T–B-cell entanglement and ICOSL-driven feed-forward regulation of germinal centre reaction

Nature ◽  
2014 ◽  
Vol 517 (7533) ◽  
pp. 214-218 ◽  
Author(s):  
Dan Liu ◽  
Heping Xu ◽  
Changming Shih ◽  
Zurong Wan ◽  
Xiaopeng Ma ◽  
...  
Keyword(s):  
B Cell ◽  
Germinal Centre ◽  
Feed Forward ◽  
Germinal Centre Reaction

scholarly journals SARS-CoV-2 mRNA vaccines induce a robust germinal centre reaction in humans

2021 ◽  
Author(s):  
Ali Ellebedy ◽  
Jackson Turner ◽  
Jane O'Halloran ◽  
Elizaveta Kalaidina ◽  
Wooseob Kim ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Messenger Rna ◽  
Neutralizing Antibodies ◽  
Germinal Centre ◽  
S Protein ◽  
Fine Needle Aspirates ◽  
Cell Responses ◽  
Cell Clones ◽  
Shared Epitopes

Abstract Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) messenger RNA (mRNA)-based vaccines are ~95% effective in preventing coronavirus disease 2019. However, the dynamics of antibody secreting plasmablasts (PBs) and germinal centre (GC) B cells induced by these vaccines in SARS-CoV-2 naïve and antigen-experienced humans remains unclear. Here we examined peripheral blood and/or lymph node (LN) antigen-specific B cell responses in 32 individuals who received two doses of BNT162b2, an mRNA-based vaccine encoding the full-length SARS-CoV-2 spike (S) gene. Circulating IgG- and IgA-secreting PBs targeting the S protein peaked one week after the second immunization then declined and were undetectable three weeks later. PB responses coincided with maximal levels of serum anti-S binding and neutralizing antibodies to a historical strain as well as emerging variants, especially in individuals previously infected with SARS-CoV-2, who produced the most robust serological responses. Fine needle aspirates of draining axillary LNs identified GC B cells that bind S protein in all participants sampled after primary immunization. GC responses increased after boosting and were detectable in two distinct LNs in several participants. Remarkably, high frequencies of S-binding GC B cells and PBs were maintained in draining LNs for up to seven weeks after first immunization, with a substantial fraction of the PB pool class-switched to IgA. GC B cell-derived monoclonal antibodies predominantly targeted the RBD, with fewer clones binding to the N-terminal domain or shared epitopes within the S proteins of human betacoronaviruses OC43 and HKU1. Our studies demonstrate that SARS-CoV-2 mRNA-based vaccination of humans induces a robust and persistent GC B cell response that engages pre-existing as well as new B cell clones, which enables generation of high-affinity, broad, and durable humoral immunity.

Murine Scrapie Infection Causes an Abnormal Germinal Centre Reaction in the Spleen

2004 ◽  
Vol 130 (2-3) ◽  
pp. 181-194 ◽  
Author(s):  
G McGovern ◽  
K.L Brown ◽  
M.E Bruce ◽  
M Jeffrey
Keyword(s):  
Germinal Centre ◽  
Scrapie Infection ◽  
Germinal Centre Reaction

scholarly journals Ubiquitination of IgG1 cytoplasmic tail modulates B-cell signalling and activation

2020 ◽  
Vol 32 (6) ◽  
pp. 385-395
Author(s):  
Tadahiro Kodama ◽  
Mika Hasegawa ◽  
Yui Sakamoto ◽  
Kei Haniuda ◽  
Daisuke Kitamura
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Plasma Cells ◽  
Cell Signalling ◽  
Cytoplasmic Tail ◽  
Cell Receptor ◽  
Germinal Centre ◽  
Antigen Stimulation

