scholarly journals TG2-gluten complexes as antigens for gluten-specific and transglutaminase-2 specific B cells in celiac disease

PLoS ONE ◽  
2021 ◽  
Vol 16 (11) ◽  
pp. e0259082
Author(s):  
Christian B. Lindstad ◽  
Alisa E. Dewan ◽  
Jorunn Stamnaes ◽  
Ludvig M. Sollid ◽  
M. Fleur du Pré
Keyword(s):  
T Cells ◽  
Celiac Disease ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Plasma Cells ◽  
Transglutaminase 2 ◽  
Celiac Patient ◽  
Cell Clones ◽  
To Receive

A hallmark of celiac disease is the gluten-dependent production of antibodies specific for deamidated gluten peptides (DGP) and the enzyme transglutaminase 2 (TG2). Both types of antibodies are believed to result from B cells receiving help from gluten-specific CD4+ T cells and differentiating into antibody-producing plasma cells. We have here studied the collaboration between DGP- and TG2-specific B cells with gluten-specific CD4+ T cells using transgenic mice expressing celiac patient-derived T-cell and B-cell receptors, as well as between B-cell transfectants and patient-derived gluten-specific T-cell clones. We show that multivalent TG2-gluten complexes are efficient antigens for both TG2-specific and DGP-specific B cells and allow both types of B cells to receive help from gluten-specific T cells of many different specificities.

scholarly journals Potential anti-EBV effects associated with elevated interleukin-21 levels: a case report

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Kristian Assing ◽  
Christian Nielsen ◽  
Marianne Jakobsen ◽  
Charlotte B. Andersen ◽  
Kristin Skogstrand ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Plasma Cell ◽  
Germinal Center ◽  
Plasma Cells ◽  
Cell Formation ◽  
Memory B Cells ◽  
Memory B Cell

Abstract Background Germinal center derived memory B cells and plasma cells constitute, in health and during EBV reactivation, the largest functional EBV reservoir. Hence, by reducing germinal center derived formation of memory B cells and plasma cells, EBV loads may be reduced. Animal and in-vitro models have shown that IL-21 can support memory B and plasma cell formation and thereby potentially contribute to EBV persistence. However, IL-21 also displays anti-viral effects, as mice models have shown that CD4+ T cell produced IL-21 is critical for the differentiation, function and survival of anti-viral CD8+ T cells able to contain chronic virus infections. Case presentation We present immunological work-up (flow-cytometry, ELISA and genetics) related to a patient suffering from a condition resembling B cell chronic active EBV infection, albeit with moderately elevated EBV copy numbers. No mutations in genes associated with EBV disease, common variable immunodeficiency or pertaining to the IL-21 signaling pathway (including hypermorphic IL-21 mutations) were found. Increased (> 5-fold increase 7 days post-vaccination) CD4+ T cell produced (p < 0.01) and extracellular IL-21 levels characterized our patient and coexisted with: CD8+ lymphopenia, B lymphopenia, hypogammaglobulinemia, compromised memory B cell differentiation, absent induction of B-cell lymphoma 6 protein (Bcl-6) dependent peripheral follicular helper T cells (pTFH, p = 0.01), reduced frequencies of peripheral CD4+ Bcl-6+ T cells (p = 0.05), compromised plasmablast differentiation (reduced protein vaccine responses (p < 0.001) as well as reduced Treg frequencies. Supporting IL-21 mediated suppression of pTFH formation, pTFH and CD4+ IL-21+ frequencies were strongly inversely correlated, prior to and after vaccination, in the patient and in controls, Spearman’s rho: − 0.86, p < 0.001. Conclusions To the best of our knowledge, this is the first report of elevated CD4+ IL-21+ T cell frequencies in human EBV disease. IL-21 overproduction may, apart from driving T cell mediated anti-EBV responses, disrupt germinal center derived memory B cell and plasma cell formation, and thereby contribute to EBV disease control.

