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Class-switched anti-insulin antibodies originate from unconventional antigen presentation in multiple lymphoid sites.
Wan X, Thomas JW, Unanue ER
(2016) J Exp Med 213: 967-78
MeSH Terms: Animals, Antigen Presentation, B-Lymphocytes, CD40 Antigens, Diabetes Mellitus, Type 1, Germinal Center, Immunoglobulin Class Switching, Insulin, Interleukin-4, Islets of Langerhans, Mice, Mice, Knockout, T-Lymphocytes
Show Abstract · Added November 23, 2016
Autoantibodies to insulin are a harbinger of autoimmunity in type 1 diabetes in humans and in non-obese diabetic mice. To understand the genesis of these autoantibodies, we investigated the interactions of insulin-specific T and B lymphocytes using T cell and B cell receptor transgenic mice. We found spontaneous anti-insulin germinal center (GC) formation throughout lymphoid tissues with GC B cells binding insulin. Moreover, because of the nature of the insulin epitope recognized by the T cells, it was evident that GC B cells presented a broader repertoire of insulin epitopes. Such broader recognition was reproduced by activating naive B cells ex vivo with a combination of CD40 ligand and interleukin 4. Thus, insulin immunoreactivity extends beyond the pancreatic lymph node-islets of Langerhans axis and indicates that circulating insulin, despite its very low levels, can have an influence on diabetogenesis.
© 2016 Wan et al.
2 Communities
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13 MeSH Terms
Reversing Tolerance in Isotype Switch-Competent Anti-Insulin B Lymphocytes.
Williams JM, Bonami RH, Hulbert C, Thomas JW
(2015) J Immunol 195: 853-64
MeSH Terms: Animals, Autoantibodies, Autoimmunity, B-Lymphocytes, CD40 Antigens, Diabetes Mellitus, Type 1, Immune Tolerance, Immunoglobulin G, Immunoglobulin M, Insulin, Insulin Antibodies, Lipopolysaccharides, Mice, Mice, Inbred C57BL, Mice, Transgenic, Molecular Sequence Data, VDJ Exons
Show Abstract · Added December 4, 2015
Autoreactive B lymphocytes that escape central tolerance and mature in the periphery are a liability for developing autoimmunity. IgG insulin autoantibodies that predict type 1 diabetes and complicate insulin therapies indicate that mechanisms for tolerance to insulin are flawed. To examine peripheral tolerance in anti-insulin B cells, we generated C57BL/6 mice that harbor anti-insulin VDJH-125 site directed to the native IgH locus (VH125(SD)). Class switch-competent anti-insulin B cells fail to produce IgG Abs following T cell-dependent immunization of VH125(SD) mice with heterologous insulin, and they exhibit markedly impaired proliferation to anti-CD40 plus insulin in vitro. In contrast, costimulation with LPS plus insulin drives robust anti-insulin B cell proliferation. Furthermore, VH125(SD) mice produce both IgM and IgG2a anti-insulin Abs following immunization with insulin conjugated to type 1 T cell-independent Brucella abortus ring test Ag (BRT). Anti-insulin B cells undergo clonal expansion in vivo and emerge as IgM(+) and IgM(-) GL7(+)Fas(+) germinal center (GC) B cells following immunization with insulin-BRT, but not BRT alone. Analysis of Igκ genes in VH125(SD) mice immunized with insulin-BRT reveals that anti-insulin Vκ from the preimmune repertoire is selected into GCs. These data demonstrate that class switch-competent anti-insulin B cells remain functionally silent in T cell-dependent immune responses, yet these B cells are vulnerable to reversal of anergy following combined BCR/TLR engagement that promotes Ag-specific GC responses and Ab production. Environmental factors that lead to infection and inflammation could play a critical yet underappreciated role in driving loss of tolerance and promoting autoimmune disease.
Copyright © 2015 by The American Association of Immunologists, Inc.
2 Communities
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17 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
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21 MeSH Terms
Altered BCR and CD40 signalling are associated with clinical outcome in small lymphocytic lymphoma/chronic lymphocytic leukaemia and marginal zone lymphoma patients.
