Vai ai contenuti. | Spostati sulla navigazione | Spostati sulla ricerca | Vai al menu | Contatti | Accessibilità

| Crea un account

Bonoli, Laura (2015) Profiling the molecular mechanisms driving the fate of human B cells in response to vaccination. [Tesi di dottorato]

Full text disponibile come:

[img]
Anteprima
Documento PDF
4Mb

Abstract (inglese)

Antigen (Ag) encounter activates B cells to proliferate and mature through the formation of germinal centers. Here somatic hypermutation of the variable regions and Immunolgobulin (Ig) isotype switching lead the high affinity Ag-specific clones to two possible differentiation outcomes: antibody (Ab) secreting plasmablasts (PB) or quiescent memory B cells (MBC). The molecular mechanism that drives the fate of a human B cell to differentiate into PB or MBC is poorly understood. Recent studies have provided new insights into the transcriptional program responsible for B cell maturation in mice or human bulk populations. The limited availability of samples and the difficulties in isolating Ag-specific MBCs from peripheral blood make this analysis particularly challenging in humans. We collected samples from human donors that received the seasonal influenza vaccine; those were processed and sorted immediately after the bleed at two different time points: day 8 and day 22 post vaccination, namely the peaks of PBs and MBCs response respectively. The blood samples were used to collect PBs, Ag-specific MBCs and naive B cells (NAIVE) by flow cytometry sorting, exploiting classical surface markers strategies. A new protocol was set up to allow qPCR analysis of multiple genes from sorted single human B cells. This protocol was first used in a pilot study on cells sorted from a first vaccinee, to perform gene expression profiling of 21 relevant genes that allowed us to discriminate the three different B cell populations. Then we up-scaled and optimized the protocol taking advantage of the 96.96 Fluidigm Dynamic Array technology, which enables to perform RT-qPCR for 96 single cells against 96 target genes in one single reaction. This new high-throughput approach was then applied to 240 single cells belonging to Ag-specific MBCs, PBs and NAIVE B cells (80 each) of a second vaccinee, to perform gene expression profiling of 96 genes involved in several pathways of B cell differentiation. By performing unsupervised hierarchical clustering on all the cells, we observed that NAIVE, PBs and MBCs clustered separately and it was possible to identify signatures of gene expression characterizing the three populations. Linear Discriminant Analysis, a dimensionality-reduction analysis, shows that PBs are particularly different from MBCs and NAIVE, that instead share more similarities. By performing statistical analysis we identified the significant differentially expressed genes, which include genes involved in known B cell expression networks and, interestingly, also novel observations (FOXP1, POU2AF1, IRF2). We then compared the gene expression profile of Ag-specific MBCs with MBCs isolated from a healthy donor, to investigate possible differences in the expression patterns of recently activated MBCs and steady-state MBCs. With this analysis we identified 16 genes with a significant differential expression level, denoting a more active profile for the recently activated MBCs isolated from the vaccinee. To further investigate the heterogeneity of Ag-specific MBCs we also recovered immunoglobulin VH sequences from the same cells by sequencing the specific PCR products. Correlation studies showed only weak association between B cell receptor (BCR) maturation (in terms of VH mutation rate) and gene expression data. Conversely, significant association was found between the expression of two genes and the Ig isotype. In particular RORα is associated with IgA, while TBX21 with IgG, in accordance to previous studies performed on mouse bulk B cell populations. The genes identified with this study could be further investigated as they represent potential markers of B cell response to human vaccination.

Abstract (italiano)

Nell’ambito del processo di attivazione dovuto all’interazione con l’antigene (Ag), le cellule B proliferano e iniziano un processo di maturazione terminale attraverso la formazione dei centri germinativi (GC). All’interno dei GC, a seguito dell’ipermutazione somatica delle regioni variabili del recettore delle cellule B (BCR) ed il cambiamento di isotipo delle immunoglobuline, i cloni che hanno raggiunto alta affinità per l’Ag possono andare incontro a due possibili destini: differenziamento in plasmablasti (PB) che secernono anticorpi (Ab) o in cellule B della memoria quiescenti (MBC). Il meccanismo molecolare che determina il destino delle cellule B umane durante il differenziamento tardivo in PB o MBC è poco conosciuto. Studi recenti hanno rivelato nuovi aspetti del programma trascrizionale responsabile della maturazione di cellule B in topo o in popolazioni di cellule umane, ma la disponibilità limitata di campioni e la difficoltà nell'isolamento di MBC Ag-specifiche da sangue periferico hanno reso l’analisi di questi tipi cellulari particolarmente complicata. Per questo sono stati raccolti campioni di sangue da donatori sottoposti a vaccinazione stagionale contro l’influenza. Questi campioni sono stati processati immediatamente dopo il prelievo, effettuato in corrispondenza di due particolari momenti: 8 e 22 giorni dopo la vaccinazione, rispettivamente picchi della risposta mediata da PB e da MBC . I campioni di sangue periferico sono stati usati per l’isolamento di PB, NAIVE e MBC Ag-specifiche sfruttando marcatori di superficie. Per l’analisi del profilo di espressione genica è stato ottimizzato un metodo che permette di effettuare qPCR di numerosi geni in cellule B umane isolate come singola cellula. Tale approccio è stato usato inizialmente per uno studio pilota dell’espressione di 21 geni di interesse su cellule isolate da un primo soggetto, permettendoci di discriminare cellule appartenenti alle tre diverse popolazioni. Successivamente questo protocollo è stato ottimizzato sfruttando la tecnologia del 96.96 Dynamic Array prodotto da Fluidigm, sistema che permette di effettuare RT-qPCR su 96 singole cellule per 96 geni in una singola reazione. Con questo metodo ad alta resa abbiamo analizzato 240 singole cellule appartenenti alle popolazioni di MBC Ag-specifiche, PB e NAIVE (80 cellule ciascuna) di un secondo soggetto, permettendoci di analizzare il profilo di espressione di 96 geni coinvolti nelle vie di differenziamento delle cellule B. Attraverso un’analisi statistica di raggruppamento gerarchico dei dati di espressione appartenenti a tutti i campioni processati, abbiamo riunito sotto tre gruppi diversi per espressione genica le cellule appartenenti alle tre diverse popolazioni e abbiamo identificato i geni che le caratterizzano. La Linear Discriminant Analysis, una tecnica di riduzione dimensionale supervisionata, sottolinea come i PB siano particolarmente differenti da MBC Ag-specifiche e NAIVE, che invece condividono un profilo più simile. Sfruttando diversi metodi di analisi statistica, sono stati identificati i geni significativamente espressi in maniera diversa tra le tre popolazioni. Così facendo sono stati individuati sia geni il cui ruolo nella maturazione delle cellule B è noto, sia geni conosciuti principalmente per la loro funzione in altri processi o altre fasi dello sviluppo di queste cellule (FOXP1, POU2AF1, IRF2). Inoltre abbiamo confrontato i profili di espressione delle MBC Ag-specifiche con MBC isolate da un donatore sano non vaccinato, per identificare possibili differenze nei profili di espressione di MBC recentemente attivate e MBC circolanti, lontane dall'attivazione Ag-specifica. Tale analisi ha identificato 16 geni espressi differentemente in maniera significativa, evidenziando un profilo di espressione che denota uno stato di attivazione per le MBC recentemente contattate dall'Ag. Per studiare ulteriormente l’eterogeneità delle MBC Ag-specifiche, tramite PCR abbiamo amplificato e sequenziato le regioni variabili delle catene pesanti (VH) delle immunoglobuline espresse dalle stesse cellule, ma gli studi di correlazione mostrano solo deboli associazioni tra maturazione del BCR (in termini di tasso di mutazione delle VH) e dati di espressione genica. Al contrario, è stata individuata associazione significativa tra la selezione dell'isotipo del BCR e l’espressione di due geni, in particolare l’espressione di RORα è associata alla classe IgA, mentre TBX21 all’IgG, in accordo con studi precedenti effettuati in popolazioni di cellule B murine. In conclusione, i geni identificati da questo studio come discriminanti delle MBC recentemente attivate dall'Ag potrebbero essere ulteriormente studiati in qualità di potenziali marker della risposta B alla vaccinazione in uomo.

