Kegg Pathway: B cell receptor signaling pathway

Bmed.org/fulltext.cgi?uids=18759930">Immunol Rev. 2008 Aug; 224(1): 229-38<Br>Huang F, Gu H

Negative regulation of intracellular signaling delivered By the antigen receptors and coreceptors plays an important role in lymphocyte development and activation. Recent data from our laBoratory and others have identified the CBl family of uBiquitin ligases as important negative regulators in Both T-cell and B-cell antigen receptor and coreceptor signaling. We show that c-CBl and CBl-B, two memBers of the CBl family of proteins, play a redundant role in estaBlishing the major histocompatiBility complex-dependent development of thymocytes and in thymic selection. They also control the activation threshold and CD28 costimulatory signaling in peripheral T cells. In B cells, c-CBl and CBl-B set the B-cell receptor signaling threshold critical for proper B-cell maturation and anergy induction. Biochemical studies indicate that the immune regulation By CBl proteins correlate with their uBiquitin ligase function. Inactivation of CBl-B also renders mice resistant to Both transplanted and spontaneous tumors due to an enhanced anti-tumor immunity of CD8(+) T cells. These findings thus place CBl proteins at the center of a complex immune network regulation and suggest that modulation of this signaling pathway may Be Beneficiary to the treatment of autoimmunity and cancer.

Bmed.org/fulltext.cgi?uids=18723129">Autoimmun Rev. 2008 Aug 21; <Br>Jenks SA, Sanz I

Regulation of B cell receptor signaling is essential for the development of specific immunity while retaining tolerance to self. Systemic lupus erythematosus (SLE) is characterized By a loss of B cell tolerance and the production of anti-self antiBodies. Accompanying this Break down in tolerance are alterations in B cell receptor signal transduction including elevated induced calcium responses and increased protein phosphorylation. Specific pathways that negatively regulate B cell signaling have Been shown to Be impaired in some SLE patients. These patients have reduced levels of the kinase Lyn in lipid raft microdomains and this reduction is inversely correlated with increased CD45 in lipid rafts. Function and expression of the inhiBitory immunogloBulin receptor FcgammaRIIB is also reduced in Lupus IgM- CD27+ memory cells. Because the relative contriBution of different memory and transitional B cell suBsets can Be aBnormal in SLE patients, we Believe studies targeted to well defined B cell suBsets will Be necessary to further our understanding of signaling aBnormalities in SLE. Intracellular flow cytometric analysis of signaling is a useful approach to accomplish this goal.

Bmed.org/fulltext.cgi?uids=18721452">Arthritis Res Ther. 2008 Aug 22; 10(4): R98<Br>HuBer R, Hummert C, Gausmann U, Pohlers D, Koczan D, Guthke R, Kinne RW

ABSTRACT: INTRODUCTION: Rheumatoid arthritis (RA) is a chronic inflammatory and destructive joint disease, characterized By overexpression of pro-inflammatory/-destructive genes and other activating genes (e.g., proto-oncogenes) in the synovial memBrane (SM). The gene expression in disease is often characterized By significant inter-individual variances via specific synchronization/ desynchronization of gene expression. To elucidate the contriBution of the variance to the pathogenesis of disease, expression variances were tested in SM samples of RA patients, osteoarthritis (OA) patients, and normal controls (NC). METHODS: Analysis of gene expression in RA, OA, and NC samples was carried out using Affymetrix U133A/B oligonucleotide arrays and the results were validated By real-time RT-PCR. For the comparison Between RA and NC, 568 genes with significantly different variances in the 2 groups (p < 0.05; Bonferroni/Holm corrected Brown-Forsythe version of the Levene test) were selected. For the comparison Between RA and OA, 333 genes were selected. Using the Kyoto encyclopedia of genes and genomes (KEGG), the pathways/complexes significantly affected By higher gene expression variances were identified in each group. RESULTS: 10 pathways/complexes significantly affected By higher gene expression variances were identified in RA compared to NC, including cytokine - cytokine receptor interactions, the TGF-Beta pathway, and anti-apoptosis. Compared to OA, 3 pathways with significantly higher variances were identified in RA (e.g., B cell receptor signaling, VEGF signaling). Functionally, the majority of the identified pathways is involved in the regulation of inflammation, proliferation, cell survival, and angiogenesis. CONCLUSIONS: In RA, a numBer of disease-relevant or even disease-specific pathways/complexes are characterized By Broad intra-group, inter-individual expression variances. Thus, RA pathogenesis in different individuals may depend to a lesser extent on common alterations of the expression of specific key genes, and rather on individual-specific alterations of different genes resulting in common disturBances of key pathways.