Blix ES, Irish JM, Husebekk A, Delabie J, Tierens AM, Myklebust JH, Kolstad A
(2012) Br J Haematol 159: 604-8
MeSH Terms: Aged, CD40 Antigens, Female, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Lymphoma, B-Cell, Marginal Zone, Male, Middle Aged, Prognosis, Proto-Oncogene Proteins c-bcr, Signal Transduction
Added February 15, 2013
1 Communities
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11 MeSH Terms
Agonistic antibody to CD40 boosts the antitumor activity of adoptively transferred T cells in vivo.
Liu C, Lewis CM, Lou Y, Xu C, Peng W, Yang Y, Gelbard AH, Lizée G, Zhou D, Overwijk WW, Hwu P
(2012) J Immunother 35: 276-82
MeSH Terms: Adoptive Transfer, Animals, Antibodies, Monoclonal, Antigen Presentation, B7-1 Antigen, B7-2 Antigen, Bone Marrow Cells, CD40 Antigens, Cell Line, Female, Interleukin-2, Melanoma, Experimental, Mice, Mice, Inbred C57BL, Mice, Knockout, T-Lymphocytes, gp100 Melanoma Antigen
Show Abstract · Added April 11, 2014
CD40, a member of the tumor necrosis factor receptor superfamily, is broadly expressed on antigen-presenting cells and other cells, including fibroblasts and endothelial cells. Binding of CD40 and its natural ligand CD40L (CD154) triggers cytokine secretion, and increased expression of costimulatory molecules is required for T-cell activation and proliferation. However, to our knowledge, the use of agonistic antibodies to CD40 to boost adoptively transferred T cells in vivo has not been investigated. The purpose of this study was to determine whether anti-CD40 monoclonal antibody (mAb) in combination with interleukin (IL)-2 could improve the efficacy of in vitro-activated T cells to enhance antitumor activity. Mice bearing B16 melanoma tumors expressing the gp100 tumor antigen were treated with cultured, activated T cells transgenic for a T-cell receptor specifically recognizing gp100, with or without anti-CD40 mAb. In this model, the combination of anti-CD40 mAb with IL-2 led to expansion of adoptively transferred T cells and induced a more robust antitumor response. Furthermore, the expression of CD40 on bone marrow-derived cells and the presence of CD80/CD86 in the host were required for the expansion of adoptively transferred T cells. The use of neutralizing mAb to IL-12 provided direct evidence that enhanced IL-12 secretion induced by anti-CD40 mAb was crucial for the expansion of adoptively transferred T cells. Collectively, these findings provide a rationale to evaluate the potential application of anti-CD40 mAb in adoptive T-cell therapy for cancer.
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17 MeSH Terms
B-cell signaling networks reveal a negative prognostic human lymphoma cell subset that emerges during tumor progression.
Irish JM, Myklebust JH, Alizadeh AA, Houot R, Sharman JP, Czerwinski DK, Nolan GP, Levy R
(2010) Proc Natl Acad Sci U S A 107: 12747-54
MeSH Terms: B-Lymphocytes, CD40 Antigens, Disease Progression, Enzyme Activation, Extracellular Space, Humans, Lymphocyte Subsets, Lymphocytes, Tumor-Infiltrating, Lymphoma, Follicular, Models, Immunological, Phenotype, Phosphoprotein Phosphatases, Prognosis, Receptors, Antigen, B-Cell, Reproducibility of Results, Signal Transduction, Survival Analysis
Show Abstract · Added February 15, 2013
Human tumors contain populations of both cancerous and host immune cells whose malignant signaling interactions may define each patient's disease trajectory. We used multiplexed phospho-flow cytometry to profile single cells within human follicular lymphoma tumors and discovered a subpopulation of lymphoma cells with impaired B cell antigen receptor (BCR) signaling. The abundance of BCR-insensitive cells in each tumor negatively correlated with overall patient survival. These lymphoma negative prognostic (LNP) cells increased as tumors relapsed following chemotherapy. Loss of antigen receptor expression did not explain the absence of BCR signaling in LNP tumor cells, and other signaling responses were intact in these cells. Furthermore, BCR signaling responses could be reactivated in LNP cells, indicating that BCR signaling is not missing but rather specifically suppressed. LNP cells were also associated with changes to signaling interactions in the tumor microenvironment. Lower IL-7 signaling in tumor infiltrating T cells was observed in tumors with high LNP cell counts. The strength of signaling through T cell mediator of B cell function CD40 also stratified patient survival, particularly for those whose tumors contained few LNP cells. Thus, analysis of cell-cell interactions in heterogeneous primary tumors using signaling network profiles can identify and mechanistically define new populations of rare and clinically significant cells. Both the existence of these LNP cells and their aberrant signaling profiles provide targets for new therapies for follicular lymphoma.
