scholarly journals Metabolic Swifts Govern Normal and Malignant B Cell Lymphopoiesis

2021 ◽  
Vol 22 (15) ◽  
pp. 8269
Author(s):  
Aikaterini Poulaki ◽  
Stavroula Giannouli
Keyword(s):  
B Cell ◽  
B Lymphocytes ◽  
Control Program ◽  
Memory B Cells ◽  
Immunologic Memory ◽  
Human Immune System ◽  
B Cell Malignancies ◽  
Stringent Control ◽  
Human Immune ◽  
New Research

B lymphocytes are an indispensable part of the human immune system. They are the effective mediators of adaptive immunity and memory. To accomplish specificity against an antigen, and to establish the related immunologic memory, B cells differentiate through a complicated and strenuous training program that is characterized by multiple drastic genomic modifications. In order to avoid malignant transformation, these events are tightly regulated by multiple checkpoints, the vast majority of them involving bioenergetic alterations. Despite this stringent control program, B cell malignancies are amongst the top ten most common worldwide. In an effort to better understand malignant pathobiology, in this review, we summarize the metabolic swifts that govern normal B cell lymphopoiesis. We also review the existent knowledge regarding malignant metabolism as a means to unravel new research goals and/or therapeutic targets.

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.

Different Expression of FcgammaRIIb in Chronic Lymphocytic Leukemia and Human Normal B Lymphocytes

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3134-3134
Author(s):  
Carol Moreno ◽  
Rajendra Damle ◽  
Sonia Jansa ◽  
Gerardo Ferrer ◽  
Pau Abrisqueta ◽  
...  
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
B Lymphocytes ◽  
Surface Membrane ◽  
Memory B Cells ◽  
Lymphocytic Leukemia ◽  
Cd38 Expression ◽  
B Cell Subsets

Abstract The Fcgamma receptors (FcγRs) are a family of molecules that modulate immune responses. FcγRIIb is an inhibitory FcγR that bears immunoreceptor tyrosine-based inhibitory motifs which transduce inhibitory signals on coligation with the surface membrane Ig of the B-cell antigen receptor (BCR). The role of FcγRIIb in controlling B cell activation through inhibition of BCR signaling has been extensively studied in animal models. Nevertheless, data on FcγRIIb are scant in human normal and neoplastic B cells, this being due to the lack of a specific antibody for human FcγRIIb. Consequently, there is little information on this receptor in chronic lymphocytic leukemia (CLL). Considering the activated nature of CLL cells and the central role of the BCR in the biology of the disease, studies of FcγRs are warranted. We used a novel specific mAb directly conjugated with Alexa 488 fluorophore that solely reacts with the human FcγRIIb (MacroGenics, Inc.) to investigate the receptors expression on CLL and normal human B cells. The study population included 84 patients with CLL and 24 age- and sex-matched controls. FcγRIIb expression was assessed as the mean fluorescence intensity (MFI) of surface membrane staining. In CLL cells, FcγRIIb was measured on CD19+CD5+ cells in combination with CD38, CD49d or CD69. Normal B cells were immunostained for CD19, CD5, IgD and CD38 expression and B cell subsets: naïve (IgD+CD38−), activated (IgD+CD38+) and memory B cells (IgD−CD38−) were studied for their relative expression of FcγRIIb. FcγRIIb expression was found significantly higher in naïve B cells compared to activated and memory B cells [median MFI: 17420 (11960–21180) vs. 11.140 (7899–16970) and 11.830 (6984–17100); p<0.001]. Significant differences were also observed between CD5− and CD5+ normal B cells. In contrast, FcγRIIb expression was lower in CLL cells than in CD5+ and CD5− normal B lymphocytes [median MFI: 6901(1034–42600), 10180 (5856–14820) and 12120 (7776–16040); p<0.05)]. Interestingly, FcγRIIb expression was variable within individual CLL clones, this being higher in CD38+ and CD49d+ cells than in CD38− and CD49d− cells (p<0.05). Furthermore, the highest density of FcγRIIb was observed on those cells which coexpressed CD38 and CD49d. In contrast, no significant differences were observed between FcγRIIb and the expression of the activation antigen CD69. Although CD69 and CD38 expression was significantly higher on unmutated IGHV cases, no correlation was found between FcγRIIb levels and IGHV mutational status. Similarly, there was no correlation between FcγRIIb and other poor prognostic variables such as ZAP-70 (≥20%), CD38 (≥ 30%) or high risk cytogenetics. Nevertheless, cases with ≥ 30% CD49d+ cells had higher FcγRIIb expression than those with <30% CD49d+ cells (p=0.006). The findings presented in this study suggest a hierarchy of FcγRIIb expression in normal B-cells, CLL cells and their subpopulations: circulating normal CD5− B cells > circulating normal CD5+ B cells > circulating CD5+ CLL B cells. In addition, although FcγRIIb is present on all normal B cell subsets its expression is higher in naïve B cells. Furthermore, in CLL FcγRIIb density is greater in CD38+ and CD49d+ cells within the clone. Although CD49d and FcγRIIb on CLL clones is linked in a direct manner, there is no relationship with FcγRIIb density and IGHV mutations, ZAP-70, CD38 and unfavorable cytogenetic markers. Finally, the relationship between FcγRIIb expression on CLL cells and functional responses to BCR and other receptor-mediated signals deserve further investigation.

