2015
DOI: 10.1073/pnas.1521206112
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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 (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 establishe… Show more

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Cited by 21 publications
(26 citation statements)
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“…The proposed mode of action was supported by loss-of-function experiments using B cell-deficient (μMT) mice and IL-10-knockout animals (neither of which responded to the fibrils), which established the critical role of IL-10-secreting regulatory B cells (8). Reciprocal gain-of-function experiments, in which as few as 3 × 10 5 B1a cells were reintroduced into μMT mice, reconstituted the ability of the fibrils to ameliorate clinical paralysis.…”
mentioning
confidence: 95%
See 1 more Smart Citation
“…The proposed mode of action was supported by loss-of-function experiments using B cell-deficient (μMT) mice and IL-10-knockout animals (neither of which responded to the fibrils), which established the critical role of IL-10-secreting regulatory B cells (8). Reciprocal gain-of-function experiments, in which as few as 3 × 10 5 B1a cells were reintroduced into μMT mice, reconstituted the ability of the fibrils to ameliorate clinical paralysis.…”
mentioning
confidence: 95%
“…Injection or inhalation of fibrils composed of amyloidogenic peptides as short as six amino acids from a variety of proteins induces several pathways of immune suppression, resulting in reduction of the proinflammatory cytokines IL-6, IL-1β, and TNF-α and reduction of T cell activation (7). The fibrils are bound specifically and endocytosed by peritoneal macrophages (MΦs) and B2 and B1a lymphocytes, but not T lymphocytes, mast cells, or eosinophils (8,9). The binding results in changes in gene expression, leading to several coordinated antiinflammatory responses: (i) activation of the cells, defined as an increased expression of CD83, CD80, and CD86 on the MΦs, and of CD80, CD86, CD25, and CD83 on the B1a lymphocytes; (ii) decreased expression of integrins and chemokine receptors, which allows both cell populations to traffic from the peritoneum to secondary lymph organs; and (iii) evidence of continued high expression of IL-10 in both cell types, with induced expression of CTLA4, BTLA, IRF4, and Siglec G in the B1a cells, thus increasing their immune-suppressive potential.…”
mentioning
confidence: 99%
“…In his Inaugural Article, Steinman deepens the investigation by looking for the mechanism of action of the immunedampening response. The work shows that in the presence of intraperitoneal, or even intranasal, administration of amyloids, regulatory B cells secrete IL-10 and suppress neuroinflammation (2).…”
Section: Fresh Perspective On Amyloidmentioning
confidence: 95%
“…"Since I was going to focus on the brain and disease, it was natural," Steinman says. MS, he adds, was the "most prevalent (2). In the 1980s, as monoclonal antibody production was becoming state-of-the-art, they studied how antibodies to various immune system proteins can block the development of EAE (6).…”
Section: Experience With the Pipelinementioning
confidence: 99%
“…In addition to producing natural and antigen-specific antibodies, innate-like B-1a cells are the main source of B-cell-derived IL-10 ( Kurnellas et al, 2015;Aziz et al, 2017;O'Garra et al, 1992). Both IL-10 and natural antibodies produced by B-1a cells are required to maintain physiological and immune homeostasis (Grönwall et al, 2012;Kaveri et al, 2012).…”
Section: Hsc-independent B Lymphopoiesismentioning
confidence: 99%