scholarly journals Spleen cells from animals tolerant to a thymus-dependent antigen can be activated by lipopolysaccharide to synthesize antibodies against the tolerogen.

1976 ◽  
Vol 143 (6) ◽  
pp. 1429-1438 ◽  
Author(s):  
G Möller ◽  
E Gronowicz ◽  
U Persson ◽  
A Coutinho ◽  
E Möller ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Immunological Tolerance ◽  
Cell Tolerance ◽  
Normal Numbers ◽  
Spleen Cells ◽  
B Cell Tolerance ◽  
Adult Mice ◽  
Protein Conjugate

Immunological tolerance was induced in adult mice by the injection of 5 mg of deaggregated hapten-protein conjugate. The tolerant state was confirmed 4-19 days later by the failure of such animals to mount an immune response against an aggregated form of the same thymus-dependent hapten-protein conjugate as well as by the inability of spleen cells from tolerant animals to respond to a thymus-independent hapten-carrier conjugate. Even though the animals were fully tolerant, their spleen cells were activated by lipopolysaccharide (LPS) in vitro to produce normal numbers of plaque-forming cells against the hapten. The finding that spleen cells from tolerant animals could be activated by LPS into synthesis of antibodies against the tolerogen indicates that tolerance to thymus-dependent antigens does not affect B cells, but presumably only T cells. It is suggested that the only stringent test for the existence of B-cell tolerance is the inability of polyclonal B-cell activators to activate antibody synthesis against the tolerogen. The findings make it unlikely that B-cell tolerance to autologous thymus-dependent antigens exists and further indicate that such antigens cannot deliver activating or tolerogenic signals to B cells, although they are competent to combine with and block the Ig receptors.

scholarly journals B-cell tolerance. II. Trinitrophenyl human gamma globulin-induced tolerance in adult and neonatal murine B cells responsive to thymus- dependent and independent forms of the same hapten

1977 ◽  
Vol 145 (3) ◽  
pp. 778-783 ◽  
Author(s):  
JC Cambier ◽  
ES Vitetta ◽  
JW Uhr ◽  
Kettman JR
Keyword(s):  
B Cells ◽  
B Cell ◽  
Gamma Globulin ◽  
Tolerance Induction ◽  
Cell Tolerance ◽  
B Cell Tolerance ◽  
Adult Mice ◽  
Human Gamma Globulin ◽  
Induction Of Tolerance

Neonatal splenic B cells which are responsive to thymus-dependent antigens (TD) are exquisitely susceptible to induction of tolerance (1,2). This state of tolerance is not mediated by suppressor T cells and is not a result of suboptimal macrophage function (1 and footnote one). In adult mice, induction of B-cell tolerance is not achieved with doses of antigen 1,000-fold higher (1) than those required to produce the same degree of unresponsiveness in neonates. In contrast to these results, studies with T-independent (TI) antigens indicate that neonatal and adult splenic B cells are equally susceptible to tolerance induction (3,4). However, such studies have not ascertained whether the neonate is more resistant to tolerance induction or the adult is hypersusceptible, i.e., does the induction of tolerance in cells responsive to TI antigens resemble that of adult or neonatal cells responsive to TD antigens? The answer is pertinent to determining the relative maturity of the B cells which can be tolerized or respond to TI or TD antigens. We report here the direct comparison of tolerogen sensitivity of adult and neonatal TD and TI responses by inducing tolerance in vitro with trinitophenyl human gamma globulin (TNP(17)HgG) and assaying unresponsiveness with TD and TI forms of the TNP determinant.

