BAFF Accelerates Development of Chronic Lymphocytic Leukemia in TCL1 Transgenic Mice.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1117-1117
Author(s):  
Thomas Enzler ◽  
George F. Widhopf ◽  
Jason Lee ◽  
Weizhou Zhang ◽  
Carlo M. Croce ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Mononuclear Cells ◽  
Lymphoproliferative Disease ◽  
Lymphocytic Leukemia ◽  
Brdu Incorporation

Abstract The B cell- activating factor of the tumor necrosis factor family (BAFF) is a potent regulator of normal B cells. We recently showed that BAFF supports chronic lymphocytic leukemia (CLL) B cell survival in vitro through activation of the canonical NF-kB pathway. To study the influence of BAFF on CLL development, we crossed BAFF transgenic (Tg) mice with mice that express human TCL1 under a B cell specific promoter/enhancer, and that are known to develop a lymphoproliferative disease resembling human B-CLL. BAFF/TCL1-Tg mice had a shorter mean survival than either TCL1-Tg or BAFF-Tg mice (12 mice each; BAFF/TCL1-Tg mice 9.6±3.4 months; TCL1-Tg 17.2±3.9; BAFF-Tg 17.9±3.6; B6 wildtype (wt) >19.2). To monitor for the development of CLL, mice were bled at 6-week intervals starting at 3 months of age, and blood mononuclear cells (PBMC) were analyzed via flow cytometry using fluorochrome-conjugated antibodies for murine CD5, CD3, CD45R, and human TCL1. Whereas all BAFF/TCL1-Tg mice began to develop a pathological CD5+CD3−CD45Rlo cell population at 3 months of age, such a population was not observed in TCL1-Tg mice before 6 months of age. BAFF-Tg or wt mice did not develop CD5+CD3−CD45Rlo cells over the entire observation period (26 months). CD5+CD3−CD45Rlo B cells expressed the TCL1 transgene. Over time, the CD5+CD3−CD45Rlo population increased in BAFF/TCL1-Tg mice, coming to represent >99% of the total PBMC of 9-month-old animals. To examine the capacity of these cells to propagate, 1x106 CD5+CD3−CD45Rlo B cells were transferred i.v. into either BAFF-Tg or wt mice that previously were irradiated with 600 rad. Ten days after transfer, CD5+TCL1+ cells were detected in BAFF-Tg, but not in wt recipients. Most CLL cells were located in the liver and spleen, as assessed by bioluminescent-based imaging of mice that received luciferase expressing CLL cells. Subsequent examination upon autopsy at 6 months of age, however, revealed that the majority of CLL cells populated the spleens of the recipient mice, which were massively enlarged. At this age, CLL cells also were found in wt recipient mice, although tumor burden was less than 20% of that of BAFF-Tg recipients (n=3 per group). We found that BAFF did not promote CLL cell proliferation in vitro or in vivo using assays to measure BrdU incorporation and flow cytometry to evaluate for enhanced intracellular expression of Ki67. However, BAFF induced CLL cells to express high levels of several anti-apoptotic proteins (e.g. Bcl-XL, Bcl-2, Bim, and A1/Bfl1). Also, while death-associated protein kinase 1 was repressed in CLL cells of TCL1-Tg mice, CLL cells of BAFF/TCL1-Tg mice expressed high-levels. Because of this, we examined whether treatment with BAFF-neutralizing BR3-Fc could influence the survival of CLL cells that were adoptively transferred into BAFF-Tg mice. We found that i.p. injection of 200 ug BR3-Fc into the recipient animals reduced the numbers of circulating CLL cells by nearly 20% (18.2%±5.3%; n=3) within 6 days. These data indicate that BAFF can accelerate the development of CLL cells in TCL1-Tg mice by promoting their survival. Because BAFF can similarly promote survival of human CLL cells, BAFF, and the signaling pathways it activates in neoplastic B cells, could be targeted for the development of novel therapies for this disease.

Survivin is expressed on CD40 stimulation and interfaces proliferation and apoptosis in B-cell chronic lymphocytic leukemia

Blood ◽  
2001 ◽  
Vol 97 (9) ◽  
pp. 2777-2783 ◽  
Author(s):  
Luisa Granziero ◽  
Paolo Ghia ◽  
Paola Circosta ◽  
Daniela Gottardi ◽  
Giuliana Strola ◽  
...  
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Molecular Mechanisms ◽  
Mononuclear Cells ◽  
Survivin Expression ◽  
Lymphocytic Leukemia ◽  
Cd40 Stimulation ◽  
Cell Chronic Lymphocytic Leukemia

Abstract In B-cell chronic lymphocytic leukemia (B-CLL), defective apoptosis causes the accumulation of mature CD5+ B cells in lymphoid organs, bone marrow (BM), and peripheral blood (PB). These cells are the progeny of a proliferating pool that feeds the accumulating compartment. The authors sought to determine which molecular mechanisms govern the proliferating pool, how they relate to apoptosis, and what the role is of the microenvironment. To begin to resolve these problems, the expression and modulation of the family of inhibitor of apoptosis proteins (IAPs) were investigated, with consideration given to the possibility that physiological stimuli, such as CD40 ligand (CD40L), available to B cells in the microenvironment, might modulate IAP expression. The in vitro data on mononuclear cells from PB or BM of 30 patients demonstrate that B-CLL cells on CD40 stimulation express Survivin and that Survivin is the only IAP whose expression is induced by CD40L. Through immunohistochemistry, in vivo Survivin expression in lymph node (LN) and BM biopsies was evaluated. In reactive LN, Survivin was detected only in highly proliferating germinal center cells. In LN from patients with B-CLL, Survivin was detected only in pseudofollicles. Pseudofollicle Survivin+ cells were actively proliferating and, in contrast to Survivin+ B cells found in normal GC, were Bcl-2+. In B-CLL BM biopsies, CD5+, Survivin+ cells were observed in clusters interspersed with T cells. These findings establish that Survivin controls the B-CLL proliferative pool interfacing apoptosis and that its expression may be modulated by microenvironmental stimuli.

