Abstract
Dysfunction of receptors for IgG (FcγRs) has been thought to be involved in the pathogenesis of systemic lupus erythematosus (SLE). We show that a recently described SLE-associated polymorphism of FcγRIIb (FcγRIIbT232), encoding a single transmembrane amino acid substitution, is functionally impaired. FcγRIIbT232 is unable to inhibit activatory receptors because it is excluded from sphingolipid rafts, resulting in the unopposed proinflammatory signaling thought to promote SLE.
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Acknowledgements
This research was funded by the Medical Research Council UK and the Wellcome Trust. R.A.F. holds an Academy of Medical Sciences Medical Research Council Clinician Scientist Fellowship. M.R.C. is supported by a Wellcome Trust Clinical Training Fellowship and K.G.C.S. by a Wellcome Research Leave Award for Clinical Academics. We are grateful to the staff and donors of the National Blood Service Cambridge Apheresis Clinic, to E. Walker for technical assistance and to M. Mahaut-Smith for the use of the Cairn Spectrophotometer.
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Supplementary information
Supplementary Fig. 1
Assessment of phagocytosis by differentiated U937 cell lines. (PDF 3878 kb)
Supplementary Fig. 2
FcγRIIb1T232 expression alters primary B cell proliferation. (PDF 289 kb)
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Floto, R., Clatworthy, M., Heilbronn, K. et al. Loss of function of a lupus-associated FcγRIIb polymorphism through exclusion from lipid rafts. Nat Med 11, 1056–1058 (2005). https://doi.org/10.1038/nm1288
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DOI: https://doi.org/10.1038/nm1288
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