Statistiche Download - Aggiungi a RefWorks
Tipo di EPrint:Tesi di dottorato
Relatore:Montecucco, Cesare
Dottorato (corsi e scuole):Ciclo 28 > Scuole 28 > BIOSCIENZE E BIOTECNOLOGIE > BIOLOGIA CELLULARE
Data di deposito della tesi:27 Gennaio 2016
Anno di Pubblicazione:27 Gennaio 2015
Parole chiave (italiano / inglese):B cells differentiation, gene expression profile, differenziamento cellule B, human, uomo
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/13 Biologia applicata
Area 05 - Scienze biologiche > BIO/11 Biologia molecolare
Struttura di riferimento:Dipartimenti > Dipartimento di Biologia
Codice ID:9214
Depositato il:24 Ott 2016 14:51
Simple Metadata
Full Metadata
EndNote Format

Bibliografia

I riferimenti della bibliografia possono essere cercati con Cerca la citazione di AIRE, copiando il titolo dell'articolo (o del libro) e la rivista (se presente) nei campi appositi di "Cerca la Citazione di AIRE".
Le url contenute in alcuni riferimenti sono raggiungibili cliccando sul link alla fine della citazione (Vai!) e tramite Google (Ricerca con Google). Il risultato dipende dalla formattazione della citazione.

[1] Kondo M. Lymphoid and myeloid lineage commitment in multipotent hematopoietic progenitors. Immunol Rev 2010;238:37–46. doi:10.1111/j.1600-065X.2010.00963.x. Cerca con Google

[2] Pelanda R, Torres RM. Central B-cell tolerance: where selection begins. Cold Spring Harb Perspect Biol 2012;4:a007146. doi:10.1101/cshperspect.a007146. Cerca con Google

[3] Mårtensson I-L, Almqvist N, Grimsholm O, Bernardi AI. The pre-B cell receptor checkpoint. FEBS Lett 2010;584:2572–9. doi:10.1016/j.febslet.2010.04.057. Cerca con Google

[4] LeBien TW, Tedder TF. B lymphocytes: how they develop and function. Blood 2008;112:1570–80. doi:10.1182/blood-2008-02-078071. Cerca con Google

[5] Loder BF, Mutschler B, Ray RJ, Paige CJ, Sideras P, Torres R, et al. B Cell Development in the Spleen Takes Place in Discrete Steps and Is Determined by the Quality of B Cell Receptor-Derived Signals. J Exp Med 1999;190:75–90. doi:10.1084/jem.190.1.75. Cerca con Google

[6] Chung JB, Silverman M, Monroe JG. Transitional B cells: step by step towards immune competence. Trends Immunol 2003;24:342–8. doi:10.1016/S1471-4906(03)00119-4. Cerca con Google

[7] Cerutti A, Cols M, Puga I. Marginal zone B cells: virtues of innate-like antibody-producing lymphocytes. Nat Rev Immunol 2013;13:118–32. doi:10.1038/nri3383. Cerca con Google

[8] De Silva NS, Klein U. Dynamics of B cells in germinal centres. Nat Rev Immunol 2015;15:137–48. doi:10.1038/nri3804. Cerca con Google

[9] Heesters BA, Myers RC, Carroll MC. Follicular dendritic cells: dynamic antigen libraries. Nat Rev Immunol 2014;14:495–504. doi:10.1038/nri3689. Cerca con Google

[10] Willard-Mack C. Normal Structure, Function, and Histology of Lymph Nodes. Toxicol Pathol 2006;34:409–24. doi:10.1080/01926230600867727. Cerca con Google

[11] Pereira JP, Kelly LM, Cyster JG. Finding the right niche: B-cell migration in the early phases of T-dependent antibody responses. Int Immunol 2010;22:413–9. doi:10.1093/intimm/dxq047. Cerca con Google

[12] Link A, Vogt TK, Favre S, Britschgi MR, Acha-Orbea H, Hinz B, et al. Fibroblastic reticular cells in lymph nodes regulate the homeostasis of naive T cells. Nat Immunol 2007;8:1255–65. doi:10.1038/ni1513. Cerca con Google

[13] Crawford A, Macleod M, Schumacher T, Corlett L, Gray D. Primary T cell expansion and differentiation in vivo requires antigen presentation by B cells. J Immunol 2006;176:3498–506. Cerca con Google

[14] Reif K, Ekland EH, Ohl L, Nakano H, Lipp M, Förster R, et al. Balanced responsiveness to chemoattractants from adjacent zones determines B-cell position. Nature 2002;416:94–9. doi:10.1038/416094a. Cerca con Google

[15] Chevrier S, Emslie D, Shi W, Kratina T, Wellard C, Karnowski A, et al. The BTB-ZF transcription factor Zbtb20 is driven by Irf4 to promote plasma cell differentiation and longevity. J Exp Med 2014;211:827–40. doi:10.1084/jem.20131831. Cerca con Google

