases of recurrent subglottic stenosis posing difficulty in diagnosis. In each case the finding of anti-neutrophil cytoplasm antibodies (ANCA) strongly suggested an underlying vasculitic pathology, Wegener's granulomatosis. We discuss reasons for the difficulty in diagnosis in the past, the possible role of the ANCA assay in such patients, and suggest it should be more widely used in the future.

scholarly journals Genetic Variability of RXRB, PPARA, and PPARG in Wegener's Granulomatosis

PPAR Research ◽  
2009 ◽  
Vol 2009 ◽  
pp. 1-5
Author(s):  
Stefan Wieczorek ◽  
Silvia Knaup ◽  
Wolfgang L. Gross ◽  
Jörg T. Epplen
Keyword(s):  
Wegener’S Granulomatosis ◽  
Strong Association ◽  
Wegener's Granulomatosis ◽  
Epistatic Effect ◽  
Genomic Region ◽  
Peroxisome Proliferator ◽  
Retinoid Receptor ◽  
Peroxisome Proliferator Activated Receptors ◽  
Receptor Beta

A major genomic region involved in Wegener's granulomatosis includes the gene for retinoid receptor beta (RXRB) which forms heterodimers with peroxisome proliferator-activated receptors (PPARs). It is unclear whether this association directly arises from theRXRBallele(s) or via a linked variation. In order to reveal any hitherto unknown and potentially disease-relevant variation of theRXRBgene, we have genotyped four tagging SNPs of this genomic region and have directly sequenced selected WG patients and controls representing disease-associated haplotypes. Additionally, we have genotyped 2 SNPs each in the genes for PPARαand PPARγ(PPARAandPPARG). Hence, we confirmed the strong association of theRXRBlocus with WG but could not reveal any novel variation inRXRB. None of thePPARAandPPARGSNPs showed association with WG. Moreover, no epistatic effect was seen betweenRXRBandPPARA/PPARGalleles. These results do not support an etiopathological role of PPAR in WG. Analyses of further genes functionally linked to RXRB may provide additional data useful to evaluate theRXRBassociation found in WG.

scholarly journals Putative Pathobionts in HLA-B27-Associated Spondyloarthropathy

2021 ◽  
Vol 11 ◽  
Author(s):  
Tejpal Gill ◽  
James T. Rosenbaum
Keyword(s):  
Animal Models ◽  
Microbial Communities ◽  
Underlying Disease ◽  
Disease Development ◽  
Hla B27 ◽  
Disease Pathogenesis ◽  
Fecal Microbiota Transplant ◽  
Germ Free ◽  
Associated Diseases

Spondyloarthritis (SpA) is a group of immune mediated inflammatory diseases with a strong association to the major histocompatibility (MHC) class I molecule, HLA-B27. Although the association between HLA-B27 and AS has been known for almost 50 years, the mechanisms underlying disease pathogenesis are elusive. Over the years, three hypotheses have been proposed to explain HLA-B27 and disease association: 1) HLA B27 presents arthritogenic peptides and thus creates a pathological immune response; 2) HLA-B27 misfolding causes endoplasmic reticulum (ER) stress which activates the unfolded protein response (UPR); 3) HLA-B27 dimerizes on the cell surface and acts as a target for natural killer (NK) cells. None of these hypotheses explains SpA pathogenesis completely. Evidence supports the hypothesis that HLA-B27-related diseases have a microbial pathogenesis. In animal models of various SpAs, a germ-free environment abrogates disease development and colonizing these animals with gut commensal microbes can restore disease manifestations. The depth of microbial influence on SpA development has been realized due to our ability to characterize microbial communities in the gut using next-generation sequencing approaches. In this review, we will discuss various putative pathobionts in the pathogenesis of HLA-B27-associated diseases. We pursue whether a single pathobiont or a disruption of microbial community and function is associated with HLA-B27-related diseases. Furthermore, rather than a specific pathobiont, metabolic functions of various disease-associated microbes might be key. While the use of germ-free models of SpA have facilitated understanding the role of microbes in disease development, future studies with animal models that mimic diverse microbial communities instead of mono-colonization are indispensable. We discuss the causal mechanisms underlying disease pathogenesis including the role of these pathobionts on mucin degradation, mucosal adherence, and gut epithelial barrier disruption and inflammation. Finally, we review the various uses of microbes as therapeutic modalities including pre/probiotics, diet, microbial metabolites and fecal microbiota transplant. Unravelling these complex host-microbe interactions will lead to the development of new targets/therapies for alleviation of SpA and other HLA-B27 associated diseases.

scholarly journals Neutrophil activation by anti-proteinase 3 antibodies in Wegener's granulomatosis: role of exogenous arachidonic acid and leukotriene B4 generation.

1996 ◽  
Vol 184 (4) ◽  
pp. 1567-1572 ◽  
Author(s):  
F Grimminger ◽  
K Hattar ◽  
C Papavassilis ◽  
B Temmesfeld ◽  
E Csernok ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Wegener’S Granulomatosis ◽  
Wegener's Granulomatosis ◽  
Neutrophil Activation ◽  
Tnf Alpha ◽  
Lipid Mediator ◽  
Human Neutrophils ◽  
Proteinase 3 ◽  
Lipoxygenase Pathway

Among the anti-neutrophil cytoplasmic antibodies (ANCA), those targeting proteinase 3 (PR3) have a high specificity for Wegener's granulomatosis (WG). It is known that a preceding priming of neutrophils with cytokines is a prerequisite for membrane surface expression of PR3, which is then accessible to autoantibody binding. Employing a monoclonal antibody directed against human PR3 and ANCA-positive serum from WG patients with specificity for PR3, we now investigated the role of free arachidonic acid (AA) in autoantibody-related human neutrophil activation. Priming of neutrophils with tumor necrosis factor (TNF-alpha) for 15 min or exposure to anti-PR3 antibodies or incubation with free AA (10 microM) as sole events did not provoke superoxide generation, elastase secretion or generation of 5-lipoxygenase products of AA. Similarly, the combination of TNF-alpha-priming and AA incubation was ineffective. When TNF-alpha-primed neutrophils were stimulated by anti-PR3 antibodies, superoxide and elastase secretion was provoked in the absence of lipid mediator generation. However, when free AA was additionally provided, a strong activation of the 5-lipoxygenase pathway was demasked, with the appearance of excessive quantities of leukotriene (LT)B4, LTA4, and 5-hydroxyeicosatetraenoic acid. Moreover, superoxide and elastase secretion were markedly amplified, and studies with 5-lipoxygenase inhibitors and a LTB4-antagonist demonstrated this was due to an LTB4-related autocrine loop of cell activation. In contrast, the increased synthesis of platelet-activating factor in response to TNF-alpha-priming and anti-PR3 stimulation did not contribute to the amplification loop of neutrophil activation under the given conditions. We conclude that anti-PR3 antibodies are potent inductors of the 5-lipoxygenase pathway in primed human neutrophils, and extracellular free AA, as provided at an inflammatory focus, synergizes with the autoantibodies to evoke full-blown lipid mediator generation, granule secretion and respiratory burst. Such events may be enrolled in the pathogenesis of focal necrotizing vascular injury in Wegener's granulomatosis.

Sign in / Sign up

Export Citation Format

Share Document