B Cell Receptor Cross-Talk: Exposure to Lipopolysaccharide Induces an Alternate Pathway for B Cell Receptor-Induced ERK Phosphorylation and NF-κB Activation

Dye, John R.; Palvanov, Arkadiy; Guo, Benqi; Rothstein, Thomas L.

doi:10.4049/jimmunol.179.1.229

Cited by 34 publications

(27 citation statements)

References 35 publications

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“…To examine whether, like DPP4 [7] , DPP8 and DPP9 are upregulated upon lymphocyte activation, mouse splenocytes were stimulated in vitro with PWM [43][44][45] and LPS [46,47] . DPP8 and DPP9 mRNA was markedly upregulated in PWM stimulated mouse splenocytes in a time dependent manner (Figure 2A).…”

Section: Resultsmentioning

confidence: 99%

Regulation of dipeptidyl peptidase 8 and 9 expression in activated lymphocytes and injured liver

Chowdhury

Chen²,

Yao³

et al. 2013

WJG

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), human lymphoma cell lines and mouse splenocytes stimulated with pokeweed mitogen (PWM) or lipopolysaccharide (LPS), and in dithiothreitol (DTT) and mitomycin-C treated Raji cells. DPP8 and DPP9 expression were measured in epidermal growth factor (EGF) treated Huh7 hepatoma cells, in fibrotic liver samples from mice treated with carbon tetrachloride (CCl4) and from multidrug resistance gene 2 (Mdr2 /Abcb4 ) gene knockout (gko) mice with biliary fibrosis, and in human end stage primary biliary cirrhosis (PBC). RESULTS:All three lymphocyte subsets expressed DPP8 and DPP9 mRNA. DPP8 and DPP9 expression were upregulated in both PWM and LPS stimulated mouse splenocytes and in both Jurkat T-and Raji B-cell lines. DPP8 and DPP9 were downregulated in DTT treated and upregulated in mitomycin-C treated Raji cells. DPP9-transfected Raji cells exhibited more annexin V + cells and associated apoptosis. DPP8 and DPP9 mRNA were upregulated in CCl4 induced fibrotic livers but not in the lymphocytes isolated from such livers, while DPP9 was upregulated in EGF stimulated Huh7 cells. In contrast, intrahepatic DPP8 and DPP9 mRNA expression levels were low in the Mdr2 gko mouse and in human PBC compared to non-diseased livers. CONCLUSION:These expression patterns point to biological roles for DPP8 and DPP9 in lymphocyte activation and apoptosis and in hepatocytes during liver disease pathogenesis.

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Section: Resultsmentioning

confidence: 99%

Regulation of dipeptidyl peptidase 8 and 9 expression in activated lymphocytes and injured liver

Chowdhury

Chen²,

Yao³

et al. 2013

WJG

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“…However, this observation still does not eliminate the possibility of a role for Btk downstream of TACI because others have previously shown that anti-IgM-induced B cell proliferation can be restored in XID mice in the presence of second signals such as CD40L, LPS, and CpG through a mechanism called "receptor cross-talk" (53)(54)(55). According to Guo et al (56), in addition to the signalosome-dependent (classical) pathway, a signalosome-independent (alternative) pathway is activated by second signals (such as CpG) in BCR-stimulated cells.…”

Section: Discussionmentioning

confidence: 99%

Impaired B Cell Receptor Signaling Is Responsible for Reduced TACI Expression and Function in X-Linked Immunodeficient Mice

Uslu

Coleman

Allman

et al. 2014

The Journal of Immunology

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Immune response to T cell independent type 2 (TI-2) Ags, such as bacterial polysaccharides, is severely impaired in X-linked immunodeficient (XID) mice. In this study, we investigated the involvement of a proliferation-inducing ligand (APRIL) or BAFF and their receptors in the unresponsiveness of XID mouse to TI-2 Ags. We discovered that whereas serum BAFF levels were increased, the expression of the APRIL and BAFF receptor transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI) was severely reduced in XID B cells. Moreover, B cells from XID mouse were unable to secrete Igs in response to APRIL or BAFF. In correlation with reduced TACI expression and impaired TACI function, APRIL or BAFF did not activate the classical NF-κB pathway in XID cells. Also correlating with the unaltered expression of BAFF receptor, BAFF stimulation induced the activation of the alternative NF-κB pathway in XID cells. Moreover, activation of MAPK pathway was ablated in APRIL-stimulated XID cells. Prestimulation of XID B cells with the TLR9 agonist, CpG led to a significant increase in TACI expression and restored TACI-mediated functions. CpG prestimulation also restored TACI-mediated signaling in APRIL- or BAFF-stimulated XID B cells. Finally, immunization of XID mouse with the prototype TI-2 Ag NP-Ficoll induced IgG and IgM Abs when CpG was given with NP-Ficoll. Collectively, these results suggest that reduced TACI expression is responsible for the unresponsiveness of XID mouse to TI-2 Ags and BCR activation controls TACI expression.