scholarly journals Inhibition of normal B-cell function by human immunodeficiency virus envelope glycoprotein, gp120

Blood ◽  
1992 ◽  
Vol 79 (5) ◽  
pp. 1245-1254 ◽  
Author(s):  
N Chirmule ◽  
N Oyaizu ◽  
VS Kalyanaraman ◽  
S Pahwa
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cell Function ◽  
Cell Contact ◽  
Cell Proliferation And Differentiation ◽  
Cell Clones ◽  
Glycoprotein Gp120

Abstract Despite the occurrence of hypergammaglobulinemia in human immunodeficiency virus (HIV) infection, specific antibody production and in vitro B-cell differentiation responses are frequently impaired. In this study, we have examined the effects of HIV envelope glycoprotein gp120 on T-helper cell function for B cells. In the culture system used, B-cell functional responses were dependent on T-B- cell contact, since separation of T and B cells in double chambers by Transwell membranes rendered the B cells unresponsive in assays of antigen-induced B-cell proliferation and differentiation. Cytokines secreted by T cells were also essential, since anti-CD3 monoclonal antibody (mAb)-activated, paraformaldehyde-fixed T-cell clones failed to induce B-cell proliferation and differentiation. Pretreatment of the CD4+ antigen-specific T cells with gp120 was found to impair their ability to help autologous B cells, as determined by B-cell proliferation, polyclonal IgG secretion, and antigen-specific IgG secretion. The gp120-induced inhibition was specific in that it was blocked by soluble CD4. Furthermore, only fractionated small B cells (which are T-cell-dependent in their function) manifested impaired responses when cultured with gp120-treated T cells. Antigen-induced interleukin (IL)-2 and IL-4, but not IL-6, secretion were markedly reduced in gp120-treated T-cell clones. Addition of exogenous cytokines failed to compensate for defective helper function of gp120-treated T cells. The findings in this study indicate that gp120 impairs helper functions of CD4+ T cells by interfering with T-B-cell contact- dependent interaction; the inhibitory effects of soluble envelope proteins of HIV may contribute to the immunopathogenesis of the HIV- associated disease manifestations.

scholarly journals Induction of human IgE synthesis by CD4+ T cell clones. Requirement for interleukin 4 and low molecular weight B cell growth factor.

1989 ◽  
Vol 170 (5) ◽  
pp. 1477-1493 ◽  
Author(s):  
R H DeKruyff ◽  
T Turner ◽  
J S Abrams ◽  
M A Palladino ◽  
D T Umetsu
Keyword(s):  
Molecular Weight ◽  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cd4 T Cell ◽  
Low Molecular Weight ◽  
Cell Clones ◽  
B Cell Growth Factor ◽  
Ige Synthesis

We have analyzed in detail the precise requirements for the induction of human IgE synthesis using several experimental approaches with purified B cells and well-characterized alloantigen-specific CD4+ T cell clones expressing different profiles of lymphokine secretion. Using these clones under cognate conditions in which the B cells expressed alloantigens recognized by the cloned T cells, we have confirmed that IL-4 is required for the induction of IgE synthesis, but we have clearly demonstrated that IL-4 by itself is not sufficient. With several cloned CD4+ T cell lines, including an IL-4-producing clone that could not induce IgE synthesis, and cloned T cells pretreated with cyclosporin A to inhibit lymphokine synthesis, we showed that Th cell-B cell interactions are necessary for IgE synthesis, and that low molecular weight B cell growth factor (LMW-BCGF) and IL-4, in combination, are lymphokines of major importance in the induction of IgE synthesis. Together our results indicate that optimal induction of an IgE-specific response requires the exposure of B cells to a particular complex of signals that include (a) a signal(s) involving Th-B cell interaction that primes B cells to receive additional signals from soluble lymphokines, (b) a specific B cell proliferative signal provided by LMW-BCGF, and (c) a specific B cell differentiation signal provided by IL-4.

scholarly journals T cell regulation of IgG subclass antibody production in response to T-independent antigens.

