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Originally published online as doi:10.1189/jlb.0507305 on October 16, 2008

Published online before print October 16, 2008
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(Journal of Leukocyte Biology. 2009;85:55-63.)
© 2009 by Society for Leukocyte Biology

Antibody ligation of murine Ly-6G induces neutropenia, blood flow cessation, and death via complement-dependent and independent mechanisms

Katherine B. Abbitt, Matthew J. Cotter, Victoria C. Ridger, David C. Crossman, Paul G. Hellewell1,2 and Keith E. Norman1

Cardiovascular Research Unit, School of Medicine and Biomedical Sciences, University of Sheffield, Sheffield, United Kingdom

2 Correspondence: Cardiovascular Research Unit, School of Medicine and Biomedical Sciences, University of Sheffield, Sheffield, S10 2JF, UK. E-mail: p.g.hellewell{at}sheffield.ac.uk

ABSTRACT

Ly-6G is a member of the Ly-6 family of GPI-linked proteins, which is expressed on murine neutrophils. Antibodies against Ly-6G cause neutropenia, and fatal reactions also develop if mice are primed with TNF-{alpha} prior to antibody treatment. We have investigated the mechanisms behind these responses to Ly-6G ligation in the belief that similar mechanisms may be involved in neutropenia and respiratory disorders associated with alloantibody ligation of the related Ly-6 family member, NB1, in humans. Neutrophil adhesion, microvascular obstruction, breathing difficulties, and death initiated by anti-Ly-6G antibodies in TNF-{alpha}-primed mice were shown to be highly complement-dependent, partly mediated by CD11b, CD18, and Fc{gamma}R and associated with clustering of Ly-6G. Neutrophil depletion, on the other hand, was only partly complement-dependent and was not altered by blockade of CD11b, CD18, or Fc{gamma}R. Unlike other neutrophil-activating agents, Ly-6G ligation did not induce neutropenia via sequestration in the lungs. Cross-linking Ly-6G mimicked the responses seen with whole antibody in vivo and also activated murine neutrophils in vitro. Although this suggests that the responses are, in part, mediated by nonspecific properties of antibody ligation, neutrophil depletion requires an additional mechanism possibly specific to the natural function of Ly-6G.

Key Words: neutrophils • cell activation • adhesion




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