scholarly journals Efficient Acquisition of Fully Human Antibody Genes against Self-Proteins by Sorting Single B Cells Stimulated with Vaccines Based on Nitrated T Helper Cell Epitopes

2019 ◽  
Vol 2019 ◽  
pp. 1-16
Author(s):  
Liangliang Jiang ◽  
Tao Jiang ◽  
Jianhua Luo ◽  
Yanliang Kang ◽  
Yue Tong ◽  
...  
Keyword(s):  
T Cells ◽  
Immune System ◽  
B Cells ◽  
B Cell ◽  
Immune Tolerance ◽  
Human Antibody ◽  
T Helper ◽  
Human Immune System ◽  
Helper Epitope ◽  
Human Immune

Single B cell antibody technology is a method for isolating antigen-specific B cells from human peripheral blood and obtaining antibody genes in developing antibody drugs. However, owing to immune tolerance to autoantigen, human autoantigen-specific B cells are difficult to acquire by conventional single B cell technology. In this study, we constructed a nitrated T-cell epitope named NitraTh by incorporating p-nitrophenylalanine into a universal T helper epitope. NitraTh had enhanced ability to activate CD4+ T cells and can be recognized by CD4+ T cells with different HLA class II haplotypes. This NitraTh can also break immune tolerance to autoantigens, such as human epidermal growth factor receptor 2 (HER2) and cannabinoid receptor 1, and induce strong specific IgM+ B cell responses in vitro. HER2-NitraTh vaccine can also stimulate the generation of HER2-specific IgG+ B cells in human immune system mice, which was established by cotransplanting lymphocytes and autologous dendritic cells in immunodeficient mice. We obtained 30 fully human IgG antibody genes by sorting single B cells from the human immune system mice immunized with HER2-NitraTh vaccine. The analysis of antibody genes showed that sorted B cells underwent the extensive somatic mutation of the antibody genes. We randomly selected eight genes for cloning, six of which expressed antibodies that can bind to HER2. Hence, we provided a convenient and effective method in acquiring fully human antibody genes against self-proteins, which can be used in developing therapeutic antibody drugs.