Abstract Upon antigen stimulation, IgG+ B cells rapidly proliferate and differentiate into plasma cells, which has been attributed to the characteristics of membrane-bound IgG (mIgG), but the underlying molecular mechanisms remain elusive. We have found that a part of mouse mIgG1 is ubiquitinated through the two responsible lysine residues (K378 and K386) in its cytoplasmic tail and this ubiquitination is augmented upon antigen stimulation. The ubiquitination of mIgG1 involves its immunoglobulin tail tyrosine (ITT) motif, Syk/Src-family kinases and Cbl proteins. Analysis of a ubiquitination-defective mutant of mIgG1 revealed that ubiquitination of mIgG1 facilitates its ligand-induced endocytosis and intracellular trafficking from early endosome to late endosome, and also prohibits the recycling pathway, thus attenuating the surface expression level of mIgG1. Accordingly, ligation-induced activation of B-cell receptor (BCR) signalling molecules is attenuated by the mIgG1 ubiquitination, except MAP kinase p38 whose activation is up-regulated due to the ubiquitination-mediated prohibition of mIgG1 recycling. Adaptive transfer experiments demonstrated that ubiquitination of mIgG1 facilitates expansion of germinal centre B cells. These results indicate that mIgG1-mediated signalling and cell activation is regulated by ubiquitination of mIgG1, and such regulation may play a role in expansion of germinal centre B cells.

Strain specificities in influence of ageing on germinal centre reaction to inactivated influenza virus antigens in mice: Sex-based differences

2020 ◽  
Vol 133 ◽  
pp. 110857
Author(s):  
Biljana Bufan ◽  
Nevena Arsenović-Ranin ◽  
Raisa Petrović ◽  
Irena Živković ◽  
Vera Stoiljković ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Germinal Centre ◽  
Virus Antigens ◽  
Germinal Centre Reaction

Glucocorticoid-induced leucine zipper (GILZ) inhibits B cell activation in systemic lupus erythematosus

2015 ◽  
Vol 75 (4) ◽  
pp. 739-747 ◽  
Author(s):  
Sarah A Jones ◽  
Andrew E J Toh ◽  
Dragana Odobasic ◽  
Marie-Anne Virginie Oudin ◽  
Qiang Cheng ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
B Cells ◽  
B Cell ◽  
Lupus Erythematosus ◽  
Leucine Zipper ◽  
Germinal Centre ◽  
Cell Phenotype ◽  
Systemic Lupus ◽  
Human B Cells

ObjectivesSystemic lupus erythematosus (SLE) is a serious multisystem autoimmune disease, mediated by disrupted B cell quiescence and typically treated with glucocorticoids. We studied whether B cells in SLE are regulated by the glucocorticoid-induced leucine zipper (GILZ) protein, an endogenous mediator of anti-inflammatory effects of glucocorticoids.MethodsWe conducted a study of GILZ expression in blood mononuclear cells of patients with SLE, performed in vitro analyses of GILZ function in mouse and human B cells, assessed the contributions of GILZ to autoimmunity in mice, and used the nitrophenol coupled to keyhole limpet haemocyanin model of immunisation in mice.ResultsReduced B cell GILZ was observed in patients with SLE and lupus-prone mice, and impaired induction of GILZ in patients with SLE receiving glucocorticoids was associated with increased disease activity. GILZ was downregulated in naïve B cells upon stimulation in vitro and in germinal centre B cells, which contained less enrichment of H3K4me3 at the GILZ promoter compared with naïve and memory B cells. Mice lacking GILZ spontaneously developed lupus-like autoimmunity, and GILZ deficiency resulted in excessive B cell responses to T-dependent stimulation. Accordingly, loss of GILZ in naïve B cells allowed upregulation of multiple genes that promote the germinal centre B cell phenotype, including lupus susceptibility genes and genes involved in cell survival and proliferation. Finally, treatment of human B cells with a cell-permeable GILZ fusion protein potently suppressed their responsiveness to T-dependent stimuli.ConclusionsOur findings demonstrated that GILZ is a non-redundant regulator of B cell activity, with important potential clinical implications in SLE.

