Enhanced Expression of Bruton’s Tyrosine Kinase in B Cells Drives Systemic Autoimmunity by Disrupting T Cell Homeostasis

Corneth, Odilia B. J.; Bruijn, Marjolein J. W. de; Rip, Jasper; Asmawidjaja, Patrick S.; Kil, Laurens P.

doi:10.4049/jimmunol.1600208

Cited by 44 publications

(57 citation statements)

References 59 publications

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“…Remarkably, aged animals developed spontaneous GCs and produced high-titre autoantibodies, which indicates that B cell-specific expression of the risk-associated variant was sufficient to promote a break in B cell tolerance 28 . Notably, consistent with the ability of modest alterations in BCR signal strength to promote an autoimmune GC response, transgenic overexpression of the TEC family kinase BTK, which is essential for BCR-triggered phospholipase Cγ2 (PLCγ 2) activation, was sufficient to trigger analogous events and lead to T cell-dependent autoantibody production 103 .…”

Section: Receptor Crosstalk Shapes B Cell Activationmentioning

confidence: 80%

Altered B cell signalling in autoimmunity

Rawlings¹,

et al. 2017

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Recent work has provided new insights into how altered B cell-intrinsic signals — through the B cell receptor (BCR) and key co-receptors — function together to promote the pathogenesis of autoimmunity. These combined signals affect B cells at two distinct stages: first, in the selection of the naive repertoire; and second, during extrafollicular or germinal centre activation responses. Thus, dysregulated signalling can lead to both an altered naive BCR repertoire and the generation of autoantibody-producing B cells. Strikingly, high-affinity autoantibodies predate and predict disease in several autoimmune disorders, including type 1 diabetes and systemic lupus erythematosus. This Review summarizes how, rather than being a downstream consequence of autoreactive T cell activation, dysregulated B cell signalling can function as a primary driver of many human autoimmune diseases.

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Section: Receptor Crosstalk Shapes B Cell Activationmentioning

confidence: 80%

Altered B cell signalling in autoimmunity

Rawlings¹,

et al. 2017

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“…Flow cytometry was performed using Abs and reagents as described (11). For phosphoflow, total spleen cells were stained for extracellular markers and stimulated with (combinations of) anti-IgM F(ab9) 2 fragments (4 or 25 mg/ml), mouse rIL-4 (0.1 mg/ml), and anti-CD40 (4 or 20 mg/ml) at 37˚C.…”

Section: Macs Purification and B Cell Culturesmentioning

confidence: 99%

Distinct and Overlapping Functions of TEC Kinase and BTK in B Cell Receptor Signaling

Bruijn

Rip

Ploeg

et al. 2017

The Journal of Immunology

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The Tec tyrosine kinase is expressed in many cell types, including hematopoietic cells, and is a member of the Tec kinase family that also includes Btk. Although the role of Btk in B cells has been extensively studied, the role of Tec kinase in B cells remains largely unclear. It was previously shown that Tec kinase has the ability to partly compensate for loss of Btk activity in B cell differentiation, although the underlying mechanism is unknown. In this study, we confirm that Tec kinase is not essential for normal B cell development when Btk is present, but we also found that Tec-deficient mature B cells showed increased activation, proliferation, and survival upon BCR stimulation, even in the presence of Btk. Whereas Tec deficiency did not affect phosphorylation of phospholipase Cγ or Ca2+ influx, it was associated with significantly increased activation of the intracellular Akt/S6 kinase signaling pathway upon BCR and CD40 stimulation. The increased S6 kinase phosphorylation in Tec-deficient B cells was dependent on Btk kinase activity, as ibrutinib treatment restored pS6 to wild-type levels, although Btk protein and phosphorylation levels were comparable to controls. In Tec-deficient mice in vivo, B cell responses to model Ags and humoral immunity upon influenza infection were enhanced. Moreover, aged mice lacking Tec kinase developed a mild autoimmune phenotype. Taken together, these data indicate that in mature B cells, Tec and Btk may compete for activation of the Akt signaling pathway, whereby the activating capacity of Btk is limited by the presence of Tec kinase.

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“…Elevated BCR signaling, observed in various lupus mouse models as well as in human lupus patients, has been shown to contribute to the development of lupus [7, 54–58]. BCR signaling, as well as toll like receptor 4 (TLR4) signaling, is known to promote B cell proliferation and survival.…”

Section: Resultsmentioning

confidence: 99%

“…Abnormal B cell activation contributes to SLE pathogenesis through both antibody-dependent and independent fashions [1, 54, 79–81]. In addition to the impaired B cell survival, B cell-specific deletion of PKK also resulted in significant reduction of activated CD4 + T cells in Sle mice (Figure 5), and PKK-deficient Sle B cells fail to efficiently up-regulate the critical T cell-costimulatory molecules CD80 and CD86 in response to BCR stimulation (Figure 6C).…”

Section: Discussionmentioning

confidence: 99%

PKK deficiency in B cells prevents lupus development in Sle lupus mice

et al. 2017

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Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the production of autoantibodies that can result in damage to multiple organs. It is well documented that B cells play a critical role in the development of the disease. We previously showed that protein kinase C associated kinase (PKK) is required for B1 cell development as well as for the survival of recirculating mature B cells and B- lymphoma cells. Here, we investigated the role of PKK in lupus development in a lupus mouse model. We demonstrate that the conditional deletion of PKK in B cells prevents lupus development in Sle1Sle3 mice. The loss of PKK in Sle mice resulted in the amelioration of multiple classical lupus-associated phenotypes and histologic features of lupus nephritis, including marked reduction in the levels of serum autoantibodies, proteinuria, spleen size, peritoneal B-1 cell population and the number of activated CD4 T cells. In addition, the abundance of autoreactive plasma cells normally seen in Sle lupus mice was also significantly decreased in the PKK-deficient Sle mice. Sle B cells deficient in PKK display defective proliferation responses to BCR and LPS stimulation. Consistently, B cell receptor-mediated NF-κB activation, which is required for the survival of activated B cells, was impaired in the PKK-deficient B cells. Taken together, our work uncovers a critical role of PKK in lupus development and suggests that targeting the PKK-mediated pathway may represent a promising therapeutic strategy for lupus treatment.

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Enhanced Expression of Bruton’s Tyrosine Kinase in B Cells Drives Systemic Autoimmunity by Disrupting T Cell Homeostasis

Cited by 44 publications

References 59 publications

Altered B cell signalling in autoimmunity

Altered B cell signalling in autoimmunity

Distinct and Overlapping Functions of TEC Kinase and BTK in B Cell Receptor Signaling

PKK deficiency in B cells prevents lupus development in Sle lupus mice

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