[16] Ansel KM, McHeyzer-Williams LJ, Ngo VN, McHeyzer-Williams MG, Cyster JG. In vivo-activated CD4 T cells upregulate CXC chemokine receptor 5 and reprogram their response to lymphoid chemokines. J Exp Med 1999;190:1123–34. Cerca con Google

[17] Hardtke S, Ohl L, Förster R. Balanced expression of CXCR5 and CCR7 on follicular T helper cells determines their transient positioning to lymph node follicles and is essential for efficient B-cell help. Blood 2005;106:1924–31. doi:10.1182/blood-2004-11-4494. Cerca con Google

[18] Qi H, Cannons JL, Klauschen F, Schwartzberg PL, Germain RN. SAP-controlled T-B cell interactions underlie germinal centre formation. Nature 2008;455:764–9. doi:10.1038/nature07345. Cerca con Google

[19] Kerfoot SM, Yaari G, Patel JR, Johnson KL, Gonzalez DG, Kleinstein SH, et al. Germinal center B cell and T follicular helper cell development initiates in the interfollicular zone. Immunity 2011;34:947–60. doi:10.1016/j.immuni.2011.03.024. Cerca con Google

[20] Jacob J, Kelsoe G. In situ studies of the primary immune response to (4-hydroxy-3-nitrophenyl)acetyl. II. A common clonal origin for periarteriolar lymphoid sheath-associated foci and germinal centers. J Exp Med 1992;176:679–87. Cerca con Google

[21] Kitano M, Moriyama S, Ando Y, Hikida M, Mori Y, Kurosaki T, et al. Bcl6 Protein Expression Shapes Pre-Germinal Center B Cell Dynamics and Follicular Helper T Cell Heterogeneity. Immunity 2011;34:961–72. doi:10.1016/j.immuni.2011.03.025. Cerca con Google

[22] Mueller SN, Germain RN. Stromal cell contributions to the homeostasis and functionality of the immune system. Nat Rev Immunol 2009;9:618–29. doi:10.1038/nri2588. Cerca con Google

[23] Allen CDC, Ansel KM, Low C, Lesley R, Tamamura H, Fujii N, et al. Germinal center dark and light zone organization is mediated by CXCR4 and CXCR5. Nat Immunol 2004;5:943–52. doi:10.1038/ni1100. Cerca con Google

[24] Tarlinton DM, Smith KG. Dissecting affinity maturation: a model explaining selection of antibody-forming cells and memory B cells in the germinal centre. Immunol Today 2000;21:436–41. Cerca con Google

[25] Tarlinton DM. Evolution in miniature: selection, survival and distribution of antigen reactive cells in the germinal centre. Immunol Cell Biol 2008;86:133–8. doi:10.1038/sj.icb.7100148. Cerca con Google

[26] Victora GD, Mesin L. Clonal and cellular dynamics in germinal centers. Curr Opin Immunol 2014;28:90–6. doi:10.1016/j.coi.2014.02.010. Cerca con Google

[27] Vikstrom I, Tarlinton DM. B cell memory and the role of apoptosis in its formation. Mol Immunol 2011;48:1301–6. doi:10.1016/j.molimm.2010.10.026. Cerca con Google

[28] Peron S, Laffleur B, Denis-Lagache N, Cook-Moreau J, Tinguely A, Delpy L, et al. AID-Driven Deletion Causes Immunoglobulin Heavy Chain Locus Suicide Recombination in B Cells. Science (80- ) 2012;336:931–4. doi:10.1126/science.1218692. Cerca con Google

[29] Schwickert TA, Lindquist RL, Shakhar G, Livshits G, Skokos D, Kosco-Vilbois MH, et al. In vivo imaging of germinal centres reveals a dynamic open structure. Nature 2007;446:83–7. doi:10.1038/nature05573. Cerca con Google

[30] Nutt SL, Hodgkin PD, Tarlinton DM, Corcoran LM. The generation of antibody-secreting plasma cells. Nat Rev Immunol 2015;15:160–71. doi:10.1038/nri3795. Cerca con Google

[31] McHeyzer-Williams M, Okitsu S, Wang N, McHeyzer-Williams L. Molecular programming of B cell memory. Nat Rev Immunol 2012;12:24–34. doi:10.1038/nri3128. Cerca con Google

[32] Revilla-i-domingo R, Bilic I, Vilagos B, Tagoh H, Ebert A, Tamir IM, et al. The B-cell identity factor Pax5 regulates distinct transcriptional programmes in early and late B lymphopoiesis. EMBO J 2012;31:3130–46. doi:10.1038/emboj.2012.155. Cerca con Google

[33] Nutt SL, Urbánek P, Rolink A, Busslinger M. Essential functions of Pax5 (BSAP) in pro-B cell development: difference between fetal and adult B lymphopoiesis and reduced V-to-DJ recombination at the IgH locus. Genes Dev 1997;11:476–91. Cerca con Google

[34] Horcher M, Souabni A, Busslinger M. Pax5/BSAP maintains the identity of B cells in late B lymphopoiesis. Immunity 2001;14:779–90. Cerca con Google

[35] Fuxa M, Skok J, Souabni A, Salvagiotto G, Roldan E, Busslinger M. Pax5 induces V-to-DJ rearrangements and locus contraction of the immunoglobulin heavy-chain gene. Genes Dev 2004;18:411–22. doi:10.1101/gad.291504. Cerca con Google

[36] Hsu L-Y. Pax5 Activates Immunoglobulin Heavy Chain V to DJ Rearrangement in Transgenic Thymocytes. J Exp Med 2004;199:825–30. doi:10.1084/jem.20032249. Cerca con Google

[37] Delogu A, Schebesta A, Sun Q, Aschenbrenner K, Perlot T, Busslinger M. Gene repression by Pax5 in B cells is essential for blood cell homeostasis and is reversed in plasma cells. Immunity 2006;24:269–81. doi:10.1016/j.immuni.2006.01.012. Cerca con Google

[38] Lin K-I, Angelin-Duclos C, Kuo TC, Calame K. Blimp-1-dependent repression of Pax-5 is required for differentiation of B cells to immunoglobulin M-secreting plasma cells. Mol Cell Biol 2002;22:4771–80. Cerca con Google

[39] Nera K-P, Kohonen P, Narvi E, Peippo A, Mustonen L, Terho P, et al. Loss of Pax5 promotes plasma cell differentiation. Immunity 2006;24:283–93. doi:10.1016/j.immuni.2006.02.003. Cerca con Google

