Genetic or pharmaceutical blockade of p110δ phosphoinositide 3-kinase enhances IgE production

Zhang, Ting-ting; Okkenhaug, Klaus; Nashed, Baher; Puri, Kamal D.; Knight, Zachary A.; Shokat, Kevan M.; Vanhaesebroeck, Bart; Marshall, Aaron J.

doi:10.1016/j.jaci.2008.08.008

Cited by 62 publications

(83 citation statements)

References 42 publications

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“…The absence of GCs in IC87114-treated mice is consistent with previous work identifying a specific role for p110␦ in the differentiation and function of T follicular-helper (Tfh) cells, a subset of CD4 T cells required for GC formation (41). In addition, our data on NPspecific Ig production agree with previous studies showing that IC87114 does not impair class-switched antibody responses in mice (39). Indeed, p110␦ inhibition enhances IgE production (39), a finding reproduced here.…”

Section: Discussionsupporting

confidence: 92%

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Selective Inhibition of Phosphoinositide 3-Kinase p110α Preserves Lymphocyte Function*

Yea

Oak

et al. 2013

Journal of Biological Chemistry

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Background:The class IA PI3K isoform p110␣ is a promising drug target in cancer therapy yet its role in lymphocytes is not known. Results: Lymphocyte function was minimally affected by p110␣ inhibition both in vitro and in vivo. Conclusion: Selective inhibition of p110␣ preserves lymphocyte function. Significance: The study raises confidence that selective p110␣ inhibitors in cancer therapy will not be immunosuppressive.

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Section: Discussionsupporting

confidence: 92%

“…8). Furthermore, as reported previously (39), selective p110␦ inhibition with IC87114 augmented the antigen-specific IgE response (Fig. 9B, lower right graph).…”

Section: Pi3ksupporting

confidence: 89%

Selective Inhibition of Phosphoinositide 3-Kinase p110α Preserves Lymphocyte Function*

Yea

Oak

et al. 2013

Journal of Biological Chemistry

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“…8). p110d inhibition might also be beneficial in mitigating SLE symptoms by reducing B cell survival (44), and it reduces IgE-to-IgG class switch (46). PI3K activation regulates COX-2 levels (47), which are frequently increased in SLE (48); PI3K inhibition could also ameliorate SLE by reducing COX-2 levels.…”

Section: Discussionmentioning

confidence: 99%

Enhanced Phosphoinositide 3-Kinase δ Activity Is a Frequent Event in Systemic Lupus Erythematosus That Confers Resistance to Activation-Induced T Cell Death

Suárez‐Fueyo

Barber

Martínez-Ara

et al. 2011

The Journal of Immunology

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Systemic lupus erythematosus (SLE) is a human chronic inflammatory disease caused by the action of autoreactive T and B cells. Class I phosphoinositide-3-kinases (PI3K) are enzymes that trigger formation of 3-poly-phosphoinositides that induce cell survival. Enhanced PI3K activation is a frequent event in human cancer. Nonetheless, in a genetic model with enhanced activation of class IA PI3K in T cells, mice show a greater tumor index but die of a lupus-like disease. In this study, we studied the potential PI3K involvement in human SLE. The PI3K pathway was frequently activated in SLE patient PBMC and T cells (∼70% of cases), more markedly in active disease phases. We examined the mechanism for PI3K pathway activation and found enhanced activation of PI3Kδ in SLE peripheral blood T cells. The magnitude of PI3K pathway activation in patients paralleled activated/memory T cell accumulation. We examined potential tolerance mechanisms affected by increased PI3K activity; SLE patients showed reduced activation-induced cell death of activated/memory T cells. Moreover, the defective activation-induced cell death in SLE T cells was corrected after reduction of PI3Kδ activity, suggesting that PI3Kδ contributes to induction of enhanced SLE memory T cell survival. These observations point to PI3Kδ as a target of clinical interest for SLE.

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“…Also, these results are distinct from those observed in mice exhibiting global defects in PI3K signaling. For example, inactivation of the PI3K catalytic subunit p110d leads to failure to generate GCs because of impaired B cell development, proliferation, and survival (27); however, signaling via PI3K is also important for restraining activation-induced cytidine deaminase expression and class switch recombination (35,36). Clearly, PI3K-dependent signals are critical for both GC initiation and progression, and the present results implicate Bam32 as one of the PI3K-dependent effector molecules that comes into play, particularly during GC progression.…”

Section: Discussionmentioning

confidence: 99%

The Pleckstrin Homology Domain Adaptor Protein Bam32/DAPP1 Is Required for Germinal Center Progression

Zhang

Al‐Alwan²,

Marshall

2009

The Journal of Immunology

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Ab affinity maturation within germinal centers (GCs) requires weeks to complete. Several signaling pathways in B cells have been shown to be required for initiation of the GC response; however, the signaling checkpoints controlling progression and eventual dissolution of the GC reaction are poorly understood. The adaptor protein Bam32/DAPP1 was originally isolated from human GCs and functions downstream of phosphoinositide 3-kinase enzymes, which are known to have critical roles in B cell activation and GC responses. In this study we identify a unique role of Bam32/DAPP1 in promoting GC progression. Bam32-deficient mice show normal GC initiation, but premature GC dissolution after immunization with protein Ag in alum or low doses of sheep red blood cells. Adoptive transfer studies confirmed that Bam32-deficient B cells have an intrinsic impairment in the ability to mount sustained GC responses. Bam32 deficiency was also associated with impaired Ab affinity maturation. Proliferation of Bam32-deficient GC B cells was not compromised; however, these cells show impaired switch to IgG1 and increased apoptosis in situ. GCs formed by Bam32-deficient B cells contain fewer T cells, indicating that Bam32 is required for B cell–dependent T cell accumulation within established GCs. Exogenous CD40 ligand restored GC B cell numbers and switch to IgG1, indicating that Bam32-deficient B cells are competent to respond to CD40 stimulation when ligand is available. These data demonstrate that Bam32 is not required for GC initiation, but rather functions in a late checkpoint of GC progression associated with T cell recruitment and GC B cell survival.

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Genetic or pharmaceutical blockade of p110δ phosphoinositide 3-kinase enhances IgE production

Cited by 62 publications

References 42 publications

Selective Inhibition of Phosphoinositide 3-Kinase p110α Preserves Lymphocyte Function*

Selective Inhibition of Phosphoinositide 3-Kinase p110α Preserves Lymphocyte Function*

Enhanced Phosphoinositide 3-Kinase δ Activity Is a Frequent Event in Systemic Lupus Erythematosus That Confers Resistance to Activation-Induced T Cell Death

The Pleckstrin Homology Domain Adaptor Protein Bam32/DAPP1 Is Required for Germinal Center Progression

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