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Human Germinal Center B Cells Differ from Naïve and Memory B Cells in CD40 Expression and CD40L-Induced Signaling Response.
Huse K, Wogsland CE, Polikowsky HG, Diggins KE, Smeland EB, Myklebust JH, Irish JM
(2019) Cytometry A 95: 442-449
MeSH Terms: B-Lymphocytes, CD40 Antigens, CD40 Ligand, Cells, Cultured, Germinal Center, Humans, Immunologic Memory, NF-kappa B, Phosphorylation, Signal Transduction
Show Abstract · Added March 8, 2019
CD40 expression is required for germinal center (GC) formation and function, but the kinetics and magnitude of signaling following CD40 engagement remain poorly characterized in human B cells undergoing GC reactions. Here, differences in CD40 expression and signaling responses were compared across differentiation stages of mature human tonsillar B cells. A combination of mass cytometry and phospho-specific flow cytometry was used to quantify protein expression and CD40L-induced signaling in primary human naïve, GC, and memory B cells. Protein expression signatures of cell subsets were quantified using viSNE and Marker Enrichment Modeling (MEM). This approach revealed enriched expression of CD40 protein in GC B cells, compared to naïve and memory B cells. Despite this, GC B cells responded to CD40L engagement with lower phosphorylation of NFκB p65 during the first 30 min following CD40L activation. Before CD40L stimulation, GC B cells expressed higher levels of suppressor protein IκBα than naïve and memory B cells. Following CD40 activation, IκBα was rapidly degraded and reached equivalently low levels in naïve, GC, and memory B cells at 30 min following CD40L. Quantifying CD40 signaling responses as a function of bound ligand revealed a correlation between bound CD40L and degree of induced NFκB p65 phosphorylation, whereas comparable IκBα degradation occurred at all measured levels of CD40L binding. These results characterize cell-intrinsic signaling differences that exist in mature human B cells undergoing GC reactions. © 2019 International Society for Advancement of Cytometry.
© 2019 International Society for Advancement of Cytometry.
3 Communities
1 Members
0 Resources
10 MeSH Terms
Phospho-specific flow cytometry identifies aberrant signaling in indolent B-cell lymphoma.
Blix ES, Irish JM, Husebekk A, Delabie J, Forfang L, Tierens AM, Myklebust JH, Kolstad A
(2012) BMC Cancer 12: 478
MeSH Terms: CD40 Antigens, CD40 Ligand, CD79 Antigens, Cluster Analysis, Extracellular Signal-Regulated MAP Kinases, Flow Cytometry, Humans, Interleukins, Leukemia, Lymphocytic, Chronic, B-Cell, Lymphoma, B-Cell, Lymphoma, B-Cell, Marginal Zone, Models, Biological, Phospholipase C gamma, Phosphoproteins, Phosphorylation, Receptors, Antigen, B-Cell, STAT5 Transcription Factor, STAT6 Transcription Factor, Signal Transduction, T-Lymphocytes, Transcription Factor RelA
Show Abstract · Added February 15, 2013
BACKGROUND - Knowledge about signaling pathways in malignant cells may provide prognostic and diagnostic information in addition to identify potential molecular targets for therapy. B-cell receptor (BCR) and co-receptor CD40 signaling is essential for normal B cells, and there is increasing evidence that signaling via BCR and CD40 plays an important role in the pathogenesis of B-cell lymphoma. The aim of this study was to investigate basal and induced signaling in lymphoma B cells and infiltrating T cells in single-cell suspensions of biopsies from small cell lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL) and marginal zone lymphoma (MZL) patients.
METHODS - Samples from untreated SLL/CLL and MZL patients were examined for basal and activation induced signaling by phospho-specific flow cytometry. A panel of 9 stimulation conditions targeting B and T cells, including crosslinking of the B cell receptor (BCR), CD40 ligand and interleukins in combination with 12 matching phospho-protein readouts was used to study signaling.
RESULTS - Malignant B cells from SLL/CLL patients had higher basal levels of phosphorylated (p)-SFKs, p-PLCγ, p-ERK, p-p38, p-p65 (NF-κB), p-STAT5 and p-STAT6, compared to healthy donor B cells. In contrast, anti-BCR induced signaling was highly impaired in SLL/CLL and MZL B cells as determined by low p-SFK, p-SYK and p-PLCγ levels. Impaired anti-BCR-induced p-PLCγ was associated with reduced surface expression of IgM and CD79b. Similarly, CD40L-induced p-ERK and p-p38 were also significantly reduced in lymphoma B cells, whereas p-p65 (NF-κB) was equal to that of normal B cells. In contrast, IL-2, IL-7 and IL-15 induced p-STAT5 in tumor-infiltrating T cells were not different from normal T cells.