[40] Yasuda T, Hayakawa F, Kurahashi S, Sugimoto K, Minami Y, Tomita A, et al. B cell receptor-ERK1/2 signal cancels PAX5-dependent repression of BLIMP1 through PAX5 phosphorylation: a mechanism of antigen-triggering plasma cell differentiation. J Immunol 2012;188:6127–34. doi:10.4049/jimmunol.1103039. Cerca con Google

[41] Basso K, Schneider C, Shen Q, Holmes AB, Setty M, Leslie C, et al. BCL6 positively regulates AID and germinal center gene expression via repression of miR-155. J Exp Med 2012;209:2455–65. doi:10.1084/jem.20121387. Cerca con Google

[42] Baumjohann D, Okada T, Ansel KM. Cutting Edge: Distinct Waves of BCL6 Expression during T Follicular Helper Cell Development. J Immunol 2011;187:2089–92. doi:10.4049/jimmunol.1101393. Cerca con Google

[43] Basso K, Saito M, Sumazin P, Margolin AA, Wang K, Lim W-K, et al. Integrated biochemical and computational approach identifies BCL6 direct target genes controlling multiple pathways in normal germinal center B cells. Blood 2010;115:975–84. doi:10.1182/blood-2009-06-227017. Cerca con Google

[44] Huang C, Geng H, Boss I, Wang L, Melnick A. Cooperative transcriptional repression by BCL6 and BACH2 in germinal center B-cell differentiation. Blood 2014;123:1012–20. doi:10.1182/blood-2013-07-518605. Cerca con Google

[45] Tunyaplin C, Shaffer AL, Angelin-Duclos CD, Yu X, Staudt LM, Calame KL. Direct repression of prdm1 by Bcl-6 inhibits plasmacytic differentiation. J Immunol 2004;173:1158–65. Cerca con Google

[46] Angelin-Duclos C, Cattoretti G, Lin KI, Calame K. Commitment of B lymphocytes to a plasma cell fate is associated with Blimp-1 expression in vivo. J Immunol 2000;165:5462–71. Cerca con Google

[47] Kallies A, Hasbold J, Tarlinton DM, Dietrich W, Corcoran LM, Hodgkin PD, et al. Plasma cell ontogeny defined by quantitative changes in blimp-1 expression. J Exp Med 2004;200:967–77. doi:10.1084/jem.20040973. Cerca con Google

[48] Shaffer AL, Lin KI, Kuo TC, Yu X, Hurt EM, Rosenwald A, et al. Blimp-1 orchestrates plasma cell differentiation by extinguishing the mature B cell gene expression program. Immunity 2002;17:51–62. Cerca con Google

[49] Shaffer AL, Shapiro-Shelef M, Iwakoshi NN, Lee A-H, Qian S-B, Zhao H, et al. XBP1, downstream of Blimp-1, expands the secretory apparatus and other organelles, and increases protein synthesis in plasma cell differentiation. Immunity 2004;21:81–93. doi:10.1016/j.immuni.2004.06.010. Cerca con Google

[50] Kallies A, Hasbold J, Fairfax K, Pridans C, Emslie D, McKenzie BS, et al. Initiation of Plasma-Cell Differentiation Is Independent of the Transcription Factor Blimp-1. Immunity 2007;26:555–66. doi:10.1016/j.immuni.2007.04.007. Cerca con Google

[51] Todd DJ, McHeyzer-Williams LJ, Kowal C, Lee A-H, Volpe BT, Diamond B, et al. XBP1 governs late events in plasma cell differentiation and is not required for antigen-specific memory B cell development. J Exp Med 2009;206:2151–9. doi:10.1084/jem.20090738. Cerca con Google

[52] Taubenheim N, Tarlinton DM, Crawford S, Corcoran LM, Hodgkin PD, Nutt SL. High rate of antibody secretion is not integral to plasma cell differentiation as revealed by XBP-1 deficiency. J Immunol 2012;189:3328–38. doi:10.4049/jimmunol.1201042. Cerca con Google

[53] Benhamron S, Pattanayak SP, Berger M, Tirosh B. mTOR Activation Promotes Plasma Cell Differentiation and Bypasses XBP-1 for Immunoglobulin Secretion. Mol Cell Biol 2015;35:153–66. doi:10.1128/MCB.01187-14. Cerca con Google

[54] Pengo N, Scolari M, Oliva L, Milan E, Mainoldi F, Raimondi A, et al. Plasma cells require autophagy for sustainable immunoglobulin production. Nat Immunol 2013;14:298–305. doi:10.1038/ni.2524. Cerca con Google

[55] Manz RA, Thiel A, Radbruch A. Lifetime of plasma cells in the bone marrow. Nature 1997;388:133–4. doi:10.1038/40540. Cerca con Google

[56] Halliley JL, Tipton CM, Liesveld J, Rosenberg AF, Darce J, Gregoretti I V, et al. Long-Lived Plasma Cells Are Contained within the CD19(-)CD38(hi)CD138(+) Subset in Human Bone Marrow. Immunity 2015;43:132–45. doi:10.1016/j.immuni.2015.06.016. Cerca con Google

[57] Tooze RM. A Replicative Self-Renewal Model for Long-Lived Plasma Cells: Questioning Irreversible Cell Cycle Exit. Front Immunol 2013;4:460. doi:10.3389/fimmu.2013.00460. Cerca con Google

[58] Lu R. IRF-4,8 orchestrate the pre-B-to-B transition in lymphocyte development. Genes Dev 2003;17:1703–8. doi:10.1101/gad.1104803. Cerca con Google

[59] Rao S, Matsumura A, Yoon J, Simon MC. SPI-B activates transcription via a unique proline, serine, and threonine domain and exhibits DNA binding affinity differences from PU.1. J Biol Chem 1999;274:11115–24. Cerca con Google

[60] Klein U, Casola S, Cattoretti G, Shen Q, Lia M, Mo T, et al. Transcription factor IRF4 controls plasma cell differentiation and class-switch recombination. Nat Immunol 2006;7:773–82. doi:10.1038/ni1357. Cerca con Google

[61] Sciammas R, Shaffer AL, Schatz JH, Zhao H, Staudt LM, Singh H. Graded Expression of Interferon Regulatory Factor-4 Coordinates Isotype Switching with Plasma Cell Differentiation. Immunity 2006;25:225–36. doi:10.1016/j.immuni.2006.07.009. Cerca con Google

[62] Ise W, Kohyama M, Schraml BU, Zhang T, Schwer B, Basu U, et al. The transcription factor BATF controls the global regulators of class-switch recombination in both B cells and T cells. Nat Immunol 2011;12:536–43. doi:10.1038/ni.2037. Cerca con Google