1981 ◽  
Vol 153 (1) ◽  
pp. 1-12 ◽  
Author(s):  
P K Mongini ◽  
K E Stein ◽  
W E Paul
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Heavy Chain ◽  
Chain Gene ◽  
Cell Clones ◽  
T Cell Regulation ◽  
The Difference

The effect of T lymphocytes on the IgM, IgG3, IgG1, IgG2b, and IgG2a responses of B lymphocytes to the type-2 T-independent antigens, trinitrophenylated (TNP)-Ficoll, and TNP-Levan, was investigated. T cell-bearing nu/+ mice were found to produce substantially higher IgG2 serum anti-TNP antibody than their athymic counterparts, and nu/nu and nu/+ IgG2a titers exhibiting more disparity than nu/nu and nu/+ IgG2b titers. The Igm, IgG3, and IgG1 anti-TNP levels in nu/nu and nu/+ mice were indistinguishable. By cell transfer experiments, it was determined that this variance in nude and heterozygote IgG2 responses could not be explained by B cell differences between the two strains or by suppressive effects on IgG2 production within nu/nu mice. Rather, the difference was shown to be the result of the absence of T cells at the time B cells were responding to antigen. In the absence of T cells, the strength of the nu/nu anti-TNP antibody response was found to be in the following order: IgM &gt; IgG3 &gt; IgG1 &gt; IgG2b &gt; IgG2a, a heirarchy identical with the recently proposed heavy chain gene order. The possibilities that T cells influence IgG2 production via their specific recognition of IgG2-bearing B cells or via signals to increase heavy chain switching of responding B cell clones are discussed.

scholarly journals Heterogeneity of helper/inducer T lymphocytes. II. Effects of interleukin 4- and interleukin 2-producing T cell clones on resting B lymphocytes.

1988 ◽  
Vol 167 (4) ◽  
pp. 1350-1363 ◽  
Author(s):  
W H Boom ◽  
D Liano ◽  
A K Abbas
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
B Lymphocytes ◽  
Th1 Cells ◽  
Specific Class ◽  
Ifn Gamma ◽  
T Cell Clones ◽  
Cell Clones

To compare the helper function of murine T cell clones that secrete IL-2 and IFN-gamma (Th1 cells) or IL-4 and IL-5 (Th2), purified resting B cells were stimulated with F(ab')2 rabbit anti-mouse Ig (RAMG) and rabbit Ig-specific, class II MHC-restricted cloned T cells belonging to the two subsets. Both Th2 clones examined induced strong proliferative responses of B cells in the presence of RAMG, as well as the secretion of IgM and IgG1 antibodies. In contrast, the Th1 clones tested failed to stimulate B cell growth or antibody secretion. Th2-mediated B cell activation was dependent on IL-4 and IL-5, and was also inhibited by IFN-gamma or IFN-gamma produced by Th1 cells present in the same cultures. However, the failure of Th1 cells to help resting B cells could not be reversed with neutralizing anti-IFN-gamma antibody. In addition to this inhibitory effect, IFN-gamma was required for the secretion of IgG2a antibody, particularly when B cells were stimulated with polyclonal activators such as LPS. Finally, both sets of T cell clones secreted lymphokines when stimulated with purified B cells and RAMG. These experiments demonstrate that T cells that differ in lymphokine production also differ in their ability to help B cells as a result of cognate interactions at low concentrations of antigens. Moreover, IL-4, IL-5, and IFN-gamma serve different roles in the T cell-dependent proliferative and differentiative responses of resting B lymphocytes.

scholarly journals B cell tolerance and antibody production to the celiac disease autoantigen transglutaminase 2