CD19+,CD27+, IgM+ B Cells of Patients with Persistent Polyclonal B Cell (PPBL) Proliferate in a Low Intensity CD40-CD154 Interaction and Show Evidence of Immunoglobulin Isotype Switching

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4920-4920
Author(s):  
Robert Delage ◽  
Emmanuelle Dugas-Bourdages ◽  
Annie Roy ◽  
Sonia Neron ◽  
Andre Darveau
Keyword(s):  
T Cells ◽  
B Cells ◽  
B Cell ◽  
B Lymphocytes ◽  
Cell Population ◽  
Genetic Defect ◽  
Memory B Cells ◽  
Isotype Switching ◽  
Low Intensity

Abstract Persistent polyclonal B cell lymphocytosis (PPBL) is a rare disorder characterized by an expansion of memory B cells CD19+, CD27+, IgM+. PPBL occurs mainly in female, is associated with HLA DR7, an increased level of serum IgM and the lymphocytes frequently show a bi-nucleated morphology. The patients have in most cases smoking habits and the clinical evolution is usually benign but we have previously described one case of lymphoma 19 years after a diagnosis of PPBL. Although the pathophysiology remains unknown, a familial occurrence is at the basis of this disorder suggesting a genetic defect. Moreover, multiple bcl-2\Ig gene rearrangements are present in all patients and an extra isochromosome 3 (i3)(q10) is frequently shown in the B cell population. The binding of CD40 to CD154 expressed on activated T cells plays a central role in B cell activation, proliferation and Ig isotype switching. We have previously shown that PPBL B lymphocytes were unable to respond to the proliferative signal delivered in vitro by CD40 in the CD40-CD154 system, indicating a possible defect in the CD40 pathway although CD40 expression, sequencing and tyrosine phosphorylation appeared normal. However, it has been shown recently that a reduced intensity of CD40-CD154 interaction in the presence of IL-2, IL-4 and IL-10 results in the proliferation, expansion and immunoglobulin secretion of normal memory CD19+,CD27+, IgM+ B cells. PPBL B lymphocytes sharing the same phenotype as normal memory B cells, we design a study to investigate the response of B lymphocytes from patient with PPBL in culture in high and low CD154 interaction. Proliferation and flow cytometry analysis of B lymphocytes from 6 patients with PPBL were closely monitored through a 14 day culture period and the Ig secretion was determined by Elisa. Our results show that a low intensity CD40- CD154 interaction in the presence of IL-2, IL-4 and IL-10 induces proliferation of the CD19+,CD27+,IgM+ PPBL population 6 to 20 times higher compared to high CD154 interaction. Interestingly, the CD19+, IgG+ cell population that constitutes less than 5% of the cell population at the beginning of the culture, increased over 25% on day 14. As for normal controls, we observed the emergence of a CD19+,CD27− cell population and the disappearance of surface IgD. Culture of B cells from patients with PPBL resulted in high Ig secretion. Moreover on day 14, Ig isotype analysis showed higher IgG levels compared to IgM. We conclude that PPBL B lymphocytes could proliferate in the CD40- CD154 system under proper condition and that proliferation also results in IgM and IgG secretion indicating an adequate CD40 signalling pathway. Moreover, this report provides the first evidence of in vitro Ig isotype switching of CD19+,CD27+,IgM+ B lymphocytes from PPBL. These results also suggest a possible defect in the interaction with T cells as observed in the hyper-IgM syndrome or alternatively, other cells from the microenvironment.

scholarly journals Humans with chronic granulomatous disease maintain humoral immunologic memory despite low frequencies of circulating memory B cells

Blood ◽  
2012 ◽  
Vol 120 (24) ◽  
pp. 4850-4858 ◽  
Author(s):  
Susan Moir ◽  
Suk See De Ravin ◽  
Brian H. Santich ◽  
Jin Young Kim ◽  
Jacqueline G. Posada ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Chronic Granulomatous Disease ◽  
Somatic Hypermutation ◽  
Memory B Cells ◽  
Potential Contribution ◽  
Granulomatous Disease ◽  
Immunologic Memory ◽  
Activation Markers ◽  
Specific Memory

