Disease activity and autoantibodies to endothelial cells in patients with Wegener's granulomatosis

Göbel, U; Eichhorn, Jens; Kettritz, Ralph; Briedigkeit, L; Sima, Dagmar; Lindschau, Carsten; Haller, Hermann; Luft, Friedrich C.

doi:10.1016/s0272-6386(96)90300-5

Cited by 43 publications

(28 citation statements)

References 24 publications

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“…Among primary autoimmune vasculitides such as Wegener granulamatosis, Kawasaki disease, and Henoch-Schonlein purpura, there is an association between antiendothelial cell antibodies (AECA) and disease status. [22][23][24][25][26][27] Systemic lupus erythematosus also shows a relationship between AECA prevalence and disease status. 28,29 Indeed, transfer of AECA into rabbits results in systemic lupus erythematosus-like nephritis.…”

Section: Introductionmentioning

confidence: 99%

Evidence for a novel human-specific xeno-auto-antibody response against vascular endothelium

Pham¹,

Gregg²,

Karp³

et al. 2009

Blood

112

138

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Humans are genetically unable to synthesize the common mammalian sialic acid N-glycolylneuraminic acid (Neu5Gc). However, Neu5Gc can be metabolically incorporated and covalently expressed on cultured human cell surfaces. Meanwhile, humans express varying and sometimes high titers of polyclonal anti-Neu5Gc antibodies. Here, a survey of human tissues by immunohistochemistry with both a monospecific chicken anti-Neu5Gc antibody and with affinity-purified human antiNeu5Gc antibodies demonstrates endothelial expression of Neu5Gc, likely originating from Neu5Gc-rich foods like red meats. We hypothesized that the combination of Neu5Gc incorporation and anti-Neu5Gc antibodies can induce endothelial activation. Indeed, the incubation of high-titer human sera with Neu5Gc-fed endothelial cells led to Neu5Gc-dependent antibody binding, complement deposition, endothelial activation, selectin expression, increased cytokine secretion, and monocyte binding. The proinflammatory cytokine tumor necrosis factor-␣ also selectively enhanced human anti-Neu5Gc antibody reactivity. AntiNeu5Gc antibodies affinity-purified from human serum also directed Neu5Gc-dependent complement deposition onto cultured endothelial cells. These data indicate a novel human-specific mechanism in which Neu5Gc-rich foods deliver immunogenic Neu5Gc to the endothelium, giving anti-Neu5Gc antibody-and complement-dependent activation, and potentially contributing to human vascular pathologies. In the case of atherosclerosis, Neu5Gc is present both in endothelium overlying plaques and in subendothelial regions, providing multiple pathways for accelerating inflammation in this disease.

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Section: Introductionmentioning

confidence: 99%

Evidence for a novel human-specific xeno-auto-antibody response against vascular endothelium

Pham¹,

Gregg²,

Karp³

et al. 2009

Blood

112

138

View full text Add to dashboard Cite

show abstract

“…The binding of AECA in WG to EC may directly trigger local production of inflammatory cytokines or alternatively might be instrumental in inducing endothelial phenotype changes, resulting in inflammation or facilitation of cellular infiltration. 5,[32][33][34][35][36][37] AECA have been shown to recognize constitutive EC surface proteins and to fluctuate with the clinical activity of the disease. 32,33 Evidence exists that AECA from WG sera can modulate EC function.…”

Section: Discussionmentioning

confidence: 99%

“…4 The support that AECA might be pathogenic is sustained by recognition of endothelial surface proteins, induction of various adhesion molecules on endothelial cells (EC) as well as of secretion of cytokines and chemokines; promotion of thrombotic events by increased production of tissue factor and von Willebrand factor, and fluctuation with the clinical activity of the disease. 5 Experimental in vitro and in vivo models support a potential pathogenic role for AECA in sustaining immunemediated vessel inflammation. 6,7 Stress-activated protein kinases (SAPK), which are members of the mitogen-activated protein kinase (MAPK) family, include c-Jun N-terminal kinase (JNK) and p38 MAPK.…”

mentioning

confidence: 98%

Anti–Endothelial Cell Autoantibodies Selectively Activate SAPK/JNK Signalling in Wegener’s Granulomatosis

Holmén¹,

Elsheikh²,

Christensson³

et al. 2007

Journal of the American Society of Nephrology

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The pathogenic role of anti-endothelial cell antibodies (AECA) in vascular injury is debated. It was previously shown that many patients with Wegener's granulomatosis (WG) have AECA that react with human kidney microvascular endothelial cells (EC). In addition, during active disease, renal endothelium strongly expresses the inflammatory molecules vascular adhesion protein-1 (VAP-1) and MHC class I-related antigen A (MICA). This study sought to determine whether AECA mediates this upregulation of VAP-1 and MICA and to define better the signaling pathways that are activated by these autoantibodies upon binding to EC in the kidney. Stimulation of human kidney microvascular EC with AECA IgG upregulated surface expression of MICA and VAP-1, elicited a rapid Ca 2ϩ flux, induced high levels of the chemokines monocyte chemoattractant protein-1 and granulocyte chemotactic protein-2, induced specific phosphorylation of stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK) and the transcription factors c-Jun and activating transcription factor-2, and activated NF-B. Specific inhibitors of SAPK/JNK significantly reduced AECA-induced chemokine production and phosphorylation of c-Jun and activating transcription factor-2 and abrogated protein expression of MICA but not VAP-1. In kidney sections from patients with WG, infiltrating cells that expressed the ligand for MICA (NKG2D ϩ ) were identified, as were CD8 ϩ and 32 ␥␦ ϩ T cells. In conclusion, AECA may be involved in the pathogenesis of WG, and the SAPK/JNK pathway and the endothelial inflammatory protein VAP-1 may be novel therapeutic targets for vasculitis.

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“…The mechanism of endothelial cell necrosis is not yet fully elucidated. Although anti-endothelial cell antibodies have been detected in AASV, their significance in this regard is not clear [63]. ANCA antigens, PR3 and MPO, can bind to endothelial cells via endothelial cell receptors [64,65].…”

Section: Endothelial Cell Activation and Enhanced Expression Of Adhesmentioning

confidence: 99%

History, Classification and Pathophysiology of Small Vessel Vasculitis

AbdGawad¹

2013

Updates in the Diagnosis and Treatment of Vasculitis

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Disease activity and autoantibodies to endothelial cells in patients with Wegener's granulomatosis

Cited by 43 publications

References 24 publications

Evidence for a novel human-specific xeno-auto-antibody response against vascular endothelium

Evidence for a novel human-specific xeno-auto-antibody response against vascular endothelium

Anti–Endothelial Cell Autoantibodies Selectively Activate SAPK/JNK Signalling in Wegener’s Granulomatosis

History, Classification and Pathophysiology of Small Vessel Vasculitis

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