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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 (M?s), 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 (?MT) nor IL10(-/-) mice with EAE responded to the fibrils. In gain-of-function experiments, B-1a cells, adoptively transferred to ?MT mice with EAE, restored their therapeutic efficacy when Amylin 28-33 was administered. Stimulation of adoptively transferred bioluminescent M?s 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(+) M?s, 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.

SUBMITTER: Kurnellas MP 

PROVIDER: S-EPMC4679000 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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

Kurnellas Michael Phillip MP   Ghosn Eliver Eid Bou EE   Schartner Jill M JM   Baker Jeanette J   Rothbard Jesse J JJ   Negrin Robert S RS   Herzenberg Leonore A LA   Fathman C Garrison CG   Steinman Lawrence L   Rothbard Jonathan B JB  

Proceedings of the National Academy of Sciences of the United States of America 20151130 49


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  ...[more]

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