Abstract CD27+ memory B cells are reduced in the blood of patients with chronic granulomatous disease (CGD) for reasons and consequences that remain unclear. Here we confirm not only decreased CD27+ but also IgG+ B cells in the blood of CGD patients compared with healthy donors (HDs). However, among IgG+ B cells, the ratio of CD27− to CD27+ was significantly higher in CGD patients compared with HDs. Similar to conventional memory B cells, CD27−IgG+ B cells of CGD patients expressed activation markers and had undergone somatic hypermutation, albeit at levels lower than their CD27+ counterparts. Functional analyses revealed slight reductions in frequencies of total IgG but not influenza-specific memory B-cell responses, as measured by Elispot in CGD patients compared with HDs. Serum IgG levels and influenza-specific antibodies were also normal in these CGD patients. Finally, we provide evidence that influenza-specific memory B cells can be present within the CD27−IgG+ B-cell compartment. Together, these findings show that, despite reduced circulating CD27+ memory B cells, CGD patients maintain an intact humoral immunologic memory, with potential contribution from CD27− B cells.

scholarly journals An improved clonal excess assay using flow cytometry and B-cell gating

Blood ◽  
1990 ◽  
Vol 75 (5) ◽  
pp. 1178-1185
Author(s):  
BW Letwin ◽  
PK Wallace ◽  
KA Muirhead ◽  
GL Hensler ◽  
WH Kashatus ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
B Cells ◽  
B Cell ◽  
B Lymphocytes ◽  
Fluorescence Intensity ◽  
Light Scatter ◽  
B Cell Malignancies ◽  
Clonal Proliferation ◽  
Minimal Disease ◽  
Low Levels

In humans with B-cell malignancies, the presence of monoclonal B lymphocytes (clonal proliferation) can be detected by comparing the fluorescence intensity distributions of lymphocytes stained with anti- kappa and anti-lambda reagents. The sensitivity of previously described single-color immunofluorescence techniques to low levels of clonal excess is limited by background from cytophilic immunoglobulins on non- B cells and by the low proportion of circulating B cells in individuals with minimal disease. We have used two-color immunofluorescence and B- cell gating to develop an improved assay that avoids false positives due to non-B cells, without requiring restrictive light scatter gates that may exclude true positives. This method is sensitive to 0.2% monoclonal B cells admixed with fresh normal lymphocytes, to 0.6% monoclonal B cells admixed with normal lymphocytes that have been stored for up to 72 hours, and readily detects 1% monoclonal cells in patient specimens. The two color B-cell gated assay offers sensitivity equivalent to the single-color assay and improved specificity for detection of low levels of clonal excess.

scholarly journals Diffuse Large B Cell Pdtx in Humanized Mice Are Valuable Models to Study Host-Lymphoma Interactions and Immune-Modulating Agents

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2406-2406
Author(s):  
Giorgia Zanetti ◽  
Giuseppina Astone ◽  
Luca Cappelli ◽  
William Chiu ◽  
Maria Teresa Cacciapuoti ◽  
...  
Keyword(s):  
T Cells ◽  
Immune System ◽  
T Cell ◽  
B Cell ◽  
Research Funding ◽  
Ex Vivo ◽  
Human Immune System ◽  
Human T Cells ◽  
Human Immune