2019 ◽  
Vol 217 (2) ◽  
Author(s):  
M. Fleur du Pré ◽  
Jana Blazevski ◽  
Alisa E. Dewan ◽  
Jorunn Stamnaes ◽  
Chakravarthi Kanduri ◽  
...  
Keyword(s):  
Celiac Disease ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Transglutaminase 2 ◽  
General Mechanism ◽  
Cell Tolerance ◽  
B Cell Tolerance ◽  
Autoreactive B Cells ◽  
T Cell Help

Autoantibodies to transglutaminase 2 (TG2) are hallmarks of celiac disease. To address B cell tolerance and autoantibody formation to TG2, we generated immunoglobulin knock-in (Ig KI) mice that express a prototypical celiac patient–derived anti-TG2 B cell receptor equally reactive to human and mouse TG2. We studied B cell development in the presence/absence of autoantigen by crossing the Ig KI mice to Tgm2−/− mice. Autoreactive B cells in Tgm2+/+ mice were indistinguishable from their naive counterparts in Tgm2−/− mice with no signs of clonal deletion, receptor editing, or B cell anergy. The autoreactive B cells appeared ignorant to their antigen, and they produced autoantibodies when provided T cell help. The findings lend credence to a model of celiac disease where gluten-reactive T cells provide help to autoreactive TG2-specific B cells by involvement of gluten–TG2 complexes, and they outline a general mechanism of autoimmunity with autoantibodies being produced by ignorant B cells on provision of T cell help.

scholarly journals Preferential Localization of the Epstein-Barr Virus (EBV) Oncoprotein LMP-1 to Nuclei in Human T Cells: Implications for Its Role in the Development of EBV Genome-Positive T-Cell Lymphomas

2002 ◽  
Vol 76 (8) ◽  
pp. 4080-4086 ◽  
Author(s):  
Jingwu Xu ◽  
Ali Ahmad ◽  
José Menezes
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Epstein Barr Virus ◽  
Phenotypic Changes ◽  
Barr Virus ◽  
T Cell Lymphomas ◽  
Cell Clones ◽  
Epstein Barr

ABSTRACT The Epstein-Barr virus (EBV)-encoded latent membrane protein-1 (LMP-1) is thought to play a role in the EBV-induced B-cell transformation and immortalization. EBV has also been implicated in certain human T-cell lymphomas; however, the phenotypic effects of the expression of this oncoprotein in T cells are not known. To learn whether LMP-1 also induces phenotypic changes in T cells, we stably expressed it in human cell lines of T and B lineages and 25 LMP-1-expressing T-cell clones and 7 B-cell clones were examined. Our results show for the first time that, in sharp contrast to B cells, LMP-1 preferentially localizes to nuclei in T cells and does not induce the phenotypic changes in these cells that it induces in B cells, does not associate with TRAF proteins, and does not arrest the cell cycle in the G2/M phase. A computer-assisted analysis revealed that LMP-1 lacks the canonical nuclear localization signal. Our results suggest that this oncoprotein may not play the same role in the lymphomagenesis of T cells as it does in B cells.

scholarly journals B cell priming for extrafollicular antibody responses requires Bcl-6 expression by T cells

2011 ◽  
Vol 208 (7) ◽  
pp. 1377-1388 ◽  
Author(s):  
Sau K. Lee ◽  
Robert J. Rigby ◽  
Dimitra Zotos ◽  
Louis M. Tsai ◽  
Shimpei Kawamoto ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Plasma Cells ◽  
Antibody Responses ◽  
B Cell Differentiation ◽  
Tfh Cells ◽  
Follicular Helper ◽  
Microbial Infections

