title: Transfer of central nervous system autoantigens and presentation in secondary lymphoid organs.
abstract: Dendritic cells are thought to regulate tolerance induction vs immunization by transferring Ags and peripheral signals to draining lymph nodes (LN). However, whether myelin Ag transfer and presentation in LN occurs during demyelinating brain disease is unknown. In this study, we demonstrate redistribution of autoantigens from brain lesions to cervical LN in monkey experimental autoimmune encephalomyelitis (EAE) and in multiple sclerosis (MS). Immunohistochemical analysis revealed significantly more cells containing myelin Ags in cervical LN of monkeys with EAE compared with those of healthy control monkeys. Myelin Ags were observed in cells expressing dendritic cell/macrophage-specific markers, MHC class II, and costimulatory molecules. Moreover, these cells were directly juxtaposed to T cells, suggesting that cognate interactions between myelin-containing APC and T cells are taking place in brain-draining LN. Indeed, myelin Ag-reactive T cells were observed in cervical LN from marmosets and rhesus monkeys. Importantly, these findings were paralleled by our findings in human tissue. We observed significantly more myelin Ag-containing cells in LN of individuals with MS compared with those of control individuals. These cells expressed APC markers, as observed in marmosets and rhesus monkeys. These findings suggest that during MS and EAE, modulation of T cell reactivity against brain-derived Ags also takes place in cervical LN and not necessarily inside the brain. A major implication is that novel therapeutic strategies may be targeted to peripheral events, thereby circumventing the blood-brain barrier.
authors.affiliation: Department of Immunology, Erasmus Medical Centre, 3000 DR Rotterdam, The Netherlands.
authors.forename: Alex F
authors.initials: AF
authors.lastname: de Vos
authors.forename: Marjan
authors.initials: M
authors.lastname: van Meurs
authors.forename: Herbert P
authors.initials: HP
authors.lastname: Brok
authors.forename: Leonie A
authors.initials: LA
authors.lastname: Boven
authors.forename: Rogier Q
authors.initials: RQ
authors.lastname: Hintzen
authors.forename: Paul
authors.initials: P
authors.lastname: van der Valk
authors.forename: Rivka
authors.initials: R
authors.lastname: Ravid
authors.forename: Susanne
authors.initials: S
authors.lastname: Rensing
authors.forename: Louis
authors.initials: L
authors.lastname: Boon
authors.forename: Bert A
authors.initials: BA
authors.lastname: 't Hart
authors.forename: Jon D
authors.initials: JD
authors.lastname: Laman
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001324:Autoantigens / Q000032:analysis / Q000378:metabolism*; D001365:Axilla; D015415:Biomarkers / Q000032:analysis; D001921:Brain / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D002144:Callithrix; D002449:Cell Aggregation / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018984:Epitopes, T-Lymphocyte / Q000032:analysis; D006801:Humans; D007264:Inguinal Canal; D008198:Lymph Nodes / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D008252:Macaca fascicularis; D008253:Macaca mulatta; D009103:Multiple Sclerosis / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004676:Myelin Basic Protein / Q000032:analysis / Q000276:immunology / Q000378:metabolism; D009333:Neck; D021381:Protein Transport / Q000276:immunology; D013154:Spleen; D013601:T-Lymphocytes / Q000737:chemistry / Q000276:immunology / Q000473:pathology
chemical_list: D001324:Autoantigens; D015415:Biomarkers; D018984:Epitopes, T-Lymphocyte; D004676:Myelin Basic Protein