B-cell tolerance and autoimmunity

Tsubata, Takeshi

doi:10.12688/f1000research.10583.1

Cited by 41 publications

(22 citation statements)

References 89 publications

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“…The vast majority of newly generated mouse and human B cells (50%‐75%) express autoreactive BCRs and must be eliminated by central or peripheral tolerance, including events taking place in the GC . B‐cell apoptosis, especially inside the GC, is therefore critical to select high‐affinity clones, control outgrowth of self‐reactive clones and malignancies and maintain homeostasis …”

Section: Pi3kδ Enhances B‐cell Survivalmentioning

confidence: 99%

T and B‐cell signaling in activated PI3K delta syndrome: From immunodeficiency to autoimmunity

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Gómez-Rodríguez

Cannons

et al. 2019

Immunological Reviews

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Phosphatidylinositol 3 kinases (PI3K) are a family of lipid kinases that are activated by a variety of cell-surface receptors, and regulate a wide range of downstream readouts affecting cellular metabolism, growth, survival, differentiation, adhesion, and migration. The importance of these lipid kinases in lymphocyte signaling has recently been highlighted by genetic analyses, including the recognition that both activating and inactivating mutations of the catalytic subunit of PI3Kδ, p110δ, lead to human primary immunodeficiencies. In this article, we discuss how studies on the human genetic disorder "Activated PI3K-delta syndrome" and mouse models of this disease (Pik3cd E1020K/+ mice) have provided fundamental insight into pathways regulated by PI3Kδ in T and B cells and their contribution to lymphocyte function and disease, including responses to commensal bacteria and the development of autoimmunity and tumors. We highlight critical roles of PI3Kδ in T follicular helper cells and the orchestration of the germinal center reaction, as well as in CD8 + T-cell function. We further present data demonstrating the ability of the AKT-resistant FOXO1 AAA mutant to rescue IgG1 class switching defects in Pik3cd E1020K/+ B cells, as well as data supporting a role for PI3Kδ in promoting multiple T-helper effector cell lineages. K E Y W O R D S APDS/PASLI, autoimmunity, immunodeficiency, phosphatidylinositol 3 kinase, T and B lymphocytes | 155 PREITE ET al. | AC TIVATED PI3K-DELTA SYNDROMEIn 2013-2014, three studies described immunodeficient patients with heterozygous gain-of-function autosomal-dominant mutations in PIK3CD, the gene encoding the catalytic subunit of PI3K p110δ. [3][4][5] At least 11 mutations have now been identified by whole exome sequencing, with the E1021K mutant being most prevalent. 2,6 Based on similar mutations in PI3Kα found in cancers and overgrowth syndromes, p110δ mutations were predicted to activate p110δ. 4,7 Indeed, increased PI3K activity and downstream readouts including increased PIP 3 levels, pAKT and pS6, have been observed in cells from these patients. 3,4 This novel PID has been named "Activated PI3K-delta syndrome" (APDS) or "p110δ-activating mutation causing senescent T cells, lymphadenopathy and immunodeficiency" (PASLI), hereafter referred to as APDS. Activated PI3K-delta syndrome is a combined immunodeficiency syndrome characterized by altered T-and B-cell development and responses. APDS is associated with frequent respiratory infections, progressive blood lymphopenia, mucosal lymphoid nodules, defective antibody responses, and lymphoma development. 2 Patients exhibit a paucity of naïve peripheral blood T cells with a large fraction of T cells displaying activation markers. In contrast, B-cell development is partially blocked, with increased transitional and few circulating memory B cells. 4,8,9 Recurrent respiratory infections are the most common feature of APDS. However, Epstein-Barr virus (EBV) and/ or cytomegalovirus (CMV) viremia occurs in a substantial fraction of patients, ...

