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Proc Natl Acad Sci U S A. 2015 Dec 8;112(49):15016-23. doi: 10.1073/pnas.1521206112. Epub 2015 Nov 30.

Amyloid fibrils activate B-1a lymphocytes to ameliorate inflammatory brain disease.

Author information

1
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305;
2
Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305;
3
Division of Immunology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305;
4
Division of Blood and Marrow Transplantation, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305.
5
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305; steinman@stanford.edu.
6
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;

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.

KEYWORDS:

B-1a lymphocytes; IL-10; amyloid fibrils; experimental autoimmune encephalomyelitis; immune suppression

PMID:
26621719
PMCID:
PMC4679000
DOI:
10.1073/pnas.1521206112
[Indexed for MEDLINE]
Free PMC Article

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