OBJECTIVE: The vascular lesions associated with autoimmune small-vessel vasculitis may arise from activation of circulating neutrophils by antineutrophil cytoplasmic antibodies (ANCA), resulting in increased adhesion of these neutrophils to the vessel wall. The present study examined the effects of ANCA-positive IgG (ANCA IgG), derived from patients with small-vessel vasculitis, on neutrophil adhesion.
METHODS: An in vitro, flow-based adhesion assay was used to determine the effects of ANCA IgG on neutrophils rolling on P-selectin presented by a monolayer of activated platelets. The platelets act as a surrogate vessel wall and can also support beta2 integrin-mediated immobilization of neutrophils if they are purposefully activated (e.g., by FMLP).
RESULTS: In the absence of any added agents, neutrophils rolled continuously over the platelet monolayer. Superfusion of ANCA IgG over rolling cells resulted in conversion to stationary adhesion accompanied by shape change. The ANCA-mediated response was transient, peaking at 5-6 minutes and returning to baseline by 15 minutes, even in the continued presence of ANCA. In contrast, normal (ANCA-negative) IgG and ANCA F(ab')2 fragments caused minimal conversion to stationary adhesion. Pretreatment of neutrophils with blocking antibodies directed toward Fc gamma receptor type IIA or the integrin chain CD11b completely inhibited the ANCA-mediated conversion, confirming that ANCA-mediated activation occurred through Fc gamma receptors and that neutrophil immobilization was mediated by the activated beta2 integrin (CD11b/CD18).
CONCLUSION: 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.
|Number of pages||9|
|Journal||Arthritis & Rheumatism|
|Publication status||Published - Jun 2000|
- Antibodies, Antineutrophil Cytoplasmic
- Blood Platelets
- Cell Adhesion
- Cell Movement
- Immunoglobulin Fab Fragments
- Immunoglobulin G
- Macrophage-1 Antigen
- Receptors, IgG
- Time Factors