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Section: Pi3kδ Enhances B‐cell Survivalmentioning

confidence: 99%

T and B‐cell signaling in activated PI3K delta syndrome: From immunodeficiency to autoimmunity

Preite

Gómez-Rodríguez

Cannons

et al. 2019

Immunological Reviews

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“…Immature B cells in the bone marrow (BM) express IgM BCR and are susceptible to apoptosis upon self-antigen (Ag) stimulation (Melchers, 2015;Pelanda & Torres, 2012;Tsubata, 2017). As immature B cells migrate to the peripheral lymphoid organs such as spleen and lymph node, they start to express IgD and change their phenotypes form IgM + IgD − to IgM high IgD high , and finally become IgM low IgD high mature B cells, which are ready to respond to foreign Ag stimulation (Geisberger, Lamers, & Achatz, 2006;Kim & Reth, 1995).…”

Section: Introductionmentioning

confidence: 99%

Opposing roles of IgM and IgD in BCR‐induced B‐cell survival

et al. 2018

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The B-cell receptor (BCR) transmits a tonic survival signal in the absence of antigen stimulation and an antigen-triggered survival signal. Mature B cells express two types of BCR, IgM and IgD, but it remains unclear how B-cell survival is differentially regulated by these two receptors. We found that, whereas cross-linking IgM on spleen B cells greatly enhanced their survival, cross-linking IgD did not enhance, but rather decreased, their survival. Consistently, cross-linking both IgM and IgD only moderately enhanced B-cell survival, suggesting that IgM and IgD play opposing roles in B-cell survival induced by BCR stimulation. Based on these and additional experimental results, we present a mathematical model integrating IgM- and IgD-mediated survival signals. Our model shows that IgD can transmit a tonic survival signal in the absence of antigen stimulation but cross-linking IgD not only does not generate a survival signal but also disrupts its tonic signal, resulting in inhibition of B-cell survival. These results suggest that IgD attenuates BCR-induced survival in mature B cells, presumably to restrain B-cell response to weak and/or self-antigens and prevent nonspecific B-cell activation and autoimmunity.

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“…Thus, it is clear that FasL–Fas interactions play a significant role in regulating the production of pathogenic autoantibodies. It is well-established that mature B lymphocytes that have been activated through interactions with T helper (T H ) lymphocytes are susceptible to FasL-mediated apoptosis, and presumably receive this signal from the interacting T H cell ( 15 – 17 ). What has often been overlooked is that some B lymphocytes express functional FasL constitutively , and that many types of stimuli can induce FasL expression in B cells ( 18 ).…”

Section: Introductionmentioning

confidence: 99%

Killer B Lymphocytes and Their Fas Ligand Positive Exosomes as Inducers of Immune Tolerance

2015

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Induction of immune tolerance is a key process by which the immune system is educated to modulate reactions against benign stimuli such as self-antigens and commensal microbes. Understanding and harnessing the natural mechanisms of immune tolerance may become an increasingly useful strategy for treating many types of allergic and autoimmune diseases, as well as for improving the acceptance of solid organ transplants. Our laboratory and others have been interested in the natural ability of some B lymphocytes to express the death-inducing molecule Fas ligand (FasL), and their ability to kill T helper (TH) lymphocytes. We have recently shown that experimental transformation of human B cells by a non-replicative variant of Epstein-Barr virus (EBV) consistently resulted in high expression of functional FasL protein. The production and release of FasL+ exosomes that co-expressed major histocompatibility complex (MHC) class II molecules and had the capacity to kill antigen-specific TH cells was also observed. Several lines of evidence indicate that FasL+ B cells and FasL+MHCII+ exosomes have important roles in natural immune tolerance and have a great deal of therapeutic potential. Taken together, these findings suggest that EBV-immortalized human B lymphoblastoid cell lines could be used as cellular factories for FasL+ exosomes, which would be employed to therapeutically establish and/or regain immune tolerance toward specific antigens. The goals of this review are to summarize current knowledge of the roles of FasL+ B cells and exosomes in immune regulation, and to suggest methods of manipulating killer B cells and FasL+ exosomes for clinical purposes.

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B-cell tolerance and autoimmunity

Cited by 41 publications

References 89 publications

T and B‐cell signaling in activated PI3K delta syndrome: From immunodeficiency to autoimmunity

T and B‐cell signaling in activated PI3K delta syndrome: From immunodeficiency to autoimmunity

Opposing roles of IgM and IgD in BCR‐induced B‐cell survival

Killer B Lymphocytes and Their Fas Ligand Positive Exosomes as Inducers of Immune Tolerance

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