Role Of B Cell Tolerance In PF4/Heparin Antibody Production

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2396-2396
Author(s):  
Yongwei Zheng ◽  
Alexander W Wang ◽  
Mei Yu ◽  
Anand Padmanabhan ◽  
Benjamin E Tourdot ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Board Of Directors ◽  
Cell Tolerance ◽  
Inflammatory Stimulus ◽  
Wild Type ◽  
B Cell Tolerance ◽  
Advisory Committees

Abstract Heparin-induced thrombocytopenia (HIT) is an immune-mediated disorder that can cause fatal arterial or venous thrombosis/thromboembolism. Immune complexes consisting of heparin, platelet factor 4 (PF4) and PF4/heparin-reactive antibodies are central to the pathogenesis of HIT. However, heparin, a glycosoaminoglycan, and PF4 are normal body constituents and it is as yet unclear what triggers the initial induction of pathogenic antibodies. Here we described detection of B cells among peripheral blood mononuclear cells (PBMCs) from each of 9 healthy adults that produced PF4/heparin-specific IgM antibodies following in vitro stimulation with ubiquitous pro-inflammatory molecules containing unmethylated CpG dinucleotides derived from bacterial and viral DNA. PF4/heparin-specific IgM-generating B cells were present at a frequency of at least 0.03 to 1 per thousand B cells present in the PBMC population. Similarly, splenic B cells isolated from unmanipulated wild-type mice consistently produced PF4/heparin-reactive antibodies following in vitro stimulation with CpG. In addition, wild-type mice produced PF4/heparin-reactive antibodies upon in vivo challenge with CpG whereas unchallenged wild-type mice did not. These findings demonstrate that both humans and mice possess pre-existing, inactive and tolerant PF4/heparin-specific B cells. We suggest that tolerance can be broken by a strong inflammatory stimulus, leading to activation of these B cells and production of antibodies that recognize PF4/heparin in vitro and in vivo. Consistent with this concept, mice lacking protein kinase Cd (PKCd), a signaling molecule of the B-cell survival factor BAFF (B-cell activation factor), that are known to have breakdown of B-cell tolerance to self-antigens, spontaneously produced anti-PF4/heparin antibodies in the absence of an inflammatory stimulus. Taken together, these findings demonstrate that breakdown of tolerance can lead to PF4/heparin-specific antibody production and that B-cell tolerance plays an important role in HIT pathogenesis. Disclosures: White II: Bayer: Membership on an entity’s Board of Directors or advisory committees; CSL-Behring: Membership on an entity’s Board of Directors or advisory committees; NIH: Membership on an entity’s Board of Directors or advisory committees; Asklepios: Membership on an entity’s Board of Directors or advisory committees; Wyeth: Membership on an entity’s Board of Directors or advisory committees; Entegrion: Membership on an entity’s Board of Directors or advisory committees; Biogen: Membership on an entity’s Board of Directors or advisory committees; Baxter: Membership on an entity’s Board of Directors or advisory committees.

scholarly journals Induction of immunological tolerance requires that the B cells can respond to the polyclonal B-cell-activating properties of the thymus-independent antigens.

1977 ◽  
Vol 146 (1) ◽  
pp. 308-312 ◽  
Author(s):  
C Fernandez ◽  
G Möller
Keyword(s):  
B Cells ◽  
B Cell ◽  
Tolerance Induction ◽  
Immunological Tolerance ◽  
Spleen Cells ◽  
Normal Cells ◽  
Purified Protein Derivative ◽  
High Affinity

Mice were rendered specifically tolerant to the fluorescein isothiocyanatedextran (FITC) epitope by injection of FITC-dextran B512. Their spleen cells were removed at various times and cultivated in vitro with different polyclonal B-cell activators, such as lipopolysaccharide (LPS), purified protein derivative of tuberculin, and native dextran. LPS caused the appearance of high affinity anti-FITC plaque-forming cells to an equal extent with cells from untreated and tolerant animals, whereas native dextran failed to activate cells from tolerant mice, although it was a potent activator of normal cells. It was concluded that tolerance induction only affects those B cells that could respond to the polyclonal B-cell-activating properties of the tolerogen, but not other B cells having an identical set of Ig receptors directed against the tolerogen.

scholarly journals Ontogeny of B-lymphocyte function. III. In vivo and in vitro studies on the ease of tolerance induction in B lymphocytes from fetal, neonatal, and adult mice