scholarly journals Molecular characterization of centerin, a germinal centre cell serpin

2007 ◽  
Vol 405 (3) ◽  
pp. 489-494 ◽  
Author(s):  
Melinda A. Paterson ◽  
Anita J. Horvath ◽  
Robert N. Pike ◽  
Paul B. Coughlin
Keyword(s):  
B Cell ◽  
Serine Protease ◽  
Molecular Characterization ◽  
Good Prognosis ◽  
Germinal Centre ◽  
Lymphoid Malignancies ◽  
B Cell Maturation ◽  
Absolute Requirement

Centerin [SERPINA9/GCET1 (germinal centre B-cell-expressed transcript 1)] is a serpin (serine protease inhibitor) whose expression is restricted to germinal centre B-cells and lymphoid malignancies with germinal centre B-cell maturation. Expression of centerin, together with bcl-6 and GCET2, constitutes a germinal centre B-cell signature, which is associated with a good prognosis in diffuse large B-cell lymphomas, but the molecular basis for this remains to be elucidated. We report here the cloning, expression and molecular characterization of bacterial recombinant centerin. Biophysical studies demonstrated that centerin was able to undergo the ‘stressed to relaxed’ conformational change which is an absolute requirement for protease inhibitory activity. Kinetic analysis showed that centerin rapidly inhibited the serine protease trypsin (ka=1.9×105 M−1·s−1) and also demonstrated measurable inhibition of thrombin (ka=1.17×103 M−1·s−1) and plasmin (ka=1.92×103 M−1·s−1). Centerin also bound DNA and unfractionated heparin, although there was no functionally significant impact on the rate of inhibition. These results suggest that centerin is likely to function in vivo in the germinal centre as an efficient inhibitor of a trypsin-like protease.

EBV Transformation of Tonsil Germinal Centre B Cells Carrying Functionally Inactivated IgV Gene.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3248-3248
Author(s):  
Sridhar Chaganti ◽  
Noelia Begue Pastor ◽  
Mark T. Drayson ◽  
Andy I. Bell ◽  
Alan B. Rickinson
Keyword(s):  
B Cells ◽  
B Cell ◽  
Somatic Hypermutation ◽  
B Cell Lymphoma ◽  
Affinity Maturation ◽  
Germinal Centre ◽  
Chain Gene ◽  
Lymphoid Tissues ◽  
Memory B Cell

Abstract Somatic hypermutation of immunoglobulin (Ig) gene sequences in the germinal centres of lymphoid tissues is necessary for affinity maturation of B cell responses to antigen challenge. This process generates a few clones with improved affinity that are selected into B cell memory and many clones with other non favourable Ig mutations, including some cells with functionally inactivated Ig gene that normally die by apoptosis. It is postulated that infection with Epstein-Barr virus (EBV), a B lymphotropic agent linked to several types of B cell lymphoma, can rescue germinal centre cells with unfavourable mutations. This creates a pool of infected cells at greater risk of developing into lymphomas. In the present work, CD38+ germinal centre B cells were separated from tonsil by negative selection for IgD and CD39. Peripheral blood naïve and memory B cell subpopulations were FACS sorted as IgD+, CD27− and IgD−, CD27+ fractions respectively. These cells were infected with EBV (B95.8 strain) in vitro and seeded at limiting dilutions onto fibroblast feeders. EBV transformed lymphoblastoid cell lines (LCLs) from such cultures were analysed for surface Ig phenotype. Naïve B cell transformants were consistently IgM+, IgD+. Memory B cell transformants were IgM+ in some cases but more frequently IgG+ or IgA+. Germinal centre transformants showed the same spectrum of surface Ig phenotypes as memory cell transformants but in addition we identified six germinal centre derived LCLs which were consistently surface Ig negative. Sequencing from these lines confirmed that in at least three cases EBV had rescued cells with functionally inactivated Ig heavy chain gene.

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