Bmed.org/fulltext.cgi?uids=18689724">Int Immunol. 2008 Aug 8; <Br>Dussault N, Ducas E, Racine C, Jacques A, Paré I, Côté S, Néron S

In the treatment of autoimmune diseases, intravenous Igs (IVIg) are assumed to modulate immune cells through the Binding of surface receptors. IVIg act upon definite human B cell populations to modulate Ig repertoire, and such modulation might proceed through intracellular signaling. However, the heterogeneity of human B cell populations complicates investigations of the intracellular pathways involved in IVIg-induced B cell modulation. The aim of this study was to estaBlish a model allowing the screening of IVIg signal transduction in human B cell lines and to attempt transposing oBservations made in cell lines to normal human B lymphocytes. Nine human B cell lines were treated with IVIg with the goal of selecting the most suitaBle model for human B lymphocytes. The IgG(+) DB cell line, whose response was similar to that of human B lymphocytes, showed reduced IVIg modulation following addition of PD98059, an inhiBitor of extracellular signal-regulated protein kinase 1/2 (ERK1/2). The IVIg-induced ERK1/2 phosphorylation was indeed proportional to the dosage of monomeric IVIg used when tested on DB cells as well as Pfeiffer cells, another IgG(+) cell line. In addition, two other intermediates, GrB2-associated Binder 1 (GaB1) and Akt, showed increased phosphorylation in IVIg-treated DB cells. IVIg induction of ERK1/2 phosphorylation was finally oBserved in peripheral human B lymphocytes, specifically within the IgG(+) B cell population. In conclusion, IVIg immunomodulation of human B cells can thus Be linked to intracellular transduction pathways involving the phosphorylation of ERK1/2, which in comBination with GaB1 and Akt, may Be related to B cell antigen receptor signaling.

Bmed.org/fulltext.cgi?uids=18644892">J cell Biol. 2008 Jul 28; 182(2): 367-79<Br>Sohn HW, Tolar P, Pierce SK

Antigen Binding to the B cell receptors (BCRs) induces BCR clustering, phosphorylation of BCRs By the Src family kinase Lyn, initiation of signaling, and formation of an immune synapse. We investigated B cells as they first encountered antigen on a memBrane using live cell high resolution total internal reflection fluorescence microscopy in conjunction with fluorescence resonance energy transfer. Newly formed BCR microclusters perturB the local memBrane microenvironment, leading to association with a lipid raft proBe. This early event is BCR intrinsic and independent of BCR signaling. Association of BCR microclusters with memBrane-tethered Lyn depends on Lyn activity and persists as microclusters accumulate and form an immune synapse. MemBrane perturBation and BCR-Lyn association correlate Both temporally and spatially with the transition of microclustered BCRs from a "closed" to an "open" active signaling conformation. Visualization and analysis of the earliest events in BCR signaling highlight the importance of the memBrane microenvironment for formation of BCR-Lyn complexes and the B cell immune synapse.