[63] Ochiai K, Maienschein-Cline M, Simonetti G, Chen J, Rosenthal R, Brink R, et al. Transcriptional regulation of germinal center B and plasma cell fates by dynamical control of IRF4. Immunity 2013;38:918–29. doi:10.1016/j.immuni.2013.04.009. Cerca con Google

[64] Matsuyama T, Grossman A, Mittrücker HW, Siderovski DP, Kiefer F, Kawakami T, et al. Molecular cloning of LSIRF, a lymphoid-specific member of the interferon regulatory factor family that binds the interferon-stimulated response element (ISRE). Nucleic Acids Res 1995;23:2127–36. Cerca con Google

[65] Willis SN, Good-Jacobson KL, Curtis J, Light A, Tellier J, Shi W, et al. Transcription Factor IRF4 Regulates Germinal Center Cell Formation through a B Cell-Intrinsic Mechanism. J Immunol 2014;192:3200–6. doi:10.4049/jimmunol.1303216. Cerca con Google

[66] Sciammas R, Li Y, Warmflash A, Song Y, Dinner AR, Singh H. An incoherent regulatory network architecture that orchestrates B cell diversification in response to antigen signaling. Mol Syst Biol 2011;7:495. doi:10.1038/msb.2011.25. Cerca con Google

[67] Saito M, Gao J, Basso K, Kitagawa Y, Smith PM, Bhagat G, et al. A Signaling Pathway Mediating Downregulation of BCL6 in Germinal Center B Cells Is Blocked by BCL6 Gene Alterations in B Cell Lymphoma. Cancer Cell 2007;12:280–92. doi:10.1016/j.ccr.2007.08.011. Cerca con Google

[68] Lee CH, Melchers M, Wang H, Torrey TA, Slota R, Qi C-F, et al. Regulation of the germinal center gene program by interferon (IFN) regulatory factor 8/IFN consensus sequence-binding protein. J Exp Med 2006;203:63–72. doi:10.1084/jem.20051450. Cerca con Google

[69] Cattoretti G, Shaknovich R, Smith PM, Jäck H-M, Murty V V, Alobeid B. Stages of germinal center transit are defined by B cell transcription factor coexpression and relative abundance. J Immunol 2006;177:6930–9. Cerca con Google

[70] Feng J, Wang H, Shin D-M, Masiuk M, Qi C-F, Morse HC. IFN regulatory factor 8 restricts the size of the marginal zone and follicular B cell pools. J Immunol 2011;186:1458–66. doi:10.4049/jimmunol.1001950. Cerca con Google

[71] Klein U, Tu Y, Stolovitzky GA, Keller JL, Haddad J, Miljkovic V, et al. Transcriptional analysis of the B cell germinal center reaction. Proc Natl Acad Sci U S A 2003;100:2639–44. doi:10.1073/pnas.0437996100. Cerca con Google

[72] Vikstrom I, Carotta S, Lüthje K, Peperzak V, Jost PJ, Glaser S, et al. Mcl-1 is essential for germinal center formation and B cell memory. Science 2010;330:1095–9. doi:10.1126/science.1191793. Cerca con Google

[73] Schuetz JM, Johnson NA, Morin RD, Scott DW, Tan K, Ben-Nierah S, et al. BCL2 mutations in diffuse large B-cell lymphoma. Leukemia 2012;26:1383–90. doi:10.1038/leu.2011.378. Cerca con Google

[74] Hasbold J, Corcoran LM, Tarlinton DM, Tangye SG, Hodgkin PD. Evidence from the generation of immunoglobulin G–secreting cells that stochastic mechanisms regulate lymphocyte differentiation. Nat Immunol 2003;5:55–63. doi:10.1038/ni1016. Cerca con Google

[75] Tangye SG, Avery DT, Hodgkin PD. A division-linked mechanism for the rapid generation of Ig-secreting cells from human memory B cells. J Immunol 2003;170:261–9. Cerca con Google

[76] Taylor JJ, Pape KA, Steach HR, Jenkins MK. Apoptosis and antigen affinity limit effector cell differentiation of a single naïve B cell 2015;347:11214–8. Cerca con Google

[77] Takemori T, Kaji T, Takahashi Y, Shimoda M, Rajewsky K. Generation of memory B cells inside and outside germinal centers. Eur J Immunol 2014;44:1258–64. doi:10.1002/eji.201343716. Cerca con Google

[78] Allen CDC, Okada T, Tang HL, Cyster JG. Imaging of germinal center selection events during affinity maturation. Science 2007;315:528–31. doi:10.1126/science.1136736. Cerca con Google

[79] Taylor JJ, Pape KA, Jenkins MK. A germinal center-independent pathway generates unswitched memory B cells early in the primary response. J Exp Med 2012;209:597–606. doi:10.1084/jem.20111696. Cerca con Google

[80] Linterman MA, Beaton L, Yu D, Ramiscal RR, Srivastava M, Hogan JJ, et al. IL-21 acts directly on B cells to regulate Bcl-6 expression and germinal center responses. J Exp Med 2010;207:353–63. doi:10.1084/jem.20091738. Cerca con Google

[81] Dent AL, Shaffer AL, Yu X, Allman D, Staudt LM. Control of inflammation, cytokine expression, and germinal center formation by BCL-6. Science 1997;276:589–92. Cerca con Google

[82] Fischer SF, Bouillet P, O’Donnell K, Light A, Tarlinton DM, Strasser A. Proapoptotic BH3-only protein Bim is essential for developmentally programmed death of germinal center-derived memory B cells and antibody-forming cells. Blood 2007;110:3978–84. doi:10.1182/blood-2007-05-091306. Cerca con Google

[83] Jacob J, Kelsoe G, Rajewsky K, Weiss U. Intraclonal generation of antibody mutants in germinal centres. Nature 1991;354:389–92. doi:10.1038/354389a0. Cerca con Google

[84] Alugupalli KR, Leong JM, Woodland RT, Muramatsu M, Honjo T, Gerstein RM. B1b Lymphocytes Confer T Cell-Independent Long-Lasting Immunity. Immunity 2004;21:379–90. doi:10.1016/j.immuni.2004.06.019. Cerca con Google

[85] Montecino-Rodriguez E, Dorshkind K. B-1 B cell development in the fetus and adult. Immunity 2012;36:13–21. doi:10.1016/j.immuni.2011.11.017. Cerca con Google

[86] Tarlinton D, Good-Jacobson K. Diversity among memory B cells: origin, consequences, and utility. Science 2013;341:1205–11. doi:10.1126/science.1241146. Cerca con Google

[87] Berek C. The development of B cells and the B-cell repertoire in the microenvironment of the germinal center. Immunol Rev 1992;126:5–19. Cerca con Google