CONCLUSIONS - BCR signaling and CD40L-induced p-p38 was suppressed in malignant B cells from SLL/CLL and MZL patients. Single-cell phospho-specific flow cytometry for detection of basal as well as activation-induced phosphorylation of signaling proteins in distinct cell populations can be used to identify aberrant signaling pathways.
1 Communities
1 Members
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21 MeSH Terms
Comparative effects of angiotensin-converting enzyme inhibition and angiotensin-receptor blockade on inflammation during hemodialysis.
Gamboa JL, Pretorius M, Todd-Tzanetos DR, Luther JM, Yu C, Ikizler TA, Brown NJ
(2012) J Am Soc Nephrol 23: 334-42
MeSH Terms: Angiotensin Receptor Antagonists, Angiotensin-Converting Enzyme Inhibitors, Blood Coagulation, CD40 Ligand, Cross-Over Studies, Cytokines, Double-Blind Method, Female, Hemodynamics, Humans, Inflammation, Kidney Failure, Chronic, Male, Middle Aged, Oxidative Stress, Ramipril, Renal Dialysis, Renin, Tetrazoles, Valine, Valsartan
Show Abstract · Added December 10, 2013
Biomarkers of oxidative stress and inflammation predict cardiovascular events in maintenance hemodialysis patients. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) reduce cardiovascular mortality in the general population, but their benefit in maintenance hemodialysis patients is not fully explored. To test whether ACE inhibitors and ARBs differentially affect markers of oxidative stress, inflammation, and fibrinolysis during hemodialysis, we conducted a randomized, double-blind, placebo-controlled 3×3 crossover study. We randomly assigned 15 participants undergoing hemodialysis to placebo, ramipril (5 mg/d), and valsartan (160 mg/d) for 7 days, with a washout period of 3 weeks in between the treatments. On the morning of the seventh day of drug treatment, participants underwent serial blood sampling during hemodialysis. Neither ramipril nor valsartan affected BP during hemodialysis. Ramipril increased IL-1β concentrations (P=0.02) and decreased IL-10 concentrations (P=0.04) compared with placebo. Valsartan and ramipril both lowered IL-6 levels during dialysis (P<0.01 for each compared with placebo). Valsartan increased F(2)-isoprostane levels, and ramipril suggested a similar trend (P=0.09). Valsartan and ramipril both lowered D-dimer levels (P<0.01 for both), whereas only ramipril seemed to prevent a rise in vWf levels (P=0.04). In summary, during hemodialysis, valsartan induces a greater anti-inflammatory effect compared with ramipril, although ramipril seems to prevent dialysis-induced endothelial dysfunction as measured by levels of vWf. A prospective clinical trial is necessary to determine whether ACE inhibitors and ARBs also differ with respect to their effects on cardiovascular mortality in this population.
0 Communities
4 Members
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21 MeSH Terms
Blockade of GITR-GITRL interaction maintains Treg function to prolong allograft survival.
Kim JI, Sonawane SB, Lee MK, Lee SH, Duff PE, Moore DJ, O'Connor MR, Lian MM, Deng S, Choi Y, Yeh H, Caton AJ, Markmann JF
(2010) Eur J Immunol 40: 1369-74
MeSH Terms: Adoptive Transfer, Animals, Antibodies, Monoclonal, Antigen-Presenting Cells, Binding, Competitive, CD40 Ligand, Glucocorticoid-Induced TNFR-Related Protein, Graft Survival, Histocompatibility Antigens Class I, Humans, Immune Tolerance, Immunosuppressive Agents, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Transgenic, Minor Histocompatibility Antigens, Receptors, Nerve Growth Factor, Receptors, Tumor Necrosis Factor, Recombinant Fusion Proteins, Skin Transplantation, T-Lymphocytes, Regulatory, Transplantation, Homologous, Tumor Necrosis Factor Inhibitors, Tumor Necrosis Factors
Show Abstract · Added October 24, 2013
Involvement of Treg in transplant tolerance has been demonstrated in multiple models. During the active process of graft rejection, these regulatory cells are themselves regulated and inactivated, a process termed counter-regulation. We hypothesize that ligation of the costimulatory molecule glucocorticoid-induced TNF receptor-related protein (GITR) on Treg inhibits their ability to promote graft survival, and by blocking GITR ligation graft survival can be prolonged. To this aim, we have designed a soluble GITR fusion protein (GITR-Fc), which binds GITR ligand and inhibits activation of GITR. Here, we show that GITR-Fc prolonged mouse skin graft survival, and this prolongation is dependent on Treg. In a full MHC-mismatched skin graft setting, GITR-Fc significantly improved graft survival when used in combination with MR1, anti-CD40L, while GITR-Fc alone did not demonstrate graft prolongation. These results demonstrate that disruption of binding of GITR with GITR ligand may be an important strategy in prolonging allograft survival.
