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Lipid microarrays identify key mediators of autoimmune brain inflammation

Abstract

Recent studies suggest that increased T-cell and autoantibody reactivity to lipids may be present in the autoimmune demyelinating disease multiple sclerosis. To perform large-scale multiplex analysis of antibody responses to lipids in multiple sclerosis, we developed microarrays composed of lipids present in the myelin sheath, including ganglioside, sulfatide, cerebroside, sphingomyelin and total brain lipid fractions. Lipid-array analysis showed lipid-specific antibodies against sulfatide, sphingomyelin and oxidized lipids in cerebrospinal fluid (CSF) derived from individuals with multiple sclerosis. Sulfatide-specific antibodies were also detected in SJL/J mice with acute experimental autoimmune encephalomyelitis (EAE). Immunization of mice with sulfatide plus myelin peptide resulted in a more severe disease course of EAE, and administration of sulfatide-specific antibody exacerbated EAE. Thus, autoimmune responses to sulfatide and other lipids are present in individuals with multiple sclerosis and in EAE, and may contribute to the pathogenesis of autoimmune demyelination.

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Figure 1: Lipid microarrays.
Figure 2: Individuals with multiple sclerosis have increased lipid-specific antibodies.
Figure 3: Mice with EAE have increased lipid-specific antibodies.
Figure 4: Immunization with sulfatide plus myelin peptide results in a more severe disease course of EAE.

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Acknowledgements

The authors would like to thank H. Neuman de Vegvar, B.J. Lee, B. Kidd, B. Tomooka, S. Dunn, S. Youssef and other members of the Steinman and Robinson laboratories for discussions, and R. James and D. Oats from Camag Scientific for helping adapt the ATS4 to print lipid arrays. This work was supported by US National Institutes of Health (NIH) grant K08 AR02133, a NIH U19 Pilot Award, NIH National Heart, Lung, and Blood Institute (NHLBI) contract N01 HV 28183 and a Department of Veterans Affairs Merit Award to W.H.R.; and by NIH National Institute of Neurological Disorders and Stroke grant 5R01NS18235, NIH NHLBI contract N01 HV 28183, and NIH U19 DK61934 to L.S.; and J.L.K. received funding from NIH 5T32 GM07276, a Cellular and Molecular Biology training grant and a Stanford Graduate Gabilan Fellowship.

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Correspondence to William H Robinson.

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William H. Robinson and Lawrence Steinman receive financial compensation for consulting for and own shares of stock in Bayhill Therapeutics.

Supplementary information

Supplementary Table 1

Antigens printed on lipid microarrays. (PDF 18 kb)

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Kanter, J., Narayana, S., Ho, P. et al. Lipid microarrays identify key mediators of autoimmune brain inflammation. Nat Med 12, 138–143 (2006). https://doi.org/10.1038/nm1344

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