[88] Dogan I, Bertocci B, Vilmont V, Delbos F, Mégret J, Storck S, et al. Multiple layers of B cell memory with different effector functions. Nat Immunol 2009;10:1292–9. doi:10.1038/ni.1814. Cerca con Google

[89] Pape KA, Taylor JJ, Maul RW, Gearhart PJ, Jenkins MK. Different B cell populations mediate early and late memory during an endogenous immune response. Science 2011;331:1203–7. doi:10.1126/science.1201730. Cerca con Google

[90] Zuccarino-Catania G V, Sadanand S, Weisel FJ, Tomayko MM, Meng H, Kleinstein SH, et al. CD80 and PD-L2 define functionally distinct memory B cell subsets that are independent of antibody isotype. Nat Immunol 2014;15:631–7. doi:10.1038/ni.2914. Cerca con Google

[91] Wang NS, McHeyzer-Williams LJ, Okitsu SL, Burris TP, Reiner SL, McHeyzer-Williams MG. Divergent transcriptional programming of class-specific B cell memory by T-bet and RORα. Nat Immunol 2012;13:604–11. doi:10.1038/ni.2294. Cerca con Google

[92] Luckey CJ, Bhattacharya D, Goldrath AW, Weissman IL, Benoist C, Mathis D. Memory T and memory B cells share a transcriptional program of self-renewal with long-term hematopoietic stem cells 2006. Cerca con Google

[93] Graef P, Buchholz VR, Stemberger C, Flossdorf M, Henkel L, Schiemann M, et al. Serial transfer of single-cell-derived immunocompetence reveals stemness of CD8(+) central memory T cells. Immunity 2014;41:116–26. doi:10.1016/j.immuni.2014.05.018. Cerca con Google

[94] Barrington RA, Pozdnyakova O, Zafari MR, Benjamin CD, Carroll MC. B lymphocyte memory: role of stromal cell complement and FcgammaRIIB receptors. J Exp Med 2002;196:1189–99. Cerca con Google

[95] Hikida M, Casola S, Takahashi N, Kaji T, Takemori T, Rajewsky K, et al. PLC-gamma2 is essential for formation and maintenance of memory B cells. J Exp Med 2009;206:681–9. doi:10.1084/jem.20082100. Cerca con Google

[96] Maruyama M, Lam KP, Rajewsky K. Memory B-cell persistence is independent of persisting immunizing antigen. Nature 2000;407:636–42. doi:10.1038/35036600. Cerca con Google

[97] Benson MJ, Dillon SR, Castigli E, Geha RS, Xu S, Lam K-P, et al. Cutting edge: the dependence of plasma cells and independence of memory B cells on BAFF and APRIL. J Immunol 2008;180:3655–9. Cerca con Google

[98] Yu X, Tsibane T, McGraw PA, House FS, Keefer CJ, Hicar MD, et al. Neutralizing antibodies derived from the B cells of 1918 influenza pandemic survivors. Nature 2008;455:532–6. doi:10.1038/nature07231. Cerca con Google

[99] Kometani K, Nakagawa R, Shinnakasu R, Kaji T, Rybouchkin A, Moriyama S, et al. Repression of the Transcription Factor Bach2 Contributes to Predisposition of IgG1 Memory B Cells toward Plasma Cell Differentiation. Immunity 2013;39:136–47. doi:10.1016/j.immuni.2013.06.011. Cerca con Google

[100] Tonegawa S. Somatic generation of antibody diversity. Nature 1983;302:575–81. doi:10.1038/302575a0. Cerca con Google

[101] Bassing CH, Swat W, Alt FW. The mechanism and regulation of chromosomal V(D)J recombination. Cell 2002;109 Suppl:S45–55. Cerca con Google

[102] Gellert M. V(D)J recombination: RAG proteins, repair factors, and regulation. Annu Rev Biochem 2002;71:101–32. doi:10.1146/annurev.biochem.71.090501.150203. Cerca con Google

[103] Brandt VL, Roth DB. A recombinase diversified: new functions of the RAG proteins. Curr Opin Immunol 2002;14:224–9. Cerca con Google

[104] Haber JE. Partners and pathwaysrepairing a double-strand break. Trends Genet 2000;16:259–64. Cerca con Google

[105] Honjo T, Kinoshita K, Muramatsu M. Molecular mechanism of class switch recombination: linkage with somatic hypermutation. Annu Rev Immunol 2002;20:165–96. doi:10.1146/annurev.immunol.20.090501.112049. Cerca con Google

[106] Manis JP, Dudley D, Kaylor L, Alt FW. IgH class switch recombination to IgG1 in DNA-PKcs-deficient B cells. Immunity 2002;16:607–17. Cerca con Google

[107] Jacobs H, Bross L. Towards an understanding of somatic hypermutation. Curr Opin Immunol 2001;13:208–18. Cerca con Google

[108] Georgiou G, Ippolito GC, Beausang J, Busse CE, Wardemann H, Quake SR. The promise and challenge of high-throughput sequencing of the antibody repertoire. Nat Biotechnol 2014;32:158–68. doi:10.1038/nbt.2782. Cerca con Google

[109] Wang C, Liu Y, Xu LT, Jackson KJL, Roskin KM, Pham TD, et al. Effects of aging, cytomegalovirus infection, and EBV infection on human B cell repertoires. J Immunol 2014;192:603–11. doi:10.4049/jimmunol.1301384. Cerca con Google

[110] Trück J, Ramasamy MN, Galson JD, Rance R, Parkhill J, Lunter G, et al. Identification of antigen-specific B cell receptor sequences using public repertoire analysis. J Immunol 2015;194:252–61. doi:10.4049/jimmunol.1401405. Cerca con Google

[111] Jackson KJL, Liu Y, Roskin KM, Glanville J, Hoh R a, Seo K, et al. Human responses to influenza vaccination show seroconversion signatures and convergent antibody rearrangements. Cell Host Microbe 2014;16:105–14. doi:10.1016/j.chom.2014.05.013. Cerca con Google

[112] Nakaya HI, Wrammert J, Lee EK, Racioppi L, Marie-Kunze S, Haining WN, et al. Systems biology of vaccination for seasonal influenza in humans. Nat Immunol 2011;12:786–95. doi:10.1038/ni.2067. Cerca con Google

[113] Querec TD, Akondy RS, Lee EK, Cao W, Nakaya HI, Teuwen D, et al. Systems biology approach predicts immunogenicity of the yellow fever vaccine in humans. Nat Immunol 2009;10:116–25. doi:10.1038/ni.1688. Cerca con Google

