B Cell Receptor (BCR) Cross-Talk: IL-4 Creates an Alternate Pathway for BCR-Induced ERK Activation That Is Phosphatidylinositol 3-Kinase Independent

Guo, Benqi; Rothstein, Thomas L.

doi:10.4049/jimmunol.174.9.5375

Cited by 30 publications

(36 citation statements)

References 55 publications

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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: A Short History Of Smmentioning

confidence: 93%

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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Section: A Short History Of Smmentioning

confidence: 93%

The regulation of autoreactive B cells during innate immune responses

Vilen

Rutan

2008

Immunol Res

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“…We investigated the possibility that bacterial products such as LPS might create an alternate BCR signaling pathway for MAPK activation similar to the alternate BCR signaling pathways established by B cell exposure to IL-4 and CD40L (2)(3)(4)(5). To evaluate this possibility, purified primary splenic B cells from normal BALB/c mice were treated with LPS for 24 h, washed, incubated in medium for 3 h ("rested"), and stimulated then with anti-Ig (15 g/ml) after which whole cell extracts were prepared and examined by Western blotting using ERK-specific and phospho-ERK (pERK)-specific Abs.…”

Section: Bcr-induced Erk Phosphorylation Becomes Resistant To Ly29400mentioning

confidence: 99%

“…However, recent evidence indicates that following exposure to CD40L or IL-4, alternate pathways for BCR signaling are established in which downstream events take place without the need for PI3K and other signalosome members through a process of receptor cross-talk (2)(3)(4)(5). Thus, the generally accepted need for signalosome elements in BCR signaling may simply represent an initial condition applicable only to naive cells, and not to B cells in the midst of an immune response.…”

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confidence: 99%

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

Dye

Palvanov

Guo

et al. 2007

The Journal of Immunology

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BCR signaling in naive B cells depends on the function of signalosome mediators; however, prior engagement of CD40 or of IL-4R produces an alternate signaling pathway in which Bruton’s tyrosine kinase, PI3K, phospholipase Cγ2, and protein kinase Cβ are no longer required for BCR-induced downstream events. To explore the range of mediators capable of producing such an alternate pathway for BCR signaling, we examined the TLR4 agonist, LPS. B cell treatment with LPS at relatively low doses altered subsequent BCR signaling such that ERK phosphorylation and NF-κB activation occurred in a PI3K-independent manner. This effect of LPS extended to MEK phosphorylation and IκBα degradation, and it developed slowly over a period of 16–24 h. The involvement of TLRs is suggested by similar effects observed with a structurally distinct TLR agonist, PAM3CSK4 and by the need for MyD88 for induction of alternate BCR signaling by LPS. Thus, LPS-mediated TLR engagement produces an alternate pathway for BCR-triggered signal propagation that differs from the classical, signalosome-dependent pathway.

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“…29,30 CLL cells exhibit glycosylation and folding defects of the IgM and CD79a chains, 31 which results in impaired BCR assembly and reduced sIgM in CLL samples. Our recent studies [32][33][34] have shown that IL-4 reprograms sIgM expression and substantially enhances anti-Ig-initiated B-cell activation in mouse B cells. In the present study, we find that CLL cells express a low level of total CD79b protein.…”

Section: Introductionmentioning

confidence: 99%