Abstract Introduction: Immunotherapy is a promising therapeutic intervention for cancer treatment. Activation of the immune system via checkpoint blockade has been shown to produce antitumor responses in patients with both solid and hematological tumors. However, many patients do not respond to checkpoint inhibitors, and additional therapies are needed to treat these patients. Testing immunotherapies requires a functional human immune system; thus, it is difficult to evaluate their effectiveness using conventional experimental models. For this reason, establishing in vivo models that closely reproduce not only human tumors, but also their interactions with the human immune system, has become mandatory. Methods: We developed a humanized mouse model and combined it with a patient-derived tumor xenograft (PDTX). Humanized mice (HuMice) were generated by transplantation of cord blood or mobilized peripheral blood CD34+ hematopoietic stem and progenitor cells into preconditioned immunodeficient mice. We compared human engraftment in 3 different mouse strains: NSG (NOD.Cg-Prkdc scidIl2rg tm1Wjl/SzJ), NSGS (NOD.Cg-Prkdc scidIl2rg tm1Wjl Tg(CMV-IL3,CSF2,KITLG)1Eav/MloySzJ) and NBSGW (NOD.Cg-Kit W-41J Tyr + Prkdc scid Il2rg tm1Wjl/ThomJ). Immune cell profiling and distribution was performed using flow cytometry and immunohistochemistry. The B cell receptor (BCR) repertoire was evaluated using an RNA-based NGS assay. To evaluate the maturation and functionality of T cells developing in HuMice we performed proliferation, degranulation and intracellular cytokine staining. Results: Two months after CD34+ cell transplantation, we observed high levels of human hematopoietic chimerism in all the 3 strains. NSGS mice supported high-level chimerism as early as 1 month after transplantation, with more than 25% of human CD45+ cells in the blood. In all mice the majority of human circulating leukocytes were CD19+ B cells. An early appearance of CD3+ human T cells was detected in NSGS mice as compared to the other strains. Notably, the T cell expansion correlated with a decrease in relative B cell abundance while the myeloid cell contribution to the graft remained steady. We documented the differentiation of CD4+ and CD8+ human T cells at a 2:1 ratio. The characterization of the T cell subsets revealed that the majority was represented by CD45RA-CCR7- effector memory cells in both the spleen and the blood of HuMice. Nevertheless, recipient mice did not exhibit overt signs of graft-versus-host disease. We also evaluated the cytotoxic potential of T cells isolated from the spleen of HuMice: ex vivo peptide antigen (i.e. EBV) presentation let to generation of effective and specific cytotoxic T-cells. After assessing a functional human immune system reconstitution in HuMice, we challenged them in vivo with low-passage tumor fragments from a diffuse large B cell lymphoma (DLBCL) PDTX. All tumor implants were successfully engrafted in both HuMice and non-humanized controls. Remarkably, all the 3 HuMice strains showed a significant reduction in the tumor volume and/or eradication compared to matched non-humanized controls. Flow cytometry analysis of the peripheral blood of humanized PDTX revealed that the tumor engraftment elicited a significant expansion of CD3+ T cells and cytotoxic CD8+ lymphocytes. Moreover, tumors developing in HuMice exhibited intermediate to high levels of tumor infiltrating T lymphocytes commingling with the neoplastic B cells, as determined by immunohistochemistry. Large areas of necrosis were often observed in PDTX of HuMice. Infiltrating CD3+ cells were TIGIT, PD-1 and Lag-3 positive, and did not efficiently proliferate ex vivo: all features consistent with an exhaustion phenotype. PDTX of HuMice often displayed larger areas of necrosis. Conclusions: Collectively, our data demonstrate that a robust reconstitution can be achieved in different strains of immunocompromised mice and that HuMice elicit effective anti-lymphoma responses. PDTX HuMice represent a powerful platform to study host-tumor interactions, and to test novel immune-based strategies (CAR-T, bifunctional Abs) and new pharmacological approaches to counteract T-cell exhaustion. Figure 1 Figure 1. Disclosures Scandura: Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Constellation: Research Funding; MPN-RF (Foundation): Research Funding; CR&T (Foudation): Research Funding; European Leukemia net: Honoraria, Other: travel fees . Roth: Janssen: Consultancy; Merck: Consultancy.