[114] Kennedy RB, Oberg AL, Ovsyannikova IG, Haralambieva IH, Grill D, Poland GA. Transcriptomic profiles of high and low antibody responders to smallpox vaccine. Genes Immun 14:277–85. doi:10.1038/gene.2013.14. Cerca con Google

[115] Obermoser G, Presnell S, Domico K, Xu H, Wang Y, Anguiano E, et al. Systems Scale Interactive Exploration Reveals Quantitative and Qualitative Differences in Response to Influenza and Pneumococcal Vaccines. Immunity 2013;38:831–44. doi:10.1016/j.immuni.2012.12.008. Cerca con Google

[116] Dominguez MH, Chattopadhyay PK, Ma S, Lamoreaux L, McDavid A, Finak G, et al. Highly multiplexed quantitation of gene expression on single cells. J Immunol Methods 2013;391:133–45. doi:10.1016/j.jim.2013.03.002. Cerca con Google

[117] Feinerman O, Jentsch G, Tkach KE, Coward JW, Hathorn MM, Sneddon MW, et al. Single-cell quantification of IL-2 response by effector and regulatory T cells reveals critical plasticity in immune response. Mol Syst Biol 2010;6:437. doi:10.1038/msb.2010.90. Cerca con Google

[118] Arsenio J, Kakaradov B, Metz PJ, Kim SH, Yeo GW, Chang JT. Early specification of CD8(+) T lymphocyte fates during adaptive immunity revealed by single-cell gene-expression analyses. Nat Immunol 2014;15. doi:10.1038/ni.2842. Cerca con Google

[119] Weinstein JA, Zeng X, Chien Y, Quake SR. Correlation of Gene Expression and Genome Mutation in Single B-Cells 2013;8:6–10. doi:10.1371/journal.pone.0067624. Cerca con Google

[120] McHeyzer-Williams LJ, Milpied PJ, Okitsu SL, McHeyzer-Williams MG. Class-switched memory B cells remodel BCRs within secondary germinal centers. Nat Immunol 2015;16:296–305. doi:10.1038/ni.3095. Cerca con Google

[121] Mestas J, Hughes CCW. Of mice and not men: differences between mouse and human immunology. J Immunol 2004;172:2731–8. Cerca con Google

[122] Kepler TB. Reconstructing a B-cell clonal lineage. I. Statistical inference of unobserved ancestors. F1000Research 2013;2:103. doi:10.12688/f1000research.2-103.v1. Cerca con Google

[123] Flynn JM, Spusta SC, Rosen CJ, Melov S. Single cell gene expression profiling of cortical osteoblast lineage cells. Bone 2013;53:174–81. doi:10.1016/j.bone.2012.11.043. Cerca con Google

[124] Carotta S, Willis SN, Hasbold J, Inouye M, Pang SHM, Emslie D, et al. The transcription factors IRF8 and PU.1 negatively regulate plasma cell differentiation. J Exp Med 2014;211:2169–81. doi:10.1084/jem.20140425. Cerca con Google

[125] Hu H, Wang B, Borde M, Nardone J, Maika S, Allred L, et al. Foxp1 is an essential transcriptional regulator of B cell development. Nat Immunol 2006;7:819–26. doi:10.1038/ni1358. Cerca con Google

[126] Sagardoy A, Martinez-Ferrandis JI, Roa S, Bunting KL, Aznar MA, Elemento O, et al. Downregulation of FOXP1 is required during germinal center B-cell function. Blood 2013;121:4311–20. doi:10.1182/blood-2012-10-462846. Cerca con Google

[127] Corcoran LM, Hasbold J, Dietrich W, Hawkins E, Kallies A, Nutt SL, et al. Differential requirement for OBF-1 during antibody-secreting cell differentiation. J Exp Med 2005;201:1385–96. doi:10.1084/jem.20042325. Cerca con Google

[128] Nelson N, Kanno Y, Hong C, Contursi C, Fujita T, Fowlkes BJ, et al. Expression of IFN regulatory factor family proteins in lymphocytes. Induction of Stat-1 and IFN consensus sequence binding protein expression by T cell activation. J Immunol 1996;156:3711–20. Cerca con Google

[129] Calame K. Transcription factors that regulate memory in humoral responses 2006;211:269–79. Cerca con Google

[130] Kuo TC, Calame KL. B lymphocyte-induced maturation protein (Blimp)-1, IFN regulatory factor (IRF)-1, and IRF-2 can bind to the same regulatory sites. J Immunol 2004;173:5556–63. Cerca con Google

[131] Good KL, Tangye SG. Decreased expression of Kru ¨ ppel-like factors in memory B cells induces the rapid response typical of secondary antibody responses 2010. Cerca con Google

[132] Hart GT, Hogquist K a, Jameson SC. Krüppel-like factors in lymphocyte biology. J Immunol 2012;188:521–6. doi:10.4049/jimmunol.1101530. Cerca con Google

[133] Deenick EK, Avery DT, Chan A, Berglund LJ, Ives ML, Moens L, et al. Naive and memory human B cells have distinct requirements for STAT3 activation to differentiate into antibody-secreting plasma cells. J Exp Med 2013;210:2739–53. doi:10.1084/jem.20130323. Cerca con Google

[134] Gatto D, Brink R. B cell localization: regulation by EBI2 and its oxysterol ligand. Trends Immunol 2013;34:336–41. doi:10.1016/j.it.2013.01.007. Cerca con Google

[135] Han S-B, Moratz C, Huang N-N, Kelsall B, Cho H, Shi C-S, et al. Rgs1 and Gnai2 regulate the entrance of B lymphocytes into lymph nodes and B cell motility within lymph node follicles. Immunity 2005;22:343–54. doi:10.1016/j.immuni.2005.01.017. Cerca con Google

[136] Zhang S, Pruitt M, Tran D, Du Bois W, Zhang K, Patel R, et al. B cell-specific deficiencies in mTOR limit humoral immune responses. J Immunol 2013;191:1692–703. doi:10.4049/jimmunol.1201767. Cerca con Google

[137] Keating R, Hertz T, Wehenkel M, Harris TL, Edwards BA, McClaren JL, et al. The kinase mTOR modulates the antibody response to provide cross-protective immunity to lethal infection with influenza virus. Nat Immunol 2013;14:1266–76. doi:10.1038/ni.2741. Cerca con Google

[138] Limon JJ, Fruman DA. Akt and mTOR in B Cell Activation and Differentiation. Front Immunol 2012;3:228. doi:10.3389/fimmu.2012.00228. Cerca con Google

