JNK Regulatory Molecule G5PR Induces IgG Autoantibody–Producing Plasmablasts from Peritoneal B1a Cells

Kitabatake, Masahiro; Soma, Mitsuyuki; Zhang, Tianli; Kuwahara, K.; Fukushima, Yoshio; Nojima, Toshio; Kitamura, Daisuke; Sakaguchi, Nobuo

doi:10.4049/jimmunol.1401127

Cited by 6 publications

(3 citation statements)

References 57 publications

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“…PP2A-B, G5PR ( PPP2R3C ) : overexpression in lymphoid cells promotes autoantibodies and autoimmunity in aged female mice 171 .…”

Section: Phosphatase Targets In Tumour Immunotherapy and Autoimmune D...mentioning

confidence: 99%

“…B cells from lupus-prone mice and activated B cells show increased PP2A-A and PP2A-C expression and increased PP2A catalytic activity 167 . Transgenic overexpression of PP2A-B regulatory subunit G5PR ( PPP2R3C ) in lymphoid cells leads to IgM and IgG anti-double-stranded DNA (dsDNA) autoantibodies and autoimmunity in aged female mice 171 .…”

Section: Pp2a: Biology and Therapeutic Implicationsmentioning

confidence: 99%

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Targeting protein phosphatases in cancer immunotherapy and autoimmune disorders

Stanford

Bottini

2023

Nat Rev Drug Discov

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Protein phosphatases act as key regulators of multiple important cellular processes and are attractive therapeutic targets for various diseases. Although extensive effort has been dedicated to phosphatase-targeted drug discovery, early expeditions for competitive phosphatase inhibitors were plagued by druggability issues, leading to the stigmatization of phosphatases as difficult targets. Despite challenges, persistent efforts have led to the identification of several drug-like, non-competitive modulators of some of these enzymes — including SH2 domain-containing protein tyrosine phosphatase 2, protein tyrosine phosphatase 1B, vascular endothelial protein tyrosine phosphatase and protein phosphatase 1 — reigniting interest in therapeutic targeting of phosphatases. Here, we discuss recent progress in phosphatase drug discovery, with emphasis on the development of selective modulators that exhibit biological activity. The roles and regulation of protein phosphatases in immune cells and their potential as powerful targets for immuno-oncology and autoimmunity indications are assessed.

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“…PP2A-B, G5PR ( PPP2R3C ) : overexpression in lymphoid cells promotes autoantibodies and autoimmunity in aged female mice 171 .…”

Section: Phosphatase Targets In Tumour Immunotherapy and Autoimmune D...mentioning

confidence: 99%

Section: Pp2a: Biology and Therapeutic Implicationsmentioning

confidence: 99%

Targeting protein phosphatases in cancer immunotherapy and autoimmune disorders

Stanford

Bottini

2023

Nat Rev Drug Discov

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“…They secrete protective IgM autoantibodies ( 93 ) and the anti-inflammatory cytokine IL-10 ( 94 , 95 ). In some cases they do not contribute to pathogenic autoantibodies ( 96 ), but they can produce IgG autoantibodies and interact with T cells in a pro-inflammatory manner in some lupus models ( 88 , 97 , 98 ). B1a cells are reduced in Lyn −/− Btk lo mice ( 52 ) and increased in mice expressing constitutively active Btk ( 55 ), and Btk is required for their expression of IL-10 ( 25 ).…”

Section: Btk and Mouse Lupus Modelsmentioning

confidence: 99%

Bruton’s Tyrosine Kinase, a Component of B Cell Signaling Pathways, Has Multiple Roles in the Pathogenesis of Lupus

Satterthwaite

2018

Front. Immunol.

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Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the loss of adaptive immune tolerance to nucleic acid-containing antigens. The resulting autoantibodies form immune complexes that promote inflammation and tissue damage. Defining the signals that drive pathogenic autoantibody production is an important step in the development of more targeted therapeutic approaches for lupus, which is currently treated primarily with non-specific immunosuppression. Here, we review the contribution of Bruton’s tyrosine kinase (Btk), a component of B and myeloid cell signaling pathways, to disease in murine lupus models. Both gain- and loss-of-function genetic studies have revealed that Btk plays multiple roles in the production of autoantibodies. These include promoting the activation, plasma cell differentiation, and class switching of autoreactive B cells. Small molecule inhibitors of Btk are effective at reducing autoantibody levels, B cell activation, and kidney damage in several lupus models. These studies suggest that Btk may promote end-organ damage both by facilitating the production of autoantibodies and by mediating the inflammatory response of myeloid cells to these immune complexes. While Btk has not been associated with SLE in GWAS studies, SLE B cells display signaling defects in components both upstream and downstream of Btk consistent with enhanced activation of Btk signaling pathways. Taken together, these observations indicate that limiting Btk activity is critical for maintaining B cell tolerance and preventing the development of autoimmune disease. Btk inhibitors, generally well-tolerated and approved to treat B cell malignancy, may thus be a useful therapeutic approach for SLE.

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In Vitro-Induced Germinal Center B Cell Culture System

Haniuda

Nojima

Kitamura

2017

Methods in Molecular Biology

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In germinal centers (GCs), B cells undergo repeated cycles of proliferation and affinity-based selection, and differentiate into memory B cells or long-lived plasma cells. It has been difficult to elucidate regulatory mechanisms for the dynamic GC B cell maturation and differentiation, partly because experimental manipulation of GC B cells has been limited. Here we describe a culture system in which we can induce massive expansion of naive B cells that exhibit GC B cell-like phenotype and acquire abilities to differentiate into memory B cells or bone marrow plasma cells depending on cytokine conditions. This system will allow us to elucidate the molecular mechanisms of GC B cell differentiation.

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JNK Regulatory Molecule G5PR Induces IgG Autoantibody–Producing Plasmablasts from Peritoneal B1a Cells

Cited by 6 publications

References 57 publications

Targeting protein phosphatases in cancer immunotherapy and autoimmune disorders

Targeting protein phosphatases in cancer immunotherapy and autoimmune disorders

Bruton’s Tyrosine Kinase, a Component of B Cell Signaling Pathways, Has Multiple Roles in the Pathogenesis of Lupus

In Vitro-Induced Germinal Center B Cell Culture System

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