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Anti-Insulin B Cells Are Poised for Antigen Presentation in Type 1 Diabetes.
Felton JL, Maseda D, Bonami RH, Hulbert C, Thomas JW
(2018) J Immunol 201: 861-873
MeSH Terms: Animals, Antigen Presentation, Autoantibodies, Autoantigens, B-Lymphocyte Subsets, Diabetes Mellitus, Type 1, Female, Immune Tolerance, Inflammation, Insulin, Insulin Antibodies, Lymphocyte Activation, Male, Mice, Mice, Inbred NOD, Mice, Transgenic, Receptors, Antigen, B-Cell
Show Abstract · Added July 20, 2018
Early breaches in B cell tolerance are central to type 1 diabetes progression in mouse and man. Conventional BCR transgenic mouse models (VH125.Tg NOD) reveal the power of B cell specificity to drive disease as APCs. However, in conventional fixed IgM models, comprehensive assessment of B cell development is limited. To provide more accurate insight into the developmental and functional fates of anti-insulin B cells, we generated a new NOD model (V125NOD) in which anti-insulin VDJH125 is targeted to the IgH chain locus to generate a small (1-2%) population of class switch-competent insulin-binding B cells. Tracking of this rare population in a polyclonal repertoire reveals that anti-insulin B cells are preferentially skewed into marginal zone and late transitional subsets known to have increased sensitivity to proinflammatory signals. Additionally, IL-10 production, characteristic of regulatory B cell subsets, is increased. In contrast to conventional models, class switch-competent anti-insulin B cells proliferate normally in response to mitogenic stimuli but remain functionally silent for insulin autoantibody production. Diabetes development is accelerated, which demonstrates the power of anti-insulin B cells to exacerbate disease without differentiation into Ab-forming or plasma cells. Autoreactive T cell responses in V125NOD mice are not restricted to insulin autoantigens, as evidenced by increased IFN-γ production to a broad array of diabetes-associated epitopes. Together, these results independently validate the pathogenic role of anti-insulin B cells in type 1 diabetes, underscore their diverse developmental fates, and demonstrate the pathologic potential of coupling a critical β cell specificity to predominantly proinflammatory Ag-presenting B cell subsets.
Copyright © 2018 by The American Association of Immunologists, Inc.
1 Communities
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17 MeSH Terms
Myc enhances B-cell receptor signaling in precancerous B cells and confers resistance to Btk inhibition.
Moyo TK, Wilson CS, Moore DJ, Eischen CM
(2017) Oncogene 36: 4653-4661
MeSH Terms: Agammaglobulinaemia Tyrosine Kinase, Animals, B-Lymphocytes, CD79 Antigens, Cell Proliferation, Flow Cytometry, Humans, Lymphoma, Non-Hodgkin, Male, Mice, Mice, Inbred C57BL, Mitogen-Activated Protein Kinase 3, Phosphatidylinositol 3-Kinases, Phospholipase C gamma, Phosphorylation, Precancerous Conditions, Protein-Tyrosine Kinases, Proto-Oncogene Proteins c-myc, Pyrazoles, Pyrimidines, Receptors, Antigen, B-Cell, Splenic Neoplasms, Syk Kinase
Show Abstract · Added April 6, 2017
Dysregulation of the oncogenic transcription factor MYC induces B-cell transformation and is a driver for B-cell non-Hodgkin lymphoma (B-NHL). MYC overexpression in B-NHL is associated with more aggressive phenotypes and poor prognosis. Although genomic studies suggest a link between MYC overexpression and B-cell receptor (BCR) signaling molecules in B-NHL, signaling pathways essential to Myc-mediated B-cell transformation have not been fully elucidated. We utilized intracellular phospho-flow cytometry to investigate the relationship between Myc and BCR signaling in pre-malignant B cells. Utilizing the Eμ-myc mouse model, where Myc is overexpressed specifically in B cells, both basal and stimulated BCR signaling were increased in precancerous B lymphocytes from Eμ-myc mice compared with wild-type littermates. B cells overexpressing Myc displayed constitutively higher levels of activated CD79α, Btk, Plcγ2 and Erk1/2. Notably, Myc-overexpressing B cells maintained elevated BCR signaling despite treatment with ibrutinib, a Bruton's tyrosine kinase inhibitor. Furthermore, PI3K/Akt pathway signaling was also increased in Eμ-myc B cells, and this increase was partially suppressed with ibrutinib. In addition, experiments with Btk-null B cells revealed off-target effects of ibrutinib on BCR signaling. Our data show that in pre-malignant B cells, Myc overexpression is sufficient to activate BCR and PI3K/Akt signaling pathways and further enhances signaling following BCR ligation. Therefore, our results indicate that precancerous B cells have already acquired enhanced survival and growth capabilities before transformation, and that elevated MYC levels confer resistance to pharmacologic inhibitors of BCR signaling, which has significant implications for B-NHL treatment.