[139] Limon JJ, So L, Jellbauer S, Chiu H, Corado J, Sykes SM, et al. mTOR kinase inhibitors promote antibody class switching via mTORC2 inhibition. Proc Natl Acad Sci U S A 2014;111:E5076–85. doi:10.1073/pnas.1407104111. Cerca con Google

[140] Cai S, Lee CC, Kohwi-Shigematsu T. SATB1 packages densely looped, transcriptionally active chromatin for coordinated expression of cytokine genes. Nat Genet 2006;38:1278–88. doi:10.1038/ng1913. Cerca con Google

[141] Will B, Vogler TO, Bartholdy B, Garrett-Bakelman F, Mayer J, Barreyro L, et al. Satb1 regulates the self-renewal of hematopoietic stem cells by promoting quiescence and repressing differentiation commitment. Nat Immunol 2013;14:437–45. doi:10.1038/ni.2572. Cerca con Google

[142] Tomayko MM, Steinel NC, Anderson SM, Shlomchik MJ. Cutting edge: Hierarchy of maturity of murine memory B cell subsets. J Immunol 2010;185:7146–50. doi:10.4049/jimmunol.1002163. Cerca con Google

[143] Anderson SM, Tomayko MM, Ahuja A, Haberman AM, Shlomchik MJ. New markers for murine memory B cells that define mutated and unmutated subsets. J Exp Med 2007;204:2103–14. doi:10.1084/jem.20062571. Cerca con Google

[144] Bemark M, Bergqvist P, Stensson A, Holmberg A, Mattsson J, Lycke NY. A unique role of the cholera toxin A1-DD adjuvant for long-term plasma and memory B cell development. J Immunol 2011;186:1399–410. doi:10.4049/jimmunol.1002881. Cerca con Google

[145] Onodera T, Takahashi Y, Yokoi Y, Ato M, Kodama Y, Hachimura S, et al. Memory B cells in the lung participate in protective humoral immune responses to pulmonary influenza virus reinfection. Proc Natl Acad Sci U S A 2012;109:2485–90. doi:10.1073/pnas.1115369109. Cerca con Google

[146] Yates JL, Racine R, McBride KM, Winslow GM. T cell-dependent IgM memory B cells generated during bacterial infection are required for IgG responses to antigen challenge. J Immunol 2013;191:1240–9. doi:10.4049/jimmunol.1300062. Cerca con Google

[147] Seifert M, Przekopowitz M, Taudien S, Lollies A, Ronge V, Drees B, et al. Functional capacities of human IgM memory B cells in early inflammatory responses and secondary germinal center reactions. Proc Natl Acad Sci U S A 2015;112:E546–55. doi:10.1073/pnas.1416276112. Cerca con Google

[148] Tomayko MM, Anderson SM, Brayton CE, Sadanand S, Steinel NC, Behrens TW, et al. Systematic Comparison of Gene Expression between Murine Memory and Naive B Cells Demonstrates That Memory B Cells Have Unique Signaling Capabilities 1 2008. Cerca con Google

[149] Shin D-M, Lee C-H, Morse HC. IRF8 governs expression of genes involved in innate and adaptive immunity in human and mouse germinal center B cells. PLoS One 2011;6:e27384. doi:10.1371/journal.pone.0027384. Cerca con Google

[150] Schmidlin H, Diehl S a, Nagasawa M, Scheeren F a, Schotte R, Uittenbogaart CH, et al. Spi-B inhibits human plasma cell differentiation by repressing BLIMP1 and XBP-1 expression. Blood 2008;112:1804–12. doi:10.1182/blood-2008-01-136440. Cerca con Google

[151] Giesecke C, Frölich D, Reiter K, Mei HE, Wirries I, Kuhly R, et al. Tissue distribution and dependence of responsiveness of human antigen-specific memory B cells. J Immunol 2014;192:3091–100. doi:10.4049/jimmunol.1302783. Cerca con Google

[152] Haze K, Yoshida H, Yanagi H, Yura T, Mori K. Mammalian Transcription Factor ATF6 Is Synthesized as a Transmembrane Protein and Activated by Proteolysis in Response to Endoplasmic Reticulum Stress. Mol Biol Cell 1999;10:3787–99. doi:10.1091/mbc.10.11.3787. Cerca con Google

[153] Bommiasamy H, Back SH, Fagone P, Lee K, Meshinchi S, Vink E, et al. ATF6 induces XBP1-independent expansion of the endoplasmic reticulum. J Cell Sci 2009;122:1626–36. doi:10.1242/jcs.045625. Cerca con Google

[154] Ravindran R, Khan N, Nakaya HI, Li S, Loebbermann J, Maddur MS, et al. Vaccine activation of the nutrient sensor GCN2 in dendritic cells enhances antigen presentation. Science 2014;343:313–7. doi:10.1126/science.1246829. Cerca con Google

[155] Dorner T, Shock A, Goldenberg DM, Lipsky PE. The mechanistic impact of CD22 engagement with epratuzumab on B cell function: Implications for the treatment of systemic lupus erythematosus. Autoimmun Rev 2015;14:1079–86. doi:10.1016/j.autrev.2015.07.013. Cerca con Google

[156] Onodera T, Poe JC, Tedder TF, Tsubata T. CD22 regulates time course of both B cell division and antibody response. J Immunol 2008;180:907–13. doi:10.4049/jimmunol.180.2.907. Cerca con Google

[157] Banchereau J, Brière F, Liu YJ, Rousset F. Molecular control of B lymphocyte growth and differentiation. Stem Cells 1994;12:278–88. doi:10.1002/stem.5530120304. Cerca con Google

[158] Wouters BG, Koritzinsky M. Hypoxia signalling through mTOR and the unfolded protein response in cancer. Nat Rev Cancer 2008;8:851–64. doi:10.1038/nrc2501. Cerca con Google

[159] Lazarevic V, Glimcher LH. T-bet in disease. Nat Immunol 2011;12:597–606. doi:10.1038/ni.2059. Cerca con Google

[160] Cerutti A, Rescigno M. The biology of intestinal immunoglobulin A responses. Immunity 2008;28:740–50. doi:10.1016/j.immuni.2008.05.001. Cerca con Google

[161] Karp G. Cell and Molecular Biology: Concepts and Experiments. John Wiley & Sons; 2009. Cerca con Google

[162] de Villartay J-P, Fischer A, Durandy A. The mechanisms of immune diversification and their disorders. Nat Rev Immunol 2003;3:962–72. doi:10.1038/nri1247. Cerca con Google

Download statistics

Solo per lo Staff dell Archivio: Modifica questo record