1977 ◽  
Vol 145 (6) ◽  
pp. 1590-1601 ◽  
Author(s):  
MR Szewczuk ◽  
GW Siskind
Keyword(s):  
B Cells ◽  
B Lymphocytes ◽  
Tolerance Induction ◽  
Cell Tolerance ◽  
B Cell Tolerance ◽  
Adult Mice ◽  
Immature B Cells ◽  
Neonatal Liver

The ease of tolerance induction in B lymphocytes from fetal, neonatal, and adult mice was studied in vivo, in a cell transfer system, and in vitro. Three different tolerogens were used: ultracentrifuged BGG, DNP(6)-D-GL, and ultracentrifuged DNP(22)-BGG. Irradiated thymectomized mice were reconstituted with B cells from fetal or neonatal liver or adult spleen or bone marrow. The mice were injected with tolerogen 1 day later. They were given normal thymus cells and challenged with either BGG or DNP(44)-BGG between 4 and 14 days after tolerance induction. With BGG no difference in ease of B-cell tolerance induction was observed in mice reconstituted with B cells from 17-day fetal liver, neonatal liver, 8- day-old spleen, adult spleen, or adult bone marrow. B cells from 14-day fetal donors are relatively resistant to tolerance induction. In contrast, with DNP(6)-D-GL and DNP(22)-BGG B cells from neonatal donors were clearly more susceptible to tolerance induction than were B cells from adult donors. Comparable results were obtained in studies on tolerance induction in vitro. Neonatal B cells were more susceptible than adult B cells to tolerance induction upon culture with DNP(6)-D-GL or DNP(22)-BGG. However, neonatal and adult B cells were identical with respect to ease of tolerance induction in vitro with deaggregated BGG. The results suggest that there are multiple mechanisms for B-cell tolerance induction. Immature B cells appear to be more susceptible to tolerance induction by some mechanisms but not by others. It is suggested that immature B cells are more susceptible to tolerance induction with moderately polyvalent antigens such as hapten-carrier conjugates. With antigens like BGG which do not haverepeated epitopes no difference between mature and fetal B cells in regard to ease of tolerance induction is observed. These observations raise questions about the importance of relative ease of tolerance induction in immature B cells as a mechanism controlling the normal induction of self tolerance.

scholarly journals Differences in susceptibility of mature and immature mouse B lymphocytes to anti-immunoglobulin-induced immunoglobulin suppression in vitro. Possible implications for B-cell tolerance to self.

1975 ◽  
Vol 142 (5) ◽  
pp. 1052-1064 ◽  
Author(s):  
M C Raff ◽  
J J Owen ◽  
M D Cooper ◽  
A R Lawton ◽  
M Megson ◽  
...  
Keyword(s):  
B Cells ◽  
Cell Surface ◽  
B Cell ◽  
Fetal Liver ◽  
Lymphoid Tissues ◽  
Cell Tolerance ◽  
B Cell Tolerance ◽  
Low Concentrations ◽  
Immature Mouse

Purified goat antibodies against mouse mu-chains and rabbit antibodies against mouse Ig determinants, and their Fab fragments, inhibited the development of IgM-bearing B cells in explant cultures of 14-day mouse fetal liver, and caused the disappearance of cell surface IgM in explant and dissociated cell cultures of more developed lymphoid tissues. While treatment of cultures of fetal or newborn liver, or adult bone marrow, with low concentrations (less than or equal to 10 mug/ml) of anti-Ig for less than or equal to 24 h caused the complete, but reversible, disappearance (modulation) of cell surface IgM, treatment for greater than or less than 48 h produced irreversible IgM suppression. In contrast, anti-Ig-induced suppression of cell surface IgM in cultures of adult spleen or lymph nodes required much higher concentrations of antibody (greater than or equal to 100 mug/ml) and was always reversible. These differences between immature and mature IgM-bearing cells could not be related to differences in the amount of surface IgM on the cells. The remarkable sensitivity of newly formed B cells to IgM modulation and irreversible IgM suppression when ligands bind to their Ig receptors, may have important implications for B-cell tolerance to self antigens.

scholarly journals Defective B cell tolerance in adult (NZB X MZW)F1 mice.

