title: The proteoglycan biglycan enhances antigen-specific T cell activation potentially via MyD88 and TRIF pathways and triggers autoimmune perimyocarditis.
abstract: Biglycan is a proteoglycan ubiquitously present in extracellular matrix of a variety of organs, including heart, and it was reported to be overexpressed in myocardial infarction. Myocardial infarction may be complicated by perimyocarditis through unknown mechanisms. Our aim was to investigate the capacity of TLR2/TLR4 ligand biglycan to enhance the presentation of specific Ags released upon cardiomyocyte necrosis. In vitro, OVA-pulsed bone marrow-derived dendritic cells from wild-type (WT; C57BL/6) and TLR2-, TLR4-, MyD88-, or TRIF-deficient mice were cotreated with LPS, biglycan, or vehicle and incubated with OVA-recognizing MHC I- or MHC II-restricted T cells. Biglycan enhanced OVA-specific cross-priming by >80% to MHC I-restricted T cells in both TLR2- and TLR4-pathway-dependent manners. Accordingly, biglycan-induced cross-priming by both MyD88- and TRIF-deficient dendritic cells (DCs) was strongly diminished. OVA-specific activation of MHC II-restricted T cells was predominantly TLR4 dependent. Our first in vivo correlate was a model of experimental autoimmune perimyocarditis triggered by injection of cardiac Ag-pulsed DCs (BALB/c). Biglycan-treated DCs triggered perimyocarditis to a comparable extent and intensity as LPS-treated DCs (mean scores 1.3 ± 0.3 and 1.5 ± 0.4, respectively). Substitution with TLR4-deficient DCs abolished this effect. In a second in vivo approach, WT and biglycan-deficient mice were followed 2 wk after induction of myocardial infarction. WT mice demonstrated significantly greater myocardial T lymphocyte infiltration in comparison with biglycan-deficient animals. We concluded that the TLR2/4 ligand biglycan, a component of the myocardial matrix, may enhance Ag-specific T cell priming, potentially via MyD88 and TRIF, and stimulate autoimmune perimyocarditis.
authors.affiliation: Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg 69120, Germany. Z.Popovic@dkfz.de
authors.forename: Zoran V
authors.initials: ZV
authors.lastname: Popovic
authors.forename: Shijun
authors.initials: S
authors.lastname: Wang
authors.forename: Maria
authors.initials: M
authors.lastname: Papatriantafyllou
authors.forename: Ziya
authors.initials: Z
authors.lastname: Kaya
authors.forename: Stefan
authors.initials: S
authors.lastname: Porubsky
authors.forename: Maria
authors.initials: M
authors.lastname: Meisner
authors.forename: Mahnaz
authors.initials: M
authors.lastname: Bonrouhi
authors.forename: Sven
authors.initials: S
authors.lastname: Burgdorf
authors.forename: Marian F
authors.initials: MF
authors.lastname: Young
authors.forename: Liliana
authors.initials: L
authors.lastname: Schaefer
authors.forename: Hermann-Josef
authors.initials: HJ
authors.lastname: Gröne
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000172:deficiency / Q000502:physiology*; D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation / Q000235:genetics / Q000276:immunology; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D058578:Biglycan / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D045142:Cross-Priming / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000502:physiology*; D009205:Myocarditis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D041681:NIH 3T3 Cells; D010047:Ovalbumin / Q000276:immunology; D010493:Pericarditis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D058578:Biglycan; D018984:Epitopes, T-Lymphocyte; D008024:Ligands; D053594:Myeloid Differentiation Factor 88; D010047:Ovalbumin; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; C546884:BGN protein, human; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse; C495342:TLR2 protein, human; C495345:TLR4 protein, human; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse
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