Apoptotic cells protect mice from autoimmune inflammation by the induction of regulatory B cells

Gray, Mohini; Miles, Katherine; Salter, Donald; Gray, David; Savill, John

doi:10.1073/pnas.0700326104

Cited by 288 publications

(299 citation statements)

References 30 publications

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“…A number of studies suggest that IL-10-producing B cells are important for the generation and/or maintenance of the regulatory T cell (T REG ) pool [46,63-72]. However, a recent study [73] and our previously published data [23] do not support this view.…”

Section: B10 Cell Regulatory Effectsmentioning

confidence: 94%

“…IL-10 production by B cells, stimulated by contact with apoptotic cells, results from the engagement of TLR9 within the B cell after recognition of DNA-containing complexes on the surface of apoptotic cells by the BCR. An earlier study also highlights the effects of apoptotic cells on B cell IL-10 production, where apoptotic cells protected mice from developing collagen-induced arthritis (CIA) by the induction of IL-10-producing regulatory B cells [46]. Cell death products may therefore represent one of the physiologic triggers for B10 cell development by providing a combination of BCR and TLR signals.…”

Section: Biology Of B10 Cellsmentioning

confidence: 99%

“…Furthermore, the adoptive transfer of T H17 cells triggers CIA in IL-17 --/-- DBA mice; however, when T H17 cells are co-transferred with CD1d hi CD5 + B cells, the onset of CIA is significantly delayed. Finally, in a different study, administration of apoptotic thymocytes along with ovalbumin peptide and complete Freund's adjuvant to mice carrying an ovalbumin-specific rearranged T cell receptor transgene (DO11.10 mice) up to 1 month before the onset of CIA resulted in an increase in ovalbumin-specific IL-10 secretion and is protective for severe joint inflammation and bone destruction [46]. Activated spleen B cells responded directly to apoptotic cell treatment in vitro by increasing secretion of IL-10, and inhibition of IL-10 in vivo reversed the beneficial effects of apoptotic cell treatment [46].…”

Section: B10 Cells In Mouse Models Of Autoimmune Diseasementioning

confidence: 99%

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IL-10-producing regulatory B cells (B10 cells) in autoimmune disease

2013

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B cell abnormalities contribute to the development and progress of autoimmune disease. Traditionally, the role of B cells in autoimmune disease was thought to be predominantly limited to the production of autoantibodies. Nevertheless, in addition to autoantibody production, B cells have other functions potentially relevant to autoimmunity. Such functions include antigen presentation to and activation of T cells, expression of co-stimulatory molecules and cytokine production. Recently, the ability of B cells to negatively regulate cellular immune responses and inflammation has been described and the concept of regulatory B cells has emerged. A variety of cytokines produced by regulatory B cell subsets have been reported, with IL-10 being the most studied. In this review, this specific IL-10-producing subset of regulatory B cells has been labeled B10 cells to highlight that the regulatory function of these rare B cells is mediated by IL-10, and to distinguish them from other B cell subsets that regulate immune responses through different mechanisms. B10 cells are a functionally defined subset currently identified only by their competency to produce and secrete IL-10 following appropriate stimulation. Although B10 cells share surface markers with other previously defined B cell subsets, currently there is no cell surface or intracellular phenotypic marker or set of markers unique to B10 cells. The recent discovery of an effective way to expand B10 cells ex vivo opens new horizons in the potential therapeutic applications of this rare B cell subset. This review highlights the current knowledge on B10 cells and discusses their potential as novel therapeutic agents in autoimmunity.

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Section: B10 Cell Regulatory Effectsmentioning

confidence: 94%

Section: Biology Of B10 Cellsmentioning

confidence: 99%

Section: B10 Cells In Mouse Models Of Autoimmune Diseasementioning

confidence: 99%

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IL-10-producing regulatory B cells (B10 cells) in autoimmune disease

2013

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“…CIA was induced as described previously (8). The first signs of arthritis appeared between day 21 and day 35, with a prevalence of 60-90% of immunized mice.…”

Section: Methodsmentioning

confidence: 99%

“…ACs also protect mice from autoimmune-mediated inflammation (6,7) and induce B cells to adopt an IL-10-secreting regulatory B-cell phenotype (Breg) (8). Innate-like B cells have many selfreactive B-cell receptors (BCRs) and are selected by intracellular antigens expressed on ACs (9), but this is generally compatible with health (10)(11)(12)(13).…”

mentioning

confidence: 99%

A tolerogenic role for Toll-like receptor 9 is revealed by B-cell interaction with DNA complexes expressed on apoptotic cells

Miles

Heaney

Sibinska

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

124

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Intracellular protein complexes containing nucleic acids are common targets of autoantibodies in many autoimmune diseases. Central tolerance to these antigens is incomplete, yet nucleosomal DNA is expressed on the surface of cells dying by apoptosis. It is commonly believed that autoimmunity is prevented by the rapid uptake of apoptotic cells (ACs) by neighbors or professional phagocytes to which they deliver anti-inflammatory signals. Self-reactive, innate-like B cells contact and are selected by intracellular antigens expressed on ACs; however, how self-tolerance is maintained is not well understood. Here we report that IL-10 production by B cells, stimulated by contact with ACs, results from the engagement of Toll-like receptor 9 (TLR9) within the B cell after recognition of DNA-containing complexes on the surface of ACs. Until now, TLR9 ligation has been considered an inflammatory signal, but we have confirmed a hitherto unexpected immunoregulatory role by demonstrating the absence of the protective effect of ACs during experimental autoimmune encephalitis (EAE) in TLR9-deficient mice. Human circulating CD27 + B cells also respond to DNA-bearing ACs, but not to DNase-treated cells, by secreting IL-10. Chronic autoimmune disease may arise if this tolerance mechanism is not reimposed after episodes of inflammation, or if the regulatory B-cell response is subverted.

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Membrane Lipid Asymmetry in Aging and Apoptosis

Balasubramanian

Schroit

2011

Transmembrane Dynamics of Lipids

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Apoptotic cells protect mice from autoimmune inflammation by the induction of regulatory B cells

Cited by 288 publications

References 30 publications

IL-10-producing regulatory B cells (B10 cells) in autoimmune disease

IL-10-producing regulatory B cells (B10 cells) in autoimmune disease

A tolerogenic role for Toll-like receptor 9 is revealed by B-cell interaction with DNA complexes expressed on apoptotic cells

Membrane Lipid Asymmetry in Aging and Apoptosis

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