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23 MeSH Terms
Distinct patterns of B-cell receptor signaling in non-Hodgkin lymphomas identified by single-cell profiling.
Myklebust JH, Brody J, Kohrt HE, Kolstad A, Czerwinski DK, Wälchli S, Green MR, Trøen G, Liestøl K, Beiske K, Houot R, Delabie J, Alizadeh AA, Irish JM, Levy R
(2017) Blood 129: 759-770
MeSH Terms: Agammaglobulinaemia Tyrosine Kinase, CD79 Antigens, Diagnosis, Differential, Flow Cytometry, Gene Expression Regulation, Neoplastic, Humans, Immunoglobulin M, Leukemia, Lymphocytic, Chronic, B-Cell, Lymphoma, Follicular, Lymphoma, Large B-Cell, Diffuse, Lymphoma, Mantle-Cell, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Phospholipase C gamma, Phosphoproteins, Phosphorylation, Protein-Tyrosine Kinases, Proto-Oncogene Proteins c-akt, Receptors, Antigen, B-Cell, STAT1 Transcription Factor, STAT5 Transcription Factor, Signal Transduction, Single-Cell Analysis, Syk Kinase, p38 Mitogen-Activated Protein Kinases, src-Family Kinases
Show Abstract · Added December 31, 2016
Kinases downstream of B-cell antigen receptor (BCR) represent attractive targets for therapy in non-Hodgkin lymphoma (NHL). As clinical responses vary, improved knowledge regarding activation and regulation of BCR signaling in individual patients is needed. Here, using phosphospecific flow cytometry to obtain malignant B-cell signaling profiles from 95 patients representing 4 types of NHL revealed a striking contrast between chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) tumors. Lymphoma cells from diffuse large B-cell lymphoma patients had high basal phosphorylation levels of most measured signaling nodes, whereas follicular lymphoma cells represented the opposite pattern with no or very low basal levels. MCL showed large interpatient variability in basal levels, and elevated levels for the phosphorylated forms of AKT, extracellular signal-regulated kinase, p38, STAT1, and STAT5 were associated with poor outcome. CLL tumors had elevated basal levels for the phosphorylated forms of BCR-signaling nodes (Src family tyrosine kinase, spleen tyrosine kinase [SYK], phospholipase Cγ), but had low α-BCR-induced signaling. This contrasted MCL tumors, where α-BCR-induced signaling was variable, but significantly potentiated as compared with the other types. Overexpression of CD79B, combined with a gating strategy whereby signaling output was directly quantified per cell as a function of CD79B levels, confirmed a direct relationship between surface CD79B, immunoglobulin M (IgM), and IgM-induced signaling levels. Furthermore, α-BCR-induced signaling strength was variable across patient samples and correlated with BCR subunit CD79B expression, but was inversely correlated with susceptibility to Bruton tyrosine kinase (BTK) and SYK inhibitors in MCL. These individual differences in BCR levels and signaling might relate to differences in therapy responses to BCR-pathway inhibitors.
© 2017 by The American Society of Hematology.
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26 MeSH Terms
Deep sequencing and human antibody repertoire analysis.
Boyd SD, Crowe JE
(2016) Curr Opin Immunol 40: 103-9
MeSH Terms: Animals, Antibodies, B-Lymphocytes, Cell Differentiation, Cell Lineage, High-Throughput Nucleotide Sequencing, Humans, Immunity, Humoral, Immunotherapy, Receptors, Antigen, B-Cell
Show Abstract · Added April 25, 2016
In the past decade, high-throughput DNA sequencing (HTS) methods and improved approaches for isolating antigen-specific B cells and their antibody genes have been applied in many areas of human immunology. This work has greatly increased our understanding of human antibody repertoires and the specific clones responsible for protective immunity or immune-mediated pathogenesis. Although the principles underlying selection of individual B cell clones in the intact immune system are still under investigation, the combination of more powerful genetic tracking of antibody lineage development and functional testing of the encoded proteins promises to transform therapeutic antibody discovery and optimization. Here, we highlight recent advances in this fast-moving field.
Copyright © 2016. Published by Elsevier Ltd.
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10 MeSH Terms
The role of Bruton's tyrosine kinase in autoimmunity and implications for therapy.