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“…Similarly, stimulation of B cells with sCD40L, IL-4, and LPS reprograms the BCR signaling pathway, enhancing ERK activation and bypassing the requirement for phosphatidylinositol 3-kinase (PI3-K) [82][83][84][85][86]. The findings that only B cells chronically exposed to self-antigen are susceptible to repression by IL-6 and sCD40L suggests that chronic BCR-derived signals "reprogram" the outcome of IL-6R and CD40 signal transduction.…”

Section: Arresting and Silencing Sm-specific B Cellsmentioning

confidence: 92%

The regulation of autoreactive B cells during innate immune responses

Vilen

Rutan

2008

Immunol Res

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Systemic lupus erythematosus (SLE) highlights the dangers of dysregulated B cells and the importance of initiating and maintaining tolerance. In addition to central deletion, receptor editing, peripheral deletion, receptor revision, anergy, and indifference, we have described a new mechanism of B cell tolerance wherein dendritic cells (DCs) and macrophages (MΦs) regulate autoreactive B cells during innate immune responses. In part, DCs and MΦs repress autoreactive B cells by releasing IL-6 and soluble CD40L (sCD40L). This mechanism is selective in that IL-6 and sCD40L do not affect Ig secretion by naïve cells during innate immune responses, allowing immunity in the absence of autoimmunity. In lupus-prone mice, DCs and MΦs are defective in secretion of IL-6 and sCD40L and cannot effectively repress autoantibody secretion suggesting that defects in DC/MΦ-mediated tolerance may contribute to the autoimmune phenotype. Further, these studies suggest that reconstituting DCs and MΦs in SLE patients might restore regulation of autoreactive B cells and provide an alternative to immunosuppressive therapies. KeywordsSystemic lupus erythematosus; B cell tolerance; Autoimmunity; Dendritic cell; Macrophage; Smith antigen Learning tolerance: a B cell's storyA diverse B cell repertoire is critical in combating pathogens, but inherent in generating diversity is the threat of autoimmunity. In the bone marrow, central tolerance mechanisms such as deletion or receptor editing remove high-affinity autoreactive B cells before they exit to the periphery [1][2][3][4][5][6][7][8][9][10]. Those that escape are subject to receptor revision [8,[11][12][13][14], peripheral deletion [15,16], or a shortened lifespan because they fail to enter B cell follicles [17][18][19][20][21][22]. In rare cases, autoreactive B cells are fully functional but indifferent to their specific antigen [23][24][25]. Finally, many low-affinity autoreactive B cells are maintained in an unresponsive state known as anergy. Anergic B cells do not receive sufficient activation signals to differentiate into plasma cells or secrete immunoglobulin (Ig) in response to antigenic or mitogenic stimulation [26][27][28][29]. Their proliferative responses to B cell receptor (BCR) or toll-like receptor (TLR) signaling as well as their lifespans vary in different models [18,[30][31][32][33][34][35]. Some anergic B cells transduce BCR-derived signals [30, 32,[36][37][38][39][40], while others exhibit desensitized BCRs [30, 33,41]. Quiescence is dependent on chronic exposure to self-antigen and occupancy of the BCR [42,43] The affinity and avidity of the antigen-BCR interaction determines whether developing B cells will be deleted, edited, anergized, or ignored [46]. Self-reactive B cells that survive these developmental checkpoints tend to bind self-antigens with low affinity and they remain anergic in the absence of costimulation by cognate T cells. Many of the early transgenic (Tg) models expressed BCRs with high affinities. However, concerns were raised that these models...

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B Cell Receptor Cross-Talk: Exposure to Lipopolysaccharide Induces an Alternate Pathway for B Cell Receptor-Induced ERK Phosphorylation and NF-κB Activation

Cited by 34 publications

References 35 publications

Regulation of dipeptidyl peptidase 8 and 9 expression in activated lymphocytes and injured liver

Regulation of dipeptidyl peptidase 8 and 9 expression in activated lymphocytes and injured liver

Impaired B Cell Receptor Signaling Is Responsible for Reduced TACI Expression and Function in X-Linked Immunodeficient Mice

The regulation of autoreactive B cells during innate immune responses

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