0 Communities
1 Members
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25 MeSH Terms
A critical role for protein kinase C-theta-mediated T cell survival in cardiac allograft rejection.
Manicassamy S, Yin D, Zhang Z, Molinero LL, Alegre ML, Sun Z
(2008) J Immunol 181: 513-20
MeSH Terms: Animals, Antibodies, Monoclonal, Antigens, CD, CD40 Ligand, CTLA-4 Antigen, Cell Survival, Cells, Cultured, Female, Graft Rejection, Heart Transplantation, Homeodomain Proteins, Immunoglobulins, Isoenzymes, Lymphocyte Culture Test, Mixed, Mice, Mice, Knockout, Protein Kinase C, Protein Kinase C-theta, T-Lymphocytes, Transplantation, Homologous, bcl-X Protein
Show Abstract · Added December 10, 2013
Protein kinase C (PKC)-theta mediates the critical TCR signals required for T cell activation. Previously, we have shown that in response to TCR stimulation, PKC-theta-/- T cells undergo apoptosis due to greatly reduced levels of the anti-apoptotic molecule, Bcl-xL. In this study, we demonstrate that PKC-theta-regulated expression of Bcl-xL is essential for T cell-mediated cardiac allograft rejection. Rag1-/- mice reconstituted with wild-type T cells readily rejected fully mismatched cardiac allografts, whereas Rag1-/- mice reconstituted with PKC-theta-/- T cells failed to promote rejection. Transgenic expression of Bcl-xL in PKC-theta-/- T cells was sufficient to restore cardiac allograft rejection, suggesting that PKC-theta-regulated survival is required for T cell-mediated cardiac allograft rejection in this adoptive transfer model. In contrast to adoptive transfer experiments, intact PKC-theta-/- mice displayed delayed, but successful cardiac allograft rejection, suggesting the potential compensation for PKC-theta function. Finally, a subtherapeutic dose of anti-CD154 Ab or CTLA4-Ig, which was not sufficient to prevent cardiac allograft rejection in the wild-type mice, prevented heart rejection in the PKC-theta-/- mice. Thus, in combination with other treatments, inhibition of PKC-theta may facilitate achieving long-term survival of allografts.
0 Communities
1 Members
0 Resources
21 MeSH Terms
Long-term control of alloreactive B cell responses by the suppression of T cell help.
Li Y, Ma L, Yin D, Shen J, Chong AS
(2008) J Immunol 180: 6077-84
MeSH Terms: Animals, B-Lymphocytes, CD40 Ligand, Graft Rejection, Heart Transplantation, Isoantibodies, Lymphocyte Depletion, Mice, Mice, Inbred BALB C, Mice, Knockout, Receptors, Antigen, B-Cell, T-Lymphocytes, Time Factors, Transplantation Tolerance, Transplantation, Homologous
Show Abstract · Added December 10, 2013
Alloantibodies can play a key role in acute and chronic allograft rejection. However, relatively little is known of factors that control B cell responses following allograft tolerance induction. Using 3-83 Igi mice expressing an alloreactive BCR, we recently reported that allograft tolerance was associated with the sustained deletion of the alloreactive B cells at the mature, but not the immature, stage. We have now investigated the basis for the long-term control of alloreactive B cell responses in a non-BCR-transgenic model of C57BL/6 cardiac transplantation into BALB/c recipients treated with anti-CD154 and transfusion of donor-specific spleen cells. We demonstrate that the long-term production of alloreactive Abs by alloreactive B cells is actively regulated in tolerant BALB/c mice through the dominant suppression of T cell help. Deletion of CD25(+) cells resulted in a loss of tolerance and an acquisition of the ability to acutely reject allografts. In contrast, the restoration of alloantibody responses required both the deletion of CD25(+) cells and the reconstitution of alloreactive B cells. Collectively, these data suggest that alloreactive B cell responses in this model of tolerance are controlled by dominant suppression of T cell help as well as the deletion of alloreactive B cells in the periphery.