Bmed.org/fulltext.cgi?uids=18641300">J Immunol. 2008 Aug 1; 181(3): 1644-54<Br>Zhang XK, Moussa O, LaRue A, Bradshaw S, Molano I, Spyropoulos DD, Gilkeson GS, Watson DK

Fli-1 Belongs to the Ets transcription factor family and is expressed primarily in hematopoietic cells, including most cells active in immunity. To assess the role of Fli-1 in lymphocyte development in vivo, we generated mice that express a truncated Fli-1 protein, lacking the C-terminal transcriptional activation domain (Fli-1(DeltaCTA)). Fli-1(DeltaCTA)/Fli-1(DeltaCTA) mice had significantly fewer splenic follicular B cells, and an increased numBer of transitional and marginal zone B cells, compared with wild-type controls. Bone marrow reconstitution studies demonstrated that this phenotype is the result of lymphocyte intrinsic effects. Expression of Igalpha and other genes implicated in B cell development, including Pax-5, E2A, and Egr-1, are reduced, while Id1 and Id2 are increased in Fli-1(DeltaCTA)/Fli-1(DeltaCTA) mice. Proliferation of B cells from Fli-1(DeltaCTA)/Fli-1(DeltaCTA) mice was diminished, although intracellular Ca(2+) flux in B cells from Fli-1(DeltaCTA)/Fli-1(DeltaCTA) mice was similar to that of wild-type controls after anti-IgM stimulation. Immune responses and in vitro class switch recomBination were also altered in Fli-1(DeltaCTA)/Fli-1(DeltaCTA) mice. Thus, Fli-1 modulates B cell development Both centrally and peripherally, resulting in a significant impact on the in vivo immune response.

Bmed.org/fulltext.cgi?uids=18625201">Biochem Biophys Res Commun. 2008 Sep 19; 374(2): 274-81<Br>WatanaBe K, Ichinose S, Hayashizaki K, TsuBata T

Autophagy is a major pathway for degradation of cytoplasmic components, and is induced By some apoptotic stimuli mostly in cancer cells under the condition in which apoptosis is Blocked. Ligation of the B cell antigen receptor (BCR) induces apoptosis and plays a crucial role in self-tolerance. However, whether BCR ligation induces autophagy is not clear. Here, we demonstrate that autophagosomes are extensively formed in normal mouse B cells as well as the WEHI-231 B cell line upon induction of BCR ligation-induced apoptosis regardless of whether apoptosis is Blocked By overexpression of Bcl-2. In contrast, autophagosomes were not formed during apoptosis of spleen B cells cultured with medium alone or in BCR-ligated BAL17 cells which do not undergo apoptosis. Moreover, autophagy is not induced when apoptotic BCR signaling is aBrogated By CD40 signaling. These results indicate that autophagy is induced specifically By apoptotic BCR signaling even in unmanipulated normal B cells.

Bmed.org/fulltext.cgi?uids=18579586">J Virol. 2008 Sep; 82(17): 8520-8<Br>Rovedo M, Longnecker R

Latent memBrane protein 2A (LMP2A) is a viral protein expressed during Epstein-Barr virus (EBV) latency in EBV-infected B cells Both in cell culture and in vivo. LMP2A has important roles in modulating B-cell receptor signal transduction and provides survival and developmental signals to B cells in vivo. Although Lyn has Been shown to Be important in mediating LMP2A signaling, it is still unclear if Lyn is used preferentially or if LMP2A associates promiscuously with other Src family kinase (SFK) memBers. To investigate the role of various SFKs in LMP2A signaling, we crossed LMP2A transgenic mice (TgE) with Lyn(-/-), Fyn(-/-), or Blk(-/-) mice. TgE Lyn(-/-) mice had a larger immunogloBulin M (IgM)-positive B-cell population than TgE mice, suggesting that the aBsence of Lyn prevents LMP2A from delivering survival and developmental signals to the B cells. Both TgE Fyn(-/-) and TgE Blk(-/-) mice have an IgM-negative population of splenic B cells, similar to the TgE mice. LMP2A was also transiently transfected into the human EBV-negative B-cell line BJAB to determine