1 Communities
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17 MeSH Terms
Functional silencing is initiated and maintained in immature anti-insulin B cells.
Henry RA, Acevedo-Suárez CA, Thomas JW
(2009) J Immunol 182: 3432-9
MeSH Terms: Animals, Bone Marrow Cells, CD40 Antigens, Calcium Signaling, Cell Differentiation, Cell Line, Tumor, Cell Proliferation, Cells, Cultured, Clonal Anergy, Gene Silencing, Insulin, Insulin Antibodies, Interleukin-7, Mice, Mice, Inbred C57BL, Mice, Transgenic, Precursor Cells, B-Lymphoid
Show Abstract · Added November 6, 2013
Mechanisms of B cell tolerance act during development in the bone marrow and periphery to eliminate or restrict autoreactive clones to prevent autoimmune disease. B cells in the spleens of mice that harbor anti-insulin BCR transgenes (125Tg) are maintained in a functionally silenced or anergic state by endogenous hormone, but it is not clear when and where anergy is induced. An in vitro bone marrow culture system was therefore used to probe whether small protein hormones, a critical class of autoantigens, could interact with the BCR to induce anergy early during B cell development. Upon exposure to insulin, anti-insulin (125Tg) immature B cells show similar hallmarks of anergy as those observed in mature splenic B cells. These include BCR down-regulation, impaired proliferative responses to anti-CD40, and diminished calcium mobilization upon stimulation with BCR-dependent and independent stimuli. Inhibition of calcineurin also results in reduced immature B cell proliferation in a similar manner, suggesting a potential mechanism through which reduced intracellular calcium mobilization may be altering cellular proliferation. Signs of impairment appear after short-term exposure to insulin, which are reversible upon Ag withdrawal. This suggests that a high degree of functional plasticity is maintained at this stage and that constant Ag engagement is required to maintain functional inactivation. These findings indicate that tolerance observed in mature, splenic 125Tg B cells is initiated by insulin in the developing B cell compartment and thus highlight an important therapeutic window for the prevention of insulin autoimmunity.
2 Communities
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17 MeSH Terms
Prostaglandin I2 analogs inhibit proinflammatory cytokine production and T cell stimulatory function of dendritic cells.
Zhou W, Hashimoto K, Goleniewska K, O'Neal JF, Ji S, Blackwell TS, Fitzgerald GA, Egan KM, Geraci MW, Peebles RS
(2007) J Immunol 178: 702-10
MeSH Terms: Animals, B7-2 Antigen, Bone Marrow, CD40 Antigens, Cell Differentiation, Cell Proliferation, Cells, Cultured, Cyclic AMP, Cytokines, Dendritic Cells, Epoprostenol, Histocompatibility Antigens Class II, Inflammation Mediators, Lymphocyte Activation, Mice, NF-kappa B, T-Lymphocytes
Show Abstract · Added March 5, 2014
Signaling through the PGI(2) receptor (IP) has been shown to inhibit inflammatory responses in mouse models of respiratory syncytial viral infection and OVA-induced allergic responses. However, little is known about the cell types that mediate the anti-inflammatory function of PGI(2.) In this study, we determined that PGI(2) analogs modulate dendritic cell (DC) cytokine production, maturation, and function. We report that PGI(2) analogs (iloprost, cicaprost, treprostinil) differentially modulate the response of murine bone marrow-derived DC (BMDC) to LPS in an IP-dependent manner. The PGI(2) analogs decreased BMDC production of proinflammatory cytokines (IL-12, TNF-alpha, IL-1alpha, IL-6) and chemokines (MIP-1alpha, MCP-1) and increased the production of the anti-inflammatory cytokine IL-10 by BMDCs. The modulatory effect was associated with IP-dependent up-regulation of intracellular cAMP and down-regulation of NF-kappaB activity. Iloprost and cicaprost also suppressed LPS-induced expression of CD86, CD40, and MHC class II molecules by BMDCs and inhibited the ability of BMDCs to stimulate Ag-specific CD4 T cell proliferation and production of IL-5 and IL-13. These findings suggest that PGI(2) signaling through the IP may exert anti-inflammatory effects by acting on DC.
1 Communities
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17 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.
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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