Crofford LJ, Nyhoff LE, Sheehan JH, Kendall PL
(2016) Expert Rev Clin Immunol 12: 763-73
MeSH Terms: Agammaglobulinaemia Tyrosine Kinase, Animals, Anti-Inflammatory Agents, Autoantibodies, Autoimmune Diseases, Autoimmunity, B-Lymphocytes, Humans, Immune Tolerance, Lymphocyte Activation, Protein-Tyrosine Kinases, Receptors, Antigen, B-Cell, Signal Transduction
Show Abstract · Added July 18, 2017
Bruton's tyrosine kinase (BTK) mediates B cell signaling and is also present in innate immune cells but not T cells. BTK propagates B cell receptor (BCR) responses to antigen-engagement as well as to stimulation via CD40, toll-like receptors (TLRs), Fc receptors (FCRs) and chemokine receptors. Importantly, BTK can modulate signaling, acting as a "rheostat" rather than an "on-off" switch; thus, overexpression leads to autoimmunity while decreased levels improve autoimmune disease outcomes. Autoreactive B cells depend upon BTK for survival to a greater degree than normal B cells, reflected as loss of autoantibodies with maintenance of total antibody levels when BTK is absent. This review describes contributions of BTK to immune tolerance, including studies testing BTK-inhibitors for treatment of autoimmune diseases.
1 Communities
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13 MeSH Terms
Targeting Anti-Insulin B Cell Receptors Improves Receptor Editing in Type 1 Diabetes-Prone Mice.
Bonami RH, Thomas JW
(2015) J Immunol 195: 4730-41
MeSH Terms: Animals, Antibodies, Monoclonal, Autoantigens, Autoimmunity, B-Lymphocytes, DNA-Binding Proteins, Diabetes Mellitus, Type 1, Immune Tolerance, Immunoglobulin M, Immunoglobulin kappa-Chains, Immunomodulation, Insulin, Mice, Mice, Inbred C57BL, Mice, Inbred NOD, Molecular Sequence Data, Receptors, Antigen, B-Cell
Show Abstract · Added April 1, 2016
Autoreactive B lymphocytes that commonly arise in the developing repertoire can be salvaged by receptor editing, a central tolerance mechanism that alters BCR specificity through continued L chain rearrangement. It is unknown whether autoantigens with weak cross-linking potential, such as insulin, elicit receptor editing, or whether this process is dysregulated in related autoimmunity. To resolve these issues, we developed an editing-competent model in which anti-insulin Vκ125 was targeted to the Igκ locus and paired with anti-insulin VH125Tg. Physiologic, circulating insulin increased RAG-2 expression and was associated with BCR replacement that eliminated autoantigen recognition in a proportion of developing anti-insulin B lymphocytes. The proportion of anti-insulin B cells that underwent receptor editing was reduced in the type 1 diabetes-prone NOD strain relative to a nonautoimmune strain. Resistance to editing was associated with increased surface IgM expression on immature (but not transitional or mature) anti-insulin B cells in the NOD strain. The actions of mAb123 on central tolerance were also investigated, because selective targeting of insulin-occupied BCR by mAb123 eliminates anti-insulin B lymphocytes and prevents type 1 diabetes. Autoantigen targeting by mAb123 increased RAG-2 expression and dramatically enhanced BCR replacement in newly developed B lymphocytes. Administering F(ab')2123 induced IgM downregulation and reduced the frequency of anti-insulin B lymphocytes within the polyclonal repertoire of VH125Tg/NOD mice, suggesting enhanced central tolerance by direct BCR interaction. These findings indicate that weak or faulty checkpoints for central tolerance can be overcome by autoantigen-specific immunomodulatory therapy.
Copyright © 2015 by The American Association of Immunologists, Inc.
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17 MeSH Terms
Cutting Edge: Redox Signaling Hypersensitivity Distinguishes Human Germinal Center B Cells.
Polikowsky HG, Wogsland CE, Diggins KE, Huse K, Irish JM
(2015) J Immunol 195: 1364-1367
MeSH Terms: B-Lymphocyte Subsets, B-Lymphocytes, Cell Differentiation, Gene Expression, Germinal Center, Humans, Hydrogen Peroxide, Immunophenotyping, Oxidation-Reduction, Palatine Tonsil, Phenotype, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Receptors, Antigen, B-Cell, Signal Transduction
Show Abstract · Added July 13, 2015
Differences in the quality of BCR signaling control key steps of B cell maturation and differentiation. Endogenously produced H2O2 is thought to fine tune the level of BCR signaling by reversibly inhibiting phosphatases. However, relatively little is known about how B cells at different stages sense and respond to such redox cues. In this study, we used phospho-specific flow cytometry and high-dimensional mass cytometry (CyTOF) to compare BCR signaling responses in mature human tonsillar B cells undergoing germinal center (GC) reactions. GC B cells, in contrast to mature naive B cells, memory B cells, and plasmablasts, were hypersensitive to a range of H2O2 concentrations and responded by phosphorylating SYK and other membrane-proximal BCR effectors in the absence of BCR engagement. These findings reveal that stage-specific redox responses distinguish human GC B cells.