1980 ◽  
Vol 152 (3) ◽  
pp. 730-735 ◽  
Author(s):  
E A Goldings ◽  
P L Cohen ◽  
S F McFadden ◽  
M Ziff ◽  
E S Vitetta
Keyword(s):  
B Cells ◽  
Autoimmune Disease ◽  
B Cell ◽  
Gamma Globulin ◽  
Cell Tolerance ◽  
B Cell Tolerance ◽  
Epitope Density ◽  
Human Gamma Globulin ◽  
Specific Tolerance

Hapten-specific tolerance was induced in vitro by trinitrophenyl-human gamma globulin (TNP32HGG) to a comparable degree in B cells from adult autoimmune (NZB X NZW)F1 (B/W) mice and normal BDF1, CBA/J, and DBA/1J mice. When a lower epitope density tolerogen (TNP7HGG) was used, B/W mice were significantly less sensitive than normal mice to the induction of B cell tolerance. This finding of defective B cell tolerance in adult B/W mice is consistent with previous reports that document other B cell abnormalities that may relate to the expression of autoimmune disease.

BAFF/Blys Levels Correlate with Disease Activity and Alter Peripheral B Cell Subsets in Patients with Chronic GVHD.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 41-41 ◽  
Author(s):  
Stefanie Sarantopoulos ◽  
Kristen E. Stevenson ◽  
Haesook T. Kim ◽  
Nazmim S. Bhuiya ◽  
Corey S. Cutler ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Chronic Gvhd ◽  
P Value ◽  
High Dose ◽  
Cell Tolerance ◽  
B Cell Tolerance ◽  
Hematopoietic Stem ◽  
B Cell Subsets

Abstract Patients with chronic graft versus host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT) have been found to have high titers of allo-reactive antibodies, but a role for B cells in the pathology of this disease remains undefined. B Cell Activating Factor, BAFF/Blys (BAFF), promotes differentiation and expansion of antigen-activated B cells and contributes to loss of B cell tolerance in animal models. We hypothesized that the BAFF/BAFF receptor (BAFF-R) pathway may perpetuate potentially allo- or auto-reactive antigen-experienced CD27+ B cells in patients with cGVHD after HSCT. Soluble BAFF was measured in plasma from 104 patients after HSCT. Median BAFF levels were statistically different when groups were compared using a two-sided Wilcoxon-Rank-Sum test (see Table below). Logistic regression analysis revealed that higher BAFF levels were associated with active cGVHD after adjusting for other GVHD prognostic factors (p=0.0007). Patients with ≥10ng/ml BAFF levels had ten-fold increased odds of having cGVHD compared to patients with BAFF levels of <10ng/ml (OR of 10.8, p=<0.0001). High dose prednisone reduced median plasma BAFF levels (3.8ng/ml in patients receiving ≥30mg daily prednisone versus 14ng/ml for those receiving <30mg or no prednisone). Serial BAFF measurements revealed peak BAFF levels at 6 months post-HSCT in patients who later developed limited cGVHD. 81% of patients with BAFF levels >10ng/ml at 6 months subsequently developed cGVHD (median BAFF was 20ng/ml) compared to 39% of patients with BAFF levels <10ng/ml at 6 months (p=0.002). We also found that BAFF-R expression on B cells was down-regulated in vitro in the presence of BAFF. Consistent with this finding flow cytometry revealed very low BAFF-R expression on B cells in patients with active cGVHD. BAFF-R expression on peripheral B cells correlated with BAFF levels (p=0.0001), suggesting that BAFF signals via BAFF-R in cGVHD. We used 5-color FACS to characterize peripheral B cell subsets in 68 post-HSCT patients. Compared to patients without cGVHD, the proportion of antigen-experienced CD27+ B cells was increased in patients with limited cGVHD (n=20, p=0.04). The extensive cGVHD patient group was smaller (n=11) with greater variability in CD27+ B cell frequency resulting in no statistical difference (p=0.27). The proportion of CD27+ post-germinal center B cells was also increased in patients with active cGVHD (p=0.04 and p=0.03 extensive and limited cGVHD, respectively). High BAFF levels correlated with increased total numbers of CD27+ B cells (p=0.05), but not with total or naïve B cell numbers, suggesting that BAFF plays a role in perpetuation of circulating antigen-experienced and memory B cells in cGVHD patients. Our results suggest that high levels of BAFF after HSCT help break peripheral B cell tolerance and contribute to cGVHD pathobiology. Comparison of BAFF Levels Between Extensive/Limited versus Inactive/No cGVHD Groups cGVHD Type N Median BAFF (ng/ml) p-value vs. inactive p-value vs. no Extensive 15 11.5 0.14 0.02 Limited 33 9.0 0.02 0.0004 Inactive 27 5.7 - 0.02 No 29 4.4 0.16 - Normal 26 1.9 0.0002 0.004

