The generation of antibody-secreting plasma cells

Nutt, Stephen L.; Hodgkin, Philip D.; Tarlinton, David M.; Corcoran, Lynn M.

doi:10.1038/nri3795

Cited by 1,103 publications

(1,183 citation statements)

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“…2C and D). This phenotype is compatible with that of recently activated plasmablasts 12. By utilizing an alternative gating strategy, we could not find any CD19 − CD27 + CD38 + IgG ASCs in the CSF (data not shown).…”

Section: Resultssupporting

confidence: 76%

Selective intrathecal enrichment of G1m1‐positive B cells in multiple sclerosis

Lossius

Tomescu-Baciu

Holmøy

et al. 2017

Ann Clin Transl Neurol

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Immunoglobulin gamma (IgG) heavy chain genes are associated with susceptibility to multiple sclerosis (MS) and IgG levels in the cerebrospinal fluid (CSF). However, how these variants are implicated in disease mechanisms remains unknown. Here, we show that proliferating plasmablasts expressing the G1m1 allotype of IgG1 are selectively enriched in CSF of G1m1/G1m3 heterozygous MS patients, whereas plasmablasts expressing either G1m1 or G1m3 are evenly distributed in blood. Moreover, there was a preferential intrathecal synthesis of oligoclonal IgG1 of the G1m1 allotype in heterozygous patients, whereas controls with Lyme neuroborreliosis displayed oligoclonal IgG1 of both allotypes. This points to a disease‐specific mechanism involved in B‐cell establishment within the central nervous system in MS.

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Section: Resultssupporting

confidence: 76%

Selective intrathecal enrichment of G1m1‐positive B cells in multiple sclerosis

Lossius

Tomescu-Baciu

Holmøy

et al. 2017

Ann Clin Transl Neurol

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“…Moreover, the loss of E2A and E2-2 stringently arrests LPS-induced plasmablast differentiation at an activated B cell stage. Whereas plasmablasts and plasma cells are characterized by a high rate of immunoglobulin secretion (Nutt et al, 2015), the arrested DKO B cells fail to up-regulate Igh and Igk transcription and to undergo the posttranscriptional expression switch from the membrane-bound to secreted immunoglobulin heavychain. The inability to further activate Igh gene transcription is likely caused by the observed loss of open chromatin at the three Igh 3′ enhancers HS3A, HS1,2, and HS3B in activated DKO B cells.…”

Section: Discussionmentioning

confidence: 99%

“…We next studied the E-protein-dependent regulation of Igh and Igk gene expression in view of the fact that increased expression and secretion of immunoglobulins is a hallmark of plasma cells (Nutt et al, 2015). Whereas the expression of Igh and Igk transcripts was strongly increased during LPSinduced differentiation of activated B cells to plasmablasts, this increase was not observed in activated DKO cells (Fig.…”

Section: E-protein-dependent Control Of 3′ Enhancers At the Igh And Imentioning

confidence: 99%

“…Affinity-based selection in this specialized compartment leads to clonal expansion of B cells expressing high-affinity B cell receptors, which subsequently differentiate to proliferating, antibody-secreting plasmablasts (Victora and Nussenzweig, 2012). Upon migration to specialized bone marrow niches, plasmablasts differentiate into long-lived quiescent plasma cells secreting high amounts of antibodies (Nutt et al, 2015). While many transcription factors are involved in coordinating these B cell responses, we have here studied the role of E-proteins in the regulation of these processes.…”

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confidence: 99%

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Molecular functions of the transcription factors E2A and E2-2 in controlling germinal center B cell and plasma cell development

Wöhner¹,

Tagoh²,

Bilić³

et al. 2016

J. Cell Biol.

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1201B cell immunity provides acute and long-term protection of the host against infections through the generation and secretion of high-affinity antibodies that recognize a shear unlimited number of pathogens. This enormous adaptive potential of B cells is brought about by V(D)J recombination of the immunoglobulin heavy chain (Igh) and light chain (Igk and Igl) genes in early B cell development, and by subsequent affinity maturation of the Ig heavy chain in late B cell differentiation (Victora and Nussenzweig, 2012). Somatic hypermutation alters the antigen-binding V H sequences of the Ig heavy-chain, whereas class switch recombination (CSR) exchanges the C H exons to generate Ig isotypes with distinct effector functions (Chaudhuri and Alt, 2004). Whereas the activation-induced deaminase (AID) is an essential regulator of both processes (Muramatsu et al., 2000), somatic hypermutation only takes place in germinal centers (GCs), which are formed upon antigen exposure by the interplay of T follicular helper (Tfh) cells and follicular (FO) B cells in secondary lymphoid organs (Victora and Nussenzweig, 2012). Affinity-based selection in this specialized compartment leads to clonal expansion of B cells expressing high-affinity B cell receptors, which subsequently differentiate to proliferating, antibody-secreting plasmablasts (Victora and Nussenzweig, 2012). Upon migration to specialized bone marrow niches, plasmablasts differentiate into long-lived quiescent plasma cells secreting high amounts of antibodies (Nutt et al., 2015). While many transcription factors are involved in coordinating these B cell responses, we have here studied the role of E-proteins in the regulation of these processes.Basic helix-loop-helix (bHLH) transcription factors can be subdivided into different classes based on biochemical and functional properties (Murre, 2005). Class I bHLH proteins, also known as E-proteins, consist of the three members, E2A (Tcf3), E2-2 (Tcf4), and HEB (Tcf12; Murre, 2005), which bind the E-box (CAN NTG) motif with similar sequence specificity (Fig. S1 A). E-proteins are broadly expressed and heterodimerize with class II bHLH proteins in nonlymphoid cell types. Within the lymphoid system, E-proteins function as homodimers or heterodimers with a different E-protein (Bain et al., 1993;Shen and Kadesch, 1995). E-proteins are thought to mainly function as transcriptional activators, as they interact with the co-activators p300 and CBP (Bradney et al., 2003;Bayly et al., 2004), as well as the promoter recognition factor TFI ID (Chen et al., 2013). The activity of E-proteins is controlled by the inhibitor of DNA binding proteins, which are HLH proteins lacking the basic DNA-binding domain, and are thus capable of sequestering E-proteins into DNA-bindingincompetent heterodimers (Kee, 2009).E-proteins control different aspects of B cell development (Murre, 2005). E2A is required for the commitment of lymphoid progenitors to the B cell lineage (Bain et al.,