0 Communities
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15 MeSH Terms
Association of multiple inflammatory markers with carotid intimal medial thickness and stenosis (from the Framingham Heart Study).
Thakore AH, Guo CY, Larson MG, Corey D, Wang TJ, Vasan RS, D'Agostino RB, Lipinska I, Keaney JF, Benjamin EJ, O'Donnell CJ
(2007) Am J Cardiol 99: 1598-602
MeSH Terms: Aged, Biomarkers, C-Reactive Protein, CD40 Ligand, Carotid Artery, Common, Carotid Stenosis, Chemokine CCL2, Confounding Factors, Epidemiologic, Female, Humans, Inflammation Mediators, Intercellular Adhesion Molecule-1, Interleukin-6, Male, Middle Aged, P-Selectin, Predictive Value of Tests, Tunica Intima, Tunica Media, Ultrasonography
Show Abstract · Added April 15, 2014
Inflammatory markers, particularly C-reactive protein (CRP), predict incident cardiovascular disease and are associated with the presence of subclinical atherosclerosis. The relations between multiple inflammatory markers and direct measures of atherosclerosis are less well established. Participants in the Offspring Cohort of the Framingham Heart Study (n = 2,885, 53% women, mean age 59 years) received routine assessments of common carotid artery intima-media thickness (CCA-IMT), internal carotid artery intima-media thickness (ICA-IMT), and the presence or absence of > or =25% carotid stenosis by ultrasonography. Circulating inflammatory markers assessed from an examination 4 years later included CRP, interleukin-6 (IL-6), intercellular adhesion molecule-1, monocyte chemoattractant protein-1, P-selectin, and CD40 ligand. Assessed as a group, inflammatory markers were significantly associated with ICA-IMT (p = 0.01), marginally with carotid stenosis (p = 0.08), but not with CCA-IMT. Individually, with an increase from the 25th to 75th percentile in IL-6, there were significant increases in ICA-IMT and carotid stenosis (for ICA-IMT, estimated fold increase 1.04, 95% confidence interval 1.03 to 1.06, p = 0.0004; for carotid stenosis, odds ratio 1.25, 95% confidence interval 1.06 to 1.47, p = 0.007) after adjustment for age, gender, and established risk factors for atherosclerosis. There was a similar significant multivariate-adjusted association of CRP with ICA-IMT but not with carotid stenosis. Smoking appeared to modify the associations of ICA-IMT with CRP (p = 0.009) and with IL-6 (p = 0.006); the association was more pronounced in current (vs former or never) smokers. In conclusion, there were modest associations of inflammatory markers, particularly IL-6, with carotid atherosclerosis. This association appears more pronounced in current smokers than in former smokers and nonsmokers.
0 Communities
1 Members
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20 MeSH Terms
TLR engagement prevents transplantation tolerance.
Chen L, Wang T, Zhou P, Ma L, Yin D, Shen J, Molinero L, Nozaki T, Phillips T, Uematsu S, Akira S, Wang CR, Fairchild RL, Alegre ML, Chong A
(2006) Am J Transplant 6: 2282-91
MeSH Terms: Animals, Antibodies, Monoclonal, Autoantibodies, CD4-Positive T-Lymphocytes, CD40 Ligand, CD8-Positive T-Lymphocytes, Cytokines, Disease Models, Animal, Follow-Up Studies, Graft Rejection, Heart Transplantation, Immune Tolerance, Immunohistochemistry, Mice, Mice, Inbred BALB C, Mice, Inbred C3H, Mice, Inbred C57BL, RNA, Messenger, Skin Transplantation, Time Factors, Toll-Like Receptors, Transplantation, Heterotopic, Transplantation, Homologous
Show Abstract · Added December 10, 2013
In many experimental models, heart, pancreas and kidney allografts are accepted long-term following costimulation-targeting therapies, whereas skin, lung and intestine resist the induction of tolerance under the same regimens. We noted that a common feature of the resistant organs is their constant exposure to commensal microbes and hypothesized that these microorganisms may stimulate Toll-like receptors (TLRs), promote alloresponses and prevent tolerance induction. This hypothesis prompts the predictions that TLR engagement at the time of transplantation should avert tolerance to heart allografts in animals treated with costimulation-targeting therapies, whereas inhibition of TLR signaling should promote tolerance to skin allografts under the same conditions. Indeed, engagement of a single TLR was sufficient to prevent anti-CD154-mediated long-term cardiac allograft acceptance and correlated with abolished intragraft recruitment of CD4+/FoxP3+ regulatory T cells and the development of linked-suppression. Conversely, a lack of donor and recipient MyD88-dependent signaling led to successful skin allograft acceptance in anti-CD154-treated animals. Thus, the status of TLR signaling contributes to the resistance versus susceptibility of organs to transplantation tolerance.