T follicular helper cells (Tfh cells) localize to follicles where they provide growth and selection signals to mutated germinal center (GC) B cells, thus promoting their differentiation into high affinity long-lived plasma cells and memory B cells. T-dependent B cell differentiation also occurs extrafollicularly, giving rise to unmutated plasma cells that are important for early protection against microbial infections. Bcl-6 expression in T cells has been shown to be essential for the formation of Tfh cells and GC B cells, but little is known about its requirement in physiological extrafollicular antibody responses. We use several mouse models in which extrafollicular plasma cells can be unequivocally distinguished from those of GC origin, combined with antigen-specific T and B cells, to show that the absence of T cell–expressed Bcl-6 significantly reduces T-dependent extrafollicular antibody responses. Bcl-6+ T cells appear at the T–B border soon after T cell priming and before GC formation, and these cells express low amounts of PD-1. Their appearance precedes that of Bcl-6+ PD-1hi T cells, which are found within the GC. IL-21 acts early to promote both follicular and extrafollicular antibody responses. In conclusion, Bcl-6+ T cells are necessary at B cell priming to form extrafollicular antibody responses, and these pre-GC Tfh cells can be distinguished phenotypically from GC Tfh cells.

scholarly journals A dynamic T cell–limited checkpoint regulates affinity-dependent B cell entry into the germinal center

2011 ◽  
Vol 208 (6) ◽  
pp. 1243-1252 ◽  
Author(s):  
Tanja A. Schwickert ◽  
Gabriel D. Victora ◽  
David R. Fooksman ◽  
Alice O. Kamphorst ◽  
Monica R. Mugnier ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
Cell Entry ◽  
Multiphoton Imaging ◽  
Histocompatibility Complex ◽  
Cell Clones ◽  
T Cell Help

The germinal center (GC) reaction is essential for the generation of the somatically hypermutated, high-affinity antibodies that mediate adaptive immunity. Entry into the GC is limited to a small number of B cell clones; however, the process by which this limited number of clones is selected is unclear. In this study, we demonstrate that low-affinity B cells intrinsically capable of seeding a GC reaction fail to expand and become activated in the presence of higher-affinity B cells even before GC coalescence. Live multiphoton imaging shows that selection is based on the amount of peptide–major histocompatibility complex (pMHC) presented to cognate T cells within clusters of responding B and T cells at the T–B border. We propose a model in which T cell help is restricted to the B cells with the highest amounts of pMHC, thus allowing for a dynamic affinity threshold to be imposed on antigen-binding B cells.

Effects Of Bendamustine Plus Rituximab On The Distribution Of Normal Peripheral Blood Leucocyte Populations In Advanced-Stage Chronic Lymphocytic Leukemia (CLL)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5289-5289 ◽  
Author(s):  
Georgiana Grigore ◽  
Martin Perez-Andres ◽  
Susana Barrena ◽  
Rosa Ana Rivas ◽  
Marcos González ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Plasma Cells ◽  
Memory B Cells ◽  
Lymphocytic Leukemia ◽  
Cd4 T Cell ◽  
Advanced Stage ◽  
Time Point