scholarly journals Central human B cell tolerance manifests with a distinctive cell phenotype and is enforced via CXCR4 signaling in hu-mice

2021 ◽  
Vol 118 (16) ◽  
pp. e2021570118
Author(s):  
Thiago Alves da Costa ◽  
Jacob N. Peterson ◽  
Julie Lang ◽  
Jeremy Shulman ◽  
Xiayuan Liang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Immune System ◽  
B Cells ◽  
B Cell ◽  
Cell Tolerance ◽  
Human Immune System ◽  
B Cell Tolerance ◽  
Autoreactive B Cells ◽  
Cell Clones ◽  
Human Immune

Central B cell tolerance, the process restricting the development of many newly generated autoreactive B cells, has been intensely investigated in mouse cells while studies in humans have been hampered by the inability to phenotypically distinguish autoreactive and nonautoreactive immature B cell clones and the difficulty in accessing fresh human bone marrow samples. Using a human immune system mouse model in which all human Igκ+ B cells undergo central tolerance, we discovered that human autoreactive immature B cells exhibit a distinctive phenotype that includes lower activation of ERK and differential expression of CD69, CD81, CXCR4, and other glycoproteins. Human B cells exhibiting these characteristics were observed in fresh human bone marrow tissue biopsy specimens, although differences in marker expression were smaller than in the humanized mouse model. Furthermore, the expression of these markers was slightly altered in autoreactive B cells of humanized mice engrafted with some human immune systems genetically predisposed to autoimmunity. Finally, by treating mice and human immune system mice with a pharmacologic antagonist, we show that signaling by CXCR4 is necessary to prevent both human and mouse autoreactive B cell clones from egressing the bone marrow, indicating that CXCR4 functionally contributes to central B cell tolerance.

scholarly journals Active PI3K abrogates central tolerance in high-avidity autoreactive B cells

2019 ◽  
Vol 216 (5) ◽  
pp. 1135-1153 ◽  
Author(s):  
Sarah A. Greaves ◽  
Jacob N. Peterson ◽  
Pamela Strauch ◽  
Raul M. Torres ◽  
Roberta Pelanda
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
B Cell ◽  
Peripheral Tolerance ◽  
High Avidity ◽  
Cell Tolerance ◽  
B Cell Tolerance ◽  
Central Tolerance ◽  
Autoreactive B Cells ◽  
Self Antigen

Autoreactive B cells that bind self-antigen with high avidity in the bone marrow undergo mechanisms of central tolerance that prevent their entry into the peripheral B cell population. These mechanisms are breached in many autoimmune patients, increasing their risk of B cell–mediated autoimmune diseases. Resolving the molecular pathways that can break central B cell tolerance could therefore provide avenues to diminish autoimmunity. Here, we show that B cell–intrinsic expression of a constitutively active form of PI3K-P110α by high-avidity autoreactive B cells of mice completely abrogates central B cell tolerance and further promotes these cells to escape from the bone marrow, differentiate in peripheral tissue, and undergo activation in response to self-antigen. Upon stimulation with T cell help factors, these B cells secrete antibodies in vitro but remain unable to secrete autoantibodies in vivo. Overall, our data demonstrate that activation of the PI3K pathway leads high-avidity autoreactive B cells to breach central, but not late, stages of peripheral tolerance.

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