Antigen-Specific B-Lymphocyte Activation

Bishop, Gail A.; Haxhinasto, Sokol; Stunz, Laura L.; Hostager, Bruce S.

doi:10.1615/critrevimmunol.v23.i3.10

Cited by 45 publications

(36 citation statements)

References 533 publications

(587 reference statements)

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“…Thus, we wanted to establish whether SHP is able to differentiate the activation of lymphocytes in lymph nodes due to different primary cancers. Here, the paradigm of the studies is as follows: the activation of lymphocytes is initiated when antigen-presenting cells expose lymphocytes with specific molecular signatures of disease; in this case, specific or nonspecific binding of the antigen to B-cell antigen receptors occurs [74]. This binding initiates a cascade of events involving B-cell antigen receptor (BCR) molecules, which are immunoglobulin proteins found at the cell membrane.…”

Section: Ir-shp Of Lymphocyte Activation In Lymph Nodesmentioning

confidence: 99%

Molecular pathology via IR and Raman spectral imaging

Diem¹,

Mazur²,

Lenau³

et al. 2013

Journal of Biophotonics

175

115

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Journal of BIOPHOTONICSDuring the last 15 years, vibrational spectroscopic methods have been developed that can be viewed as molecular pathology methods that depend on sampling the entire genome, proteome and metabolome of cells and tissues, rather than probing for the presence of selected markers. First, this review introduces the background and fundamentals of the spectroscopies underlying the new methodologies, namely infrared and Raman spectroscopy. Then, results are presented in the context of spectral histopathology of tissues for detection of metastases in lymph nodes, squamous cell carcinoma, adenocarcinomas, brain tumors and brain metastases. Results from spectral cytopathology of cells are discussed for screening of oral and cervical mucosa, and circulating tumor cells. It is concluded that infrared and Raman spectroscopy can complement histopathology and reveal information that is available in classical methods only by costly and time-consuming steps such as immunohistochemistry, polymerase chain reaction or gene arrays. Due to the inherent sensitivity toward changes in the bio-molecular composition of different cell and tissue types, vibrational spectroscopy can even provide information that is in some cases superior to that of any one of the conventional techniques.Schematic of spectral histopathology (SHP) process: diagnostic algorithm is developed by spectral data of well documented specimens and subsequently applied to unknown dataset.

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Section: Ir-shp Of Lymphocyte Activation In Lymph Nodesmentioning

confidence: 99%

Molecular pathology via IR and Raman spectral imaging

Diem¹,

Mazur²,

Lenau³

et al. 2013

Journal of Biophotonics

175

115

View full text Add to dashboard Cite

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“…Hi5 insect cells infected with WT baculovirus (BV) or BV expressing mCD154 were described previously [50]. High-density T celldepleted splenic B cells were isolated from 8-14-wk-old C57BL/6 mice as described [50,51] and cultured 24 h with anti-CD40 Ab to up-regulate CD95 expression. Splenocytes were washed twice before additional stimulation.…”

Section: Cellsmentioning

confidence: 99%

Rapid CD40‐mediated rescue from CD95‐induced apoptosis requires TNFR‐associated factor‐6 and PI3K

Benson

Hostager²,

Bishop

2006

Eur J Immunol

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The activation molecule CD40 and the death receptor CD95/Fas play important roles in regulating B cells so that effective antimicrobial immunity occurs without autoimmunity. CD40 signaling increases CD95 expression, sensitizing cells to apoptosis, but sustained CD40 signals rescue B cells from CD95 killing. Here we describe a mechanism of early CD40-mediated rescue from CD95-induced apoptosis in B cells. Maximal rescue was achieved when CD40 signals were given within 1-2 h of initiating CD95 apoptosis. CD40 signaling did not block association of Fas-associated death domain-containing protein with CD95, but decreased CD95-induced activation of caspases 3 and 8. Rapid CD40 rescue did not require NF-jB activation and was independent of de novo protein synthesis, but was dependent upon active PI3 K. Signaling via a CD40 mutant that does not bind TNFR-associated factor (TRAF)1, TRAF2, and TRAF3 rescued B cells from CD95-induced apoptosis. TRAF1/2/3-independent rescue was confirmed in B cell lines made deficient in these TRAF molecules by gene targeting. In contrast, CD40 rescue was completely abrogated in TRAF6-deficient B cells, which showed reduced activation of Akt in response to CD40 engagement. These results reveal a new rapid mechanism to balance B cell activation and apoptosis. IntroductionB cells integrate many signals that direct proliferation and differentiation into Ig-secreting plasma cells or longlived memory cells. Ultimately, activated B cells can be eliminated through apoptosis, which is important for maintaining immune tolerance and homeostasis [1,2]. Molecules of the TNFR family play critical roles in regulating the balance between B cell activation and apoptosis. CD40 signals allow B cells to proliferate, differentiate, switch isotype, form GC, and become memory cells [3][4][5]. CD40 stimulation also induces upregulation of other members of the TNFR family, including the death receptor CD95/Fas [6].The importance of CD95 in maintaining lymphocyte homeostasis and tolerance is highlighted by the human disease autoimmune lymphoproliferative syndrome (ALPS), caused by mutations in the CD95 signaling pathway [7,8] autoantibodies are produced, and systemic autoimmunity develops [9]. Expression of the CD95 transgene exclusively in T cells of lpr/lpr mice is sufficient to decrease lymphadenopathy, splenomegaly, and the accumulation of abnormal T cells, but these mice still produce autoantibodies, causing deposition of immune complexes in kidney glomeruli [10]. In contrast, expression of the CD95 transgene in both B and T cells reduces the levels of serum Ig, autoimmune symptoms, and mortality [11]. Thus, CD95 signaling in B cells is crucial for maintaining peripheral tolerance and preventing autoimmunity. When CD95 is oligomerized, either by binding to its ligand on T cells (CD95L) or by Ab against its extracellular domain, it recruits the adaptor molecule Fas-associated death domain-containing protein (FADD) and procaspase 8 into a complex called the deathinducing signaling complex (DISC) that cleaves pro...