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“…MUM1 regulates germinal center cell formation, 31 class-switch recombination and plasma cell differentiation. 32,33 Although MUM1 expression was associated with poor survival in the pre-rituximab era, 34 recent studies have failed to find a correlation. Number at risk Fig.…”

Section: Fig 4 Survival Between Mum1mentioning

confidence: 99%

Clinicopathological Analysis of 320 Cases of Diffuse Large B-cell Lymphoma Using the Hans Classifier

Ichiki

Carreras

Miyaoka

et al. 2017

JCEH

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JC EH lin xp ematopathol Original Article INTRODUCTIONDiffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma (NHL), and accounts for 30%-40% of all adult NHL.1,2 The diagnostic category of DLBCL is heterogeneous, and the clinicopathological and molecular genetic diversity of DLBCL was reflected in the 2008 WHO classification of lymphomas. Furthermore, the updated revision in 2016 3 described many subgroups and entities based on distinct morphological, immunophenotypical, molecular and clinical parameters. Although DLBCL is a potentially curable disease with current therapy, particularly for those who achieve complete remission with first-line treatment, approximately 40% of patients will die of relapsed or refractory disease. 2,4 Factors that contribute to the outcome include age, socioeconomic conditions, comorbid conditions, performance status and several clinical features. 5,6 Therefore, it is necessary to stratify patients according to their prognostic risk in a suitable and cost-effective manner.Prognostic factors in DLBCL include standard and wellestablished factors such as the International Prognostic Index (IPI; with its variants as the original, R-IPI, age-adjusted IPI and NCCN-IPI), immunohistochemistry for cell-of-origin (e.g. Hans, Choi and Tally algorithms), imaging by positron emission tomography (PET)/CT scans, fluorescence in situ The estimation of clinical prognosis for diffuse large B-cell lymphoma (DLBCL) with a quick, cost-efficient method is necessary because of the clinical heterogeneity of this disease, which leads to death, relapsed or refractory disease in approximately 40% of patients. We analyzed 320 cases diagnosed from 2007 to 2013 treated with R-CHOP therapy at Tokai University Hospital and associated institutions. DLBCL was classified according to the cell-of-origin using the Hans algorithm [germinal center B-cell-like (GCB) vs non-GCB subtypes], and into 6 subgroups derived from combinations of CD10, BCL6 and MUM1 markers. The percentage of GCB and non-GCB (NGCB) subtypes was 35% and 65%, respectively. GCB-DLBCL was characterized by lower BCL2 immunohistochemical expression, extranodal sites <1, better therapeutic response, and favorable overall survival (OS) and progression free survival (PFS) (P<0.01). The most frequent subgroup was NGCB-1 (CD10 -, 2%). In comparison with GCB-2 and GCB-3 (both MUM1 -), the GCB-1 (MUM1 + ) was characterized by favorable PFS (5-year PFS 84% vs 65%, OR 0.368, P<0.05), independent of high LDH (associated with unfavorable PFS, OR 7.04, P<0.01) in the multivariate analysis. This predictive value of MUM1 was independent of CD10. Interestingly, triple-negative NGCB-3 tended to have a more favorable prognosis than the other NGCB subgroups. In conclusion, the Hans classifier is a valid method to evaluate the prognosis of DLBCL NOS. In the GCB subtypes, GCB subtypes, MUM1-positivity is associated with a more favorable outcome (PFS).

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The generation of antibody-secreting plasma cells

Cited by 1,103 publications

References 160 publications

Selective intrathecal enrichment of G1m1‐positive B cells in multiple sclerosis

Selective intrathecal enrichment of G1m1‐positive B cells in multiple sclerosis

Molecular functions of the transcription factors E2A and E2-2 in controlling germinal center B cell and plasma cell development

Clinicopathological Analysis of 320 Cases of Diffuse Large B-cell Lymphoma Using the Hans Classifier

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