Abstract Introduction Management of B-cell chronic lymphocytic leukemia (CLL) is currently undergoing profound changes. Accordingly, new treatment options with an expected less toxicity than standard regimens are been explored. Recent results show that chemoimmunotherapy may improve the life expectancy of CLLpatients and has proven to be more efficient than chemotherapy alone in depleting malignant cells. Despite its efficacy, little is known about its precise immunomodulatory effects. Aim To evaluate the effects of chemoimmunotherapy with bendamustine plusrituximab (BR) on the distribution of normal residual leucocyte populations in peripheral blood (PB) from advanced-stage CLL patients, with special emphasis on maturation-associated B-cell subsets (immature, naïve, memory IgM/IgG/IgA and plasma cells). Material and Methods Distribution of PB neoplastic cells and residual normal immune cell subpopulations were analyzed in 72 CLL patients with advanced disease (Binet B/C), before therapy (M0) and after 1 course of BR (M1). The same analysis was repeated 3 months after completing treatment (M3) in 31/72 patients. PB leucocyte cell subsets were identified at each time-point by 8-color flow cytometry with monoclonal antibody reagents against CD3, CD4, CD5, CD8, TCRgd, CD19, CD20, CD27, CD38, CD45, CD56, sIgM, sIgA, sIgG, sIgLambda and sIgKappa. Results After the first BR course, absolute counts of all PB myeloid subsets were significantly decreased as compared to time M0, including neutrophils (2,744±1,830 vs 4,764±2,906 cells/uL, p<0.001), eosinophils (132±185 vs 215±245 cells/uL; p<0.001), basophils (37±28 vs 59±47 cells/uL, p<0.001), monocytes (334±280 vs 504±424 cells/uL, p=0.001) and dendritic cells (DCs, 41±40 vs 89±168 cells/uL, p=0.02), as well as NK cells (120±147 vs 550±599 cells/uL, p<0.001). At M3, all these populations remained decreased when compared to M0, but at similar levels to M1 (except for the absolute number of DCs, found to be increased vs. M1 -74±46 vs 41±40 cells/uL, p=0.008- and closer to M0). In turn, total T cells were reduced in M1 as compared to M0 values (818±655 vs 3,905±2,375 cells/uL, p<0.001), due to decreased numbers of CD4+ (424±376 vs 1,573±1,204 cells/uL, p<0.001), CD8+ (342±330 vs 1,334±1,218 cells/uL, p<0.001) and TCRgd (21±28 vs 141±289 cells/uL, p=0.001) T cells, leading to an increased CD4/CD8 ratio (1.8±1.3 vs 1.4±0.8, p=0.004). Also, decreased levels of CD4 (222±156 cells/uL), CD8 (501±544 cells/uL) and TCRgd (21±40 cells/uL) T cells were observed at time M3 vs. baseline values. No changes (p>0.05) were observed for CD8 and TCRgd for M3 vs. M1, while CD4+ T-cell numbers were significantly reduced (p=0.006), resulting in an inverted CD4/CD8 ratio (0.9±1.0 vs. 1.8±1.3, p=0.005) at the M3 time-point. As regards B cells, the absolute count of both neoplastic and normal B lymphocytes were significantly decreased at time M1 vs. M0 (3,363±9,353 vs 53,521±56,602 CLL cells/uL and 2±6 vs 58±107 normal B-cells/uL, p=0.006 and p<0.001, respectively). Within the normal residual B-cell compartment, we found significantly decreased numbers of immature (0.07±0.22 vs 6.55±21.64 cells/uL, p=0.01) and memory (1.3±14.7 vs 35.1±43.6 cells/uL, p<0.001) B cells -including sIgM (0.5±2.3 vs 14.5±24.8 cells/uL, p<0.001), sIgG (0.2±1.0 vs 11.5±17.2 cells/uL; p<0.001) and sIgA (0.6±3.1 vs 9.5±12.5 cells/uL, p<0.001) memory B cells-. At time M3, decreased (p<0.01) naïve (0.46±2.58 cells/uL) and memory B-cells (1.34±6.75 cells/uL), including IgM (0.46±2.58 cells/uL), IgG (0.34±1.69 cells/uL) and IgA (0.09±0.31 cells/uL), but not immature cells (2.28±8.84 cells/uL, p=0.9), were observed as compared to time M0. Differences did not reach statistical significance when comparing M3 vs. M1. The number of circulating plasma cells did not significantly vary during treatment. Conclusions All PB leucocyte subsets are affected by BR treatment in advanced-stage CLL. Interestingly, at time M3 the CD4+ T-cell subset continues to be decreased, while the other T-cell compartments seem to remain stable. Also, normal B cells are affected by BR treatment, and the depletion induced after one course therapy is maintained even three months after finishing BR therapy, except for immature B cells, that seem to be the first to recover in PB. Further studies will offer a more accurate insight into the biology of cell recovery during and after BR therapy in CLL patients. Disclosures: No relevant conflicts of interest to declare.

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