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“…B lymphocyte activation relies on signals generated upon recognition of antigen by the B cell antigen receptor (BCR) 1 and on additional signals provided by cognate interaction with T helper cells, including CD154 binding to CD40 (for review, see Ref. 1).…”

mentioning

confidence: 99%

“…1). BCR engagement leads to activation of a myriad of intracellular signaling molecules such as members of the protein kinase C (PKC) family of serine-threonine kinases (1).…”

mentioning

confidence: 99%

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Synergistic B Cell Activation by CD40 and the B Cell Antigen Receptor

Haxhinasto

Bishop

2004

Journal of Biological Chemistry

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Protein kinase (PKD) is a downstream target of second messengers, primarily diacylglycerol, and represents a novel family of serine/threonine kinases. Previous studies show that PKD is activated by multiple signals (for review, see Ref. 5) including BCR engagement in B-lymphocytes (3, 6, 7), and it has been suggested that PKD negatively regulates BCR signaling by phosphorylating Syk and reducing its ability to phosphorylate phospholipase C␥ (3).CD40 engagement has been shown to cooperate with BCR signals particularly in the germinal center reaction, where follicular dendritic cells present antigen and T helper cells provide CD154. Additionally, detailed analysis of the phenotypic differences between naïve, germinal center, and memory cells show that CD40 and other tumor necrosis factor receptor family members are up-regulated in germinal center cells compared with naïve B cells (8). Co-engagement of the two receptors results in a synergistic activation of B cells (9, 10). Previous studies from our laboratory identified TRAF2 and TRAF3 in the CD40 signaling pathway and BCR-induced PKD activation as playing important roles in the cross-talk between these receptors (10, 11). To integrate the BCR and CD40 signaling pathways, potential ways in which PKD and TRAF molecules cooperate was examined. Because BCR signaling activates a number of kinases, we hypothesized that BCR-mediated TRAF phosphorylation might be important for the synergy. Site-directed mutagenesis of TRAF2 identified the potentially phosphorylatable tyrosine 484 as a critical residue for the synergy and led us to investigate the potential involvement of Bruton's tyrosine kinase (Btk), a tyrosine kinase, in this process. Our data showed a role for Btk in the synergy, and this was PKDand TRAF2-dependent. This work together with previous findings provides a model for BCR-CD40 synergy whereby BCRmediated activation of Btk and PKD modifies TRAF2 in a manner that allows it to block an inhibitory effect mediated by TRAF3. EXPERIMENTAL PROCEDURESCells and Mice-The mouse B cell line CH12.LX expresses surface IgM specific for phosphatidylcholine, an antigen found on the surface of sheep erythrocytes (sheep red blood cells) (12) and has been well characterized (13). The CH12.LacR subclone used for the inducible expression of stably transfected molecules has been previously described (14). Subclones of CH12.LX lacking TRAF2 were produced by homologous

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Antigen-Specific B-Lymphocyte Activation

Cited by 45 publications

References 533 publications

Molecular pathology via IR and Raman spectral imaging

Molecular pathology via IR and Raman spectral imaging

Rapid CD40‐mediated rescue from CD95‐induced apoptosis requires TNFR‐associated factor‐6 and PI3K

Synergistic B Cell Activation by CD40 and the B Cell Antigen Receptor

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