Treatment of rolling neutrophils with antineutrophil cytoplasmic antibodies causes conversion to firm integrin‐mediated adhesion

Radford, David J.; Savage, Caroline O. S.; Nash, Gerard B.

doi:10.1002/1529-0131(200006)43:6<1337::aid-anr16>3.0.co;2-m

Cited by 114 publications

(87 citation statements)

References 29 publications

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“…CD18 blockade completely inhibits ANCA-induced neutrophil SO production, and CD11b blockade reduces ANCA-induced neutrophil adherence to platelets (8,41). Our finding that CD18 blockade diminished ANCA-induced Syk phosphorylation is consistent with these reports.…”

Section: Discussionsupporting

confidence: 90%

Activation of Syk in Neutrophils by Antineutrophil Cytoplasm Antibodies Occurs via Fcγ Receptors and CD18

Hewins¹,

Williams²,

Wakelam³

et al. 2004

Journal of the American Society of Nephrology

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Abstract. Antineutrophil cytoplasm antibodies (ANCA) activate TNF-␣-primed neutrophils to undergo a respiratory burst. The intracellular signals that mediate activation have not been studied extensively but could increase the understanding of the pathogenesis small vessel vasculitis. It was demonstrated that ANCA-IgG induced phosphorylation of the tyrosine kinase Syk in TNF-␣-primed neutrophils from healthy donors. Syk was not phosphorylated in response to ANCA F(ab') 2 . Furthermore, Syk phosphorylation was attenuated by blockade of both low-affinity Fc␥ receptors and CD18. Similarly, low-affinity Fc␥ receptor blockade reduced ANCA-induced superoxide production. In patient-derived neutrophils, the high-affinity Fc␥ receptor Fc␥RI was also demonstrated to be involved in ANCA-induced superoxide production. However, Syk phosphorylation was not attenuated by blockade of the Fc␥RI, present on neutrophils from vasculitis patients. The tyrosine kinase inhibitor 4-Amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine inhibited the ANCA-induced respiratory burst and Syk phosphorylation, suggesting that Src kinases lie upstream of Syk activation but downstream of ANCA engagement of Fc␥ receptors. Piceatannol, another tyrosine kinase inhibitor, also inhibited ANCA-induced Syk phosphorylation and the ANCA-stimulated respiratory burst, supporting the proposed functional role for Syk in ANCA signaling. ANCAinduced phosphorylation of Cbl and intracellular calcium transients, potential downstream mediators of Syk activation, were also blocked by tyrosine kinase inhibitors. While it has previously been shown that pertussis toxin diminishes the ANCAinduced respiratory burst, indicating heterotrimeric G protein involvement, Syk phosphorylation and calcium transients were unaffected by pertussis toxin. Collectively, these data show that Syk phosphorylation is induced during ANCA-triggered neutrophil activation.

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Section: Discussionsupporting

confidence: 90%

Activation of Syk in Neutrophils by Antineutrophil Cytoplasm Antibodies Occurs via Fcγ Receptors and CD18

Hewins¹,

Williams²,

Wakelam³

et al. 2004

Journal of the American Society of Nephrology

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“…Others have described arrest of rolling neutrophils in vitro in response to antineutrophil cytoplasmic antibodies and an in vivo shock reaction induced by antibodies against glycoprotein IIb/IIIa on platelets that are both Fc␥ receptor dependent. 26,27 In contrast to the above, our reaction was not Fc␥ receptor dependent ( Figure 5B). Antibody 2.4G2, at a dose which blocks Fc␥ receptors II and III, 27 failed to protect mice from RB6-8C5-induced microvascular arrest and death ( Figure 5B) or to prevent leukocyte depletion by RB6-8C5 (not shown).…”

Section: A Role For Selectins In Reactions Induced By Tnf-␣/rb6-8c5contrasting

confidence: 67%

Combined anticoagulant and antiselectin treatments prevent lethal intravascular coagulation

Norman

Cotter

Stewart

et al. 2003

Blood

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“…Close proximity of the activated neutrophils to endothelial cells is required because the endothelial toxicity is inhibited by antibodies to ␤2 integrins (34). Savage and associates (35)(36)(37) showed that activation of neutrophils by ANCA causes integrin-and cytokine receptormediated adherence to cultured endothelial cells and transmigration across the endothelial layer. In addition, activation of neutrophils with ANCA causes a conformational change in ␤ integrins that enhances ligand binding (37).…”

Section: Neutrophil and Monocyte Activation By Anca In Vitromentioning

confidence: 99%

Pathogenesis of Vascular Inflammation by Anti-Neutrophil Cytoplasmic Antibodies

Jennette¹,

Xiao²,

Falk³

2006

Journal of the American Society of Nephrology

185

126

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The reports of a newborn who developed glomerulonephritis and pulmonary hemorrhage after transplacental transfer of anti-neutrophil cytoplasmic antibody (ANCA) IgG with specificity for myeloperoxidase (MPO) is compelling clinical evidence that ANCA are pathogenic. In vitro studies indicate that ANCA activate cytokine-primed neutrophils and monocytes through both direct Fab2 binding and Fc receptor engagement. Neutrophils that have been activated by ANCA release oxygen radicals, lytic enzymes, and inflammatory cytokines and adhere to and kill endothelial cells. A murine model caused by passive administration of mouse anti-mouse MPO IgG provides convincing evidence that ANCA IgG alone in the absence of antigen-specific T cells can cause necrotizing glomerulonephritis and vasculitis. This pathogenic process is enhanced by synergistic inflammatory factors, probably through priming of neutrophils. Immunization of rats with human MPO induces antibodies that cross-react with rat MPO and cause glomerulonephritis and vasculitis. These ANCA act in concert with chemokines to cause adherence of leukocytes to the walls of small vessels with subsequent injury. To date, animal models of disease that is induced by anti-proteinase 3 are less robust. Clinical and experimental data suggest but do not prove that the ANCA autoimmune response is initiated by an immune response to an antisense peptide of the ANCA antigen or its mimic that may be introduced into the body by an infectious pathogen. This antibody response elicits anti-idiotypic antibodies that cross-react with ANCA antigens. The pathogenesis of ANCA disease is multifactorial, with genetic and environmental factors influencing onset of the autoimmune response, the mediation of acute injury, and the induction of the chronic response to injury.

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Treatment of rolling neutrophils with antineutrophil cytoplasmic antibodies causes conversion to firm integrin‐mediated adhesion

Abstract: These findings support the concept that ANCA can directly activate neutrophils to become firmly adherent to vessel walls, where they may obstruct flow, initiate tissue damage, and contribute to pathogenesis of vasculitis.

Cited by 114 publications

References 29 publications

Activation of Syk in Neutrophils by Antineutrophil Cytoplasm Antibodies Occurs via Fcγ Receptors and CD18

Activation of Syk in Neutrophils by Antineutrophil Cytoplasm Antibodies Occurs via Fcγ Receptors and CD18

Combined anticoagulant and antiselectin treatments prevent lethal intravascular coagulation

Pathogenesis of Vascular Inflammation by Anti-Neutrophil Cytoplasmic Antibodies

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