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dc.contributor.authorKoenig, Paul-Albert
dc.contributor.authorSpooner, Eric
dc.contributor.authorKawamoto, Norio
dc.contributor.authorStrominger, Jack L.
dc.contributor.authorPloegh, Hidde
dc.date.accessioned2017-05-26T18:46:34Z
dc.date.available2017-05-26T18:46:34Z
dc.date.issued2013-07
dc.identifier.issn0022-1767
dc.identifier.issn1550-6606
dc.identifier.urihttp://hdl.handle.net/1721.1/109387
dc.descriptionavailable in PMC 2014 July 01en_US
dc.description.abstractMultiple sclerosis (MS) is an autoimmune disease that affects the CNS. One approved treatment for relapsing forms of MS is YEAK, a random copolymer of the amino acids tyrosine, glutamic acid, alanine, and lysine. YFAK, a second-generation copolymer composed of tyrosine, phenylalanine, alanine, and lysine, is more successful in treating experimental autoimmune encephalomyelitis, a mouse model of MS. Although originally designed and optimized based on the autoantigen myelin basic protein (MBP) and the MBP-derived peptide MBP85-99 presented to the MS-associated class II MHC molecule HLA-DR2, YEAK and YFAK also stimulate cytokine and chemokine production in APCs that lack class II MHC products. How YEAK and YFAK copolymers interact with APCs remains enigmatic. We used biotinylated YFAK to affinity-purify YFAK-interacting proteins from RAW264.7 cells and tested APCs from mice deficient in several of the newly identified interactors for their capacity to secrete CCL22 in response to YEAK and YFAK. We propose that initial contact of YFAK with cells is mediated mainly by electrostatic interactions, and find that interaction of YFAK with host proteins is strongly dependent on ionic strength. Cells deficient in enzymes involved in sulfation of proteins and proteoglycans showed strongly reduced binding of biotinylated YFAK. Lastly, cells stimulated with YFAK in the presence of heparin, structurally similar to heparan sulfates, failed to produce CCL22. We conclude that charge-dependent interactions of copolymers that alleviate MS/experimental autoimmune encephalomyelitis are critical for their effects exerted on APCs and may well be the main initial mediators of these therapeutically active copolymers.en_US
dc.description.sponsorshipNational Institutes of Health (U.S.) (NIH grant no. RO1 AI087879)en_US
dc.description.sponsorshipNational Institutes of Health (U.S.) (NIH grant AI049524)en_US
dc.language.isoen_US
dc.publisherAmerican Association of Immunologists, Inc.en_US
dc.relation.isversionofhttp://dx.doi.org/10.4049/jimmunol.1300345en_US
dc.rightsCreative Commons Attribution-Noncommercial-Share Alikeen_US
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/en_US
dc.sourcePMCen_US
dc.titleAmino Acid Copolymers That Alleviate Experimental Autoimmune Encephalomyelitis In Vivo Interact with Heparan Sulfates and Glycoprotein 96 in APCsen_US
dc.typeArticleen_US
dc.identifier.citationKoenig, Paul-Albert, Eric Spooner, Norio Kawamoto, Jack L. Strominger, and Hidde L. Ploegh. “Amino Acid Copolymers That Alleviate Experimental Autoimmune Encephalomyelitis In Vivo Interact with Heparan Sulfates and Glycoprotein 96 in APCs.” The Journal of Immunology 191, no. 1 (June 5, 2013): 208–216.en_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Biologyen_US
dc.contributor.mitauthorPloegh, Hidde
dc.relation.journalJournal of Immunologyen_US
dc.eprint.versionAuthor's final manuscripten_US
dc.type.urihttp://purl.org/eprint/type/JournalArticleen_US
eprint.statushttp://purl.org/eprint/status/PeerRevieweden_US
dspace.orderedauthorsKoenig, Paul-Albert; Spooner, Eric; Kawamoto, Norio; Strominger, Jack L.; Ploegh, Hidde L.en_US
dspace.embargo.termsNen_US
dc.identifier.orcidhttps://orcid.org/0000-0002-1090-6071
mit.licenseOPEN_ACCESS_POLICYen_US


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