期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：49
页码：15016-15023
DOI：10.1073/pnas.1521206112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceIL-10-secreting B lymphocytes and peritoneal macrophages are activated by immunization with amyloid fibrils composed of short peptides resulting in reduction of paralysis and inflammation in mice with experimental autoimmune encephalomyelitis. B-cell-deficient MT mice and IL-10 knockout animals were used to establish the critical role of regulatory B cells in the therapeutic mode of action. Reintroduction of B-1a lymphocytes into the MT animals reconstituted the ability of the fibrils to ameliorate the paralytic signs, leading to the trafficking of both populations of cells from the peritoneum to secondary lymph organs and not to the CNS. The reduction in CNS inflammation, combined with successful intranasal administration, provides support that this strategy could be translated into an effective human therapeutic. 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{Phi}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{Phi}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{Phi}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.