Copyright © 2015 by The American Association of Immunologists, Inc.
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14 MeSH Terms
Bruton's Tyrosine Kinase Synergizes with Notch2 To Govern Marginal Zone B Cells in Nonobese Diabetic Mice.
Case JB, Bonami RH, Nyhoff LE, Steinberg HE, Sullivan AM, Kendall PL
(2015) J Immunol 195: 61-70
MeSH Terms: Agammaglobulinaemia Tyrosine Kinase, Animals, Autoantibodies, Autoimmunity, B-Lymphocyte Subsets, Cell Differentiation, Cell Survival, Diabetes Mellitus, Experimental, Female, Gene Expression Regulation, Immunoglobulin Heavy Chains, Insulin, Male, Mice, Mice, Inbred C57BL, Mice, Inbred NOD, Protein-Tyrosine Kinases, Receptor, Notch2, Receptors, Antigen, B-Cell, Signal Transduction
Show Abstract · Added December 4, 2015
Expansion of autoimmune-prone marginal zone (MZ) B cells has been implicated in type 1 diabetes. To test disease contributions of MZ B cells in NOD mice, Notch2 haploinsufficiency (Notch2(+/-)) was introduced but failed to eliminate the MZ, as it does in C57BL/6 mice. Notch2(+/-)/NOD have MZ B cell numbers similar to those of wild-type C57BL/6, yet still develop diabetes. To test whether BCR signaling supports Notch2(+/-)/NOD MZ B cells, Bruton's tyrosine kinase (Btk) deficiency was introduced. Surprisingly, MZ B cells failed to develop in Btk-deficient Notch2(+/-)/NOD mice. Expression of Notch2 and its transcriptional target, Hes5, was increased in NOD MZ B cells compared with C57BL/6 MZ B cells. Btk deficiency reduced Notch2(+/-) signaling exclusively in NOD B cells, suggesting that BCR signaling enhances Notch2 signaling in this autoimmune model. The role of BCR signaling was further investigated using an anti-insulin transgenic (Tg) BCR (125Tg). Anti-insulin B cells in 125Tg/Notch2(+/-)/NOD mice populate an enlarged MZ, suggesting that low-level BCR signaling overcomes reliance on Notch2. Tracking clonotypes of anti-insulin B cells in H chain-only VH125Tg/NOD mice showed that BTK-dependent selection into the MZ depends on strength of antigenic binding, whereas Notch2-mediated selection does not. Importantly, anti-insulin B cell numbers were reduced by Btk deficiency, but not Notch2 haploinsufficiency. These studies show that 1) Notch2 haploinsufficiency limits NOD MZ B cell expansion without preventing type 1 diabetes, 2) BTK supports the Notch2 pathway in NOD MZ B cells, and 3) autoreactive NOD B cell survival relies on BTK more than Notch2, regardless of MZ location, which may have important implications for disease-intervention strategies.
Copyright © 2015 by The American Association of Immunologists, Inc.
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20 MeSH Terms
CXCR4 and a cell-extrinsic mechanism control immature B lymphocyte egress from bone marrow.
Beck TC, Gomes AC, Cyster JG, Pereira JP
(2014) J Exp Med 211: 2567-81
MeSH Terms: Animals, B-Lymphocytes, Bone Marrow Cells, Cell Differentiation, Cell Lineage, Cell Movement, Cell Shape, Down-Regulation, Integrin alpha4beta1, Mice, Inbred C57BL, Receptors, Antigen, B-Cell, Receptors, CXCR4, Signal Transduction, Vascular Cell Adhesion Molecule-1
Show Abstract · Added January 11, 2016
Leukocyte residence in lymphoid organs is controlled by a balance between retention and egress-promoting chemoattractants sensed by pertussis toxin (PTX)-sensitive Gαi protein-coupled receptors (GPCRs). Here, we use two-photon intravital microscopy to show that immature B cell retention within bone marrow (BM) was strictly dependent on amoeboid motility mediated by CXCR4 and CXCL12 and by α4β1 integrin-mediated adhesion to VCAM-1. However, B lineage cell egress from BM is independent of PTX-sensitive GPCR signaling. B lineage cells expressing PTX rapidly exited BM even though their motility within BM parenchyma was significantly reduced. Our experiments reveal that when immature B cells are near BM sinusoids their motility is reduced, their morphology is predominantly rounded, and cells reverse transmigrate across sinusoidal endothelium in a largely nonamoeboid manner. Immature B cell egress from BM was dependent on a twofold CXCR4 down-regulation that was antagonized by antigen-induced BCR signaling. This passive mode of cell egress from BM also contributes significantly to the export of other hematopoietic cells, including granulocytes, monocytes, and NK cells, and is reminiscent of erythrocyte egress.