0 Communities
1 Members
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23 MeSH Terms
Variants of the CD40 gene but not of the CD40L gene are associated with coronary artery calcification in the Diabetes Heart Study (DHS).
Burdon KP, Langefeld CD, Beck SR, Wagenknecht LE, Carr JJ, Rich SS, Freedman BI, Herrington D, Bowden DW
(2006) Am Heart J 151: 706-11
MeSH Terms: C-Reactive Protein, CD40 Antigens, CD40 Ligand, Calcium, Coronary Artery Disease, Coronary Vessels, Diabetic Angiopathies, Disease Progression, Female, Genetic Variation, Genotype, Humans, Linkage Disequilibrium, Male, Middle Aged, Polymorphism, Single Nucleotide
Show Abstract · Added February 15, 2014
BACKGROUND - CD40/CD40L signaling is known to play an important role in immune response. The proteins are expressed in a variety of cell types and ligation causes cells to produce inflammatory cytokines and cellular adhesion molecules. These processes are implicated in the development and progression of atherosclerosis. Animal models demonstrate that interruption of CD40/CD40L signaling produces a more fibrous and stable atherosclerotic lesion.
METHODS - We investigated the role of genetic variation in CD40 and CD40L genes in subclinical atherosclerosis assessed by coronary artery calcification (CAC) and carotid intima-media thickness in 620 individuals from 230 families in the DHS.
RESULTS - Two single nucleotide polymorphisms in the CD40 gene (rs1535045 and rs3765459) were significantly associated with decreased CAC (P < or = .02) in this population. CD40L single nucleotide polymorphisms were not significantly associated. In addition, no associations with carotid intima-media thickness, carotid artery calcification, or C-reactive protein levels were detected for either gene.
CONCLUSION - Genetic variation in the CD40 gene is associated with CAC in diabetic families.
0 Communities
1 Members
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16 MeSH Terms
NK cells promote islet allograft tolerance via a perforin-dependent mechanism.
Beilke JN, Kuhl NR, Van Kaer L, Gill RG
(2005) Nat Med 11: 1059-65
MeSH Terms: Animals, Antibodies, Monoclonal, CD11a Antigen, CD40 Antigens, CD40 Ligand, CD8-Positive T-Lymphocytes, Graft Survival, Histocompatibility Antigens Class I, Immune Tolerance, Immunotherapy, Intercellular Adhesion Molecule-1, Islets of Langerhans Transplantation, Killer Cells, Natural, Major Histocompatibility Complex, Membrane Glycoproteins, Mice, Mice, Knockout, Models, Animal, Models, Immunological, Perforin, Phenotype, Pore Forming Cytotoxic Proteins, Transplantation, Homologous
Show Abstract · Added December 10, 2013
Although major histocompatibility complex (MHC) class II-restricted CD4 T cells are well appreciated for their contribution to peripheral tolerance to tissue allografts, little is known regarding MHC class I-dependent reactivity in this process. Here we show a crucial role for host MHC class I-dependent NK cell reactivity for allograft tolerance in mice induced through either costimulation blockade using CD154-specific antibody therapy or by targeting LFA-1 (also known as CD11a). Tolerance induction absolutely required host expression of MHC class I, but was independent of CD8 T cell-dependent immunity. Rather, tolerance required innate immunity involving NK1.1(+) cells, but was independent of CD1d-restricted NKT cells. Therefore, NK cells seem to be generally required for induction of tolerance to islet allografts. Additional studies indicate that CD154-specific antibody-induced allograft tolerance is perforin dependent. Notably, NK cells that are perforin competent are sufficient to restore allograft tolerance in perforin-deficient recipients. Together, these results show an obligatory role for NK cells, through perforin, for induction of tolerance to islet allografts.
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23 MeSH Terms