title: Amyloid fibrils activate B-1a lymphocytes to ameliorate inflammatory brain disease.
abstract: Amyloid fibrils composed of peptides as short as six amino acids are therapeutic in experimental autoimmune encephalomyelitis (EAE), reducing paralysis and inflammation, while inducing several pathways of immune suppression. Intraperitoneal injection of fibrils selectively activates B-1a lymphocytes and two populations of resident macrophages (MΦs), increasing IL-10 production, and triggering their exodus from the peritoneum. The importance of IL-10-producing B-1a cells in this effective therapy was established in loss-of-function experiments where neither B-cell-deficient (μMT) nor IL10(-/-) mice with EAE responded to the fibrils. In gain-of-function experiments, B-1a cells, adoptively transferred to μMT mice with EAE, restored their therapeutic efficacy when Amylin 28-33 was administered. Stimulation of adoptively transferred bioluminescent MΦs and B-1a cells by amyloid fibrils resulted in rapid (within 60 min of injection) trafficking of both cell types to draining lymph nodes. Analysis of gene expression indicated that the fibrils activated the CD40/B-cell receptor pathway in B-1a cells and induced a set of immune-suppressive cell-surface proteins, including BTLA, IRF4, and Siglec G. Collectively, these data indicate that the fibrils activate B-1a cells and F4/80(+) MΦs, resulting in their migration to the lymph nodes, where IL-10 and cell-surface receptors associated with immune-suppression limit antigen presentation and T-cell activation. These mechanisms culminate in reduction of paralytic signs of EAE.
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305;
authors.forename: Michael Phillip
authors.initials: MP
authors.lastname: Kurnellas
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305;
authors.forename: Eliver Eid Bou
authors.initials: EE
authors.lastname: Ghosn
authors.affiliation: Division of Immunology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305;
authors.forename: Jill M
authors.initials: JM
authors.lastname: Schartner
authors.affiliation: Division of Blood and Marrow Transplantation, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Jeanette
authors.initials: J
authors.lastname: Baker
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305;
authors.forename: Jesse J
authors.initials: JJ
authors.lastname: Rothbard
authors.affiliation: Division of Blood and Marrow Transplantation, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Negrin
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305;
authors.forename: Leonore A
authors.initials: LA
authors.lastname: Herzenberg
authors.affiliation: Division of Immunology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305;
authors.forename: C Garrison
authors.initials: CG
authors.lastname: Fathman
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305; steinman@stanford.edu.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Steinman
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305; Division of Immunology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305;
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Rothbard
mesh_terms: D019264:Adoptive Transfer; D000682:Amyloid / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology; D004705:Endocytosis; D005260:Female; D016753:Interleukin-10 / Q000502:physiology; D058228:Islet Amyloid Polypeptide / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D000682:Amyloid; D058228:Islet Amyloid Polypeptide; D016753:Interleukin-10
keywords: B-1a lymphocytes; IL-10; amyloid fibrils; experimental autoimmune encephalomyelitis; immune suppression