Abatacept Reduces Levels of Switched Memory B Cells, Autoantibodies, and Immunoglobulins in Patients with Rheumatoid Arthritis

2014 ◽  
Vol 41 (4) ◽  
pp. 666-672 ◽  
Author(s):  
Mirko Scarsi ◽  
Lucia Paolini ◽  
Doris Ricotta ◽  
Antonio Pedrini ◽  
Silvia Piantoni ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
B Cells ◽  
B Cell ◽  
B Lymphocytes ◽  
Cell Activation ◽  
Serum Levels ◽  
Memory B Cells ◽  
Cell Phenotype ◽  
B Cell Activation ◽  
Switch Memory

Objective.Abatacept (ABA) is a chimeric molecule, able to block the CD28-mediated costimulatory pathway. To evaluate the hypothesis that, through this mechanism of action, ABA may down-modulate the immune responses of B lymphocytes in rheumatoid arthritis (RA), we investigated the serum levels of immunoglobulins (Ig), free light chains (FLC), anticitrullinated protein antibodies (ACPA), and rheumatoid factor (RF), as well as the number of B lymphocytes differentiated into post-switch memory cells in patients treated with ABA.Methods.The serum levels of Ig, FLC, different ACPA, RF isotypes, and the B cell phenotype were longitudinally evaluated in 30 patients with RA treated with ABA.Results.At baseline, the proportion of total and post-switch memory B cells was lower in RA than in healthy individuals. After 6 months of ABA treatment we observed significant reductions of serum levels of IgG, IgA, and IgM, as well as FLC, with a normalization in many patients who had initially abnormal values. A significant reduction of the titers of IgG- and IgA-ACPA, as well as of IgM-, IgA-, and IgG-RF was also observed. A decrease of autoantibodies below the upper limits of normal values was found in 2 of 26 patients (8%) initially seropositive for IgG-ACPA, 1 of 14 (7%) for IgA-ACPA, 5 of 22 (23%) for IgM-RF, 7 of 22 (30%) for IgA-RF, and 5 of 16 (31%) for IgG-RF. After treatment, the proportion of circulating post-switch memory B cells was also further significantly decreased.Conclusion.ABA treatment in patients with RA can reduce signs of polyclonal B cell activation, inducing a trend toward normalization of serum levels of different classes of Ig and of FLC, decreasing titers of ACPA and RF, and percentages of post-switch memory B cells.

scholarly journals Very Low Affinity B Cells Form Germinal Centers, Become Memory B Cells, and Participate in Secondary Immune Responses When Higher Affinity Competition Is Reduced

2002 ◽  
Vol 195 (9) ◽  
pp. 1215-1221 ◽  
Author(s):  
Joseph M. Dal Porto ◽  
Ann M. Haberman ◽  
Garnett Kelsoe ◽  
Mark J. Shlomchik
Keyword(s):  
B Cells ◽  
Immune Responses ◽  
B Cell ◽  
B Lymphocytes ◽  
Germinal Center ◽  
Germinal Centers ◽  
Association Constants ◽  
Memory B Cells ◽  
B Cell Antigen Receptor ◽  
The Relationship

To understand the relationship between the affinity of the B cell antigen receptor (BCR) and the immune response to antigen, two lines of immunoglobulin H chain transgenic (Tg) mice were created. H50Gμa and T1(V23)μa mice express μ H chain transgenes that associate with the λ1 L chains to bind the (4-hydroxy-3-nitrophenyl)acetyl hapten with association constants (Kas) of only 1.2 × 105 M−1 and 3 × 104 M−1, respectively. Both lines mounted substantial antibody-forming cell (AFC) and germinal center (GC) responses. H50Gμa Tg mice also generated memory B cells. T1(V23)μa B cells formed AFC and GCs, but were largely replaced in late GCs by antigen-specific cells that express endogenous BCRs. Thus, B lymphocytes carrying BCRs with affinities previously thought to be irrelevant in specific immune responses are in fact capable of complete T cell–dependent immune responses when relieved of substantial competition from other B cells. The failure to observe such B cells normally in late primary responses and in memory B cell populations is the result of competition, rather than an intrinsic inability of low affinity B cells.

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