© 2014 Beck et al.
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14 MeSH Terms
Gene-wide analysis detects two new susceptibility genes for Alzheimer's disease.
Escott-Price V, Bellenguez C, Wang LS, Choi SH, Harold D, Jones L, Holmans P, Gerrish A, Vedernikov A, Richards A, DeStefano AL, Lambert JC, Ibrahim-Verbaas CA, Naj AC, Sims R, Jun G, Bis JC, Beecham GW, Grenier-Boley B, Russo G, Thornton-Wells TA, Denning N, Smith AV, Chouraki V, Thomas C, Ikram MA, Zelenika D, Vardarajan BN, Kamatani Y, Lin CF, Schmidt H, Kunkle B, Dunstan ML, Vronskaya M, United Kingdom Brain Expression Consortium, Johnson AD, Ruiz A, Bihoreau MT, Reitz C, Pasquier F, Hollingworth P, Hanon O, Fitzpatrick AL, Buxbaum JD, Campion D, Crane PK, Baldwin C, Becker T, Gudnason V, Cruchaga C, Craig D, Amin N, Berr C, Lopez OL, De Jager PL, Deramecourt V, Johnston JA, Evans D, Lovestone S, Letenneur L, Hernández I, Rubinsztein DC, Eiriksdottir G, Sleegers K, Goate AM, Fiévet N, Huentelman MJ, Gill M, Brown K, Kamboh MI, Keller L, Barberger-Gateau P, McGuinness B, Larson EB, Myers AJ, Dufouil C, Todd S, Wallon D, Love S, Rogaeva E, Gallacher J, George-Hyslop PS, Clarimon J, Lleo A, Bayer A, Tsuang DW, Yu L, Tsolaki M, Bossù P, Spalletta G, Proitsi P, Collinge J, Sorbi S, Garcia FS, Fox NC, Hardy J, Naranjo MC, Bosco P, Clarke R, Brayne C, Galimberti D, Scarpini E, Bonuccelli U, Mancuso M, Siciliano G, Moebus S, Mecocci P, Zompo MD, Maier W, Hampel H, Pilotto A, Frank-García A, Panza F, Solfrizzi V, Caffarra P, Nacmias B, Perry W, Mayhaus M, Lannfelt L, Hakonarson H, Pichler S, Carrasquillo MM, Ingelsson M, Beekly D, Alvarez V, Zou F, Valladares O, Younkin SG, Coto E, Hamilton-Nelson KL, Gu W, Razquin C, Pastor P, Mateo I, Owen MJ, Faber KM, Jonsson PV, Combarros O, O'Donovan MC, Cantwell LB, Soininen H, Blacker D, Mead S, Mosley TH, Bennett DA, Harris TB, Fratiglioni L, Holmes C, de Bruijn RF, Passmore P, Montine TJ, Bettens K, Rotter JI, Brice A, Morgan K, Foroud TM, Kukull WA, Hannequin D, Powell JF, Nalls MA, Ritchie K, Lunetta KL, Kauwe JS, Boerwinkle E, Riemenschneider M, Boada M, Hiltunen M, Martin ER, Schmidt R, Rujescu D, Dartigues JF, Mayeux R, Tzourio C, Hofman A, Nöthen MM, Graff C, Psaty BM, Haines JL, Lathrop M, Pericak-Vance MA, Launer LJ, Van Broeckhoven C, Farrer LA, van Duijn CM, Ramirez A, Seshadri S, Schellenberg GD, Amouyel P, Williams J, Cardiovascular Health Study (CHS)
(2014) PLoS One 9: e94661
MeSH Terms: Alzheimer Disease, Carrier Proteins, Case-Control Studies, Genome-Wide Association Study, Heat-Shock Proteins, Humans, Polymorphism, Single Nucleotide, Receptors, Antigen, B-Cell
Show Abstract · Added December 10, 2014
BACKGROUND - Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls.
PRINCIPAL FINDINGS - In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10-6) and 14 (IGHV1-67 p = 7.9×10-8) which indexed novel susceptibility loci.
SIGNIFICANCE - The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.
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8 MeSH Terms