Protein Expression Profiling of Cytokines and Cytokine Receptors on Purified Chronic Lymphocytic Leukemia Cells.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4709-4709
Author(s):  
Zhifeng Yu ◽  
Baohua Sun ◽  
Hagop M. Kantarjian ◽  
Hesham M. Amin ◽  
Xiaoping Sun
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Conditioned Medium ◽  
Mononuclear Cells ◽  
Lymphocytic Leukemia ◽  
Cytokine Receptors ◽  
Cellular Interactions ◽  
Serum Free

Abstract Chronic lymphocytic leukemia (CLL) B-cells rapidly undergo apoptosis when cultured in vitro, which contrasts with their prolonged survival in vivo. Multiple cytokines and cytokine receptors are believed to work together to regulate the survival of CLL cells. The literature is conflicting as to whether the CLL cells themselves produce significant amounts of cytokines compared with normal B-cells and how the CLL cells respond to these cytokines. This discrepancy is largely due to the different experimental conditions that have been used whereby various amounts of exogenous cytokines were introduced into the experimental system from, for example, the serum used to supplement the culture medium and the lysate or conditioned medium of CLL cells where other types of mononuclear cells were not removed. The aim of the current study is to reveal the intrinsic production and secretion of cytokines and cytokine receptors in CLL cells when exogenous sources are minimized. We purified CD19+ cells by magnetic beads from peripheral blood mononuclear cells of five CLL patients who had stage I or II disease and had not received any therapy. CD19+ cells from healthy donors were used as control. We used a cytokine antibody array approach that simultaneously measured 174 cytokines and cytokine receptors. We determined both intracellular levels in purified CLL cells and secreted levels in serum-free conditioned medium. The intracellular levels of cytokines and cytokine receptors of the purified CLL cells and the normal B-cells were not significantly different. However, the secretion of interleukin-6 (IL-6) was 3.0 times lower (p = 0.038) and that of eotaxin was 2.2 times higher (p = 0.028) in CLL-conditioned medium than in normal B-cell-conditioned medium. We further studied the effect of IL-6 and anti-IL-6 antibody on the apoptosis of purified CLL B-cells in serum-free culture, but no significant change was found in the presence or absence of IL-6 or IL-6 antibody. Except for IL-6 and eotaxin, our results suggest that CLL cells and their normal counterparts produce and secrete similar amounts of cytokines and cytokine receptors in vitro and that the in vivo longevity of CLL cells may be due to the concerted effects of various molecules and cellular interactions in the microenvironment.

Nurselike Cells in Chronic Lymphocytic Leukemia (CLL) Express Both BAFF and APRIL that Protect CLL B Cells from Spontaneous Apoptosis by Paracrine Manner.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 965-965
Author(s):  
Mitsufumi Nishio ◽  
Nobuhiro Tsukada ◽  
Junko Ohata ◽  
Nathan J. Zvaifler ◽  
Thomas J. Kipps
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Survival ◽  
Mononuclear Cells ◽  
Lymphocytic Leukemia ◽  
B Cell Survival ◽  
Fc Fusion Protein ◽  
Blood Mononuclear Cells

Abstract Large, adherent nurse-like cells (NLC) can differentiate from the blood mononuclear cells of patients with chronic lymphocytic leukemia (CLL) that, in turn, can support leukemia cell survival in vitro, and presumably in vivo. These cells differentiate in the context of CLL B cells and can be found in the secondary lymphoid tissues of patients with this disease. NLC express high levels of B cell activating factor belonging to the tumor necrosis factor (TNF) family (BAFF), a factor that can support normal and leukemia B cell survival in vitro. BAFF binds to three distinct members of TNF-receptor superfamily : TACI (transmembrane activator and CAML interactor), BCMA (B cell maturation antigen) and BAFF-R, the latter two of which are expressed by CLL B cells. We found that addition of saturating amounts of a recombinant BAFF-receptor-Fc fusion protein (BAFF-R:Fc) to cultures of NLC and CLL B cells failed to inhibit the protective effect(s) of NLC on CLL B cell survival in vitro. This suggested that another factor(s) made by NLC can contribute to the survival effect(s) of BAFF on CLL B cells. A candidate for this is a proliferation-inducing ligand (APRIL), another member of the TNF family that can interact with TACI and BCMA, but not BAFF-R. We found that, in contrast to CLL B cells or blood mononuclear cells, NLC express high-levels of APRIL mRNA and protein, as assessed by quantitative RT-PCR and immunoblot analyses. Furthermore, recombinant human APRIL also could support CLL B cell survival via mechanism similar to that used by recombinant BAFF. Consistent with the fact that APRIL and BAFF each can function to support CLL B cell survival, we found that a recombinant BCMA-Fc fusion protein could significantly inhibit the protective effects of NLC on CLL B cells in vitro. These data suggest that BCMA-Fc might be better suited than BAFF-R:Fc to inhibit the interactions between NLC and CLL B cells in vivo.

scholarly journals The novel plant-derived agent silvestrol has B-cell selective activity in chronic lymphocytic leukemia and acute lymphoblastic leukemia in vitro and in vivo

Blood ◽  
2009 ◽  
Vol 113 (19) ◽  
pp. 4656-4666 ◽  
Author(s):  
David M. Lucas ◽  
Ryan B. Edwards ◽  
Gerard Lozanski ◽  
Derek A. West ◽  
Jungook D. Shin ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Leukemia Cell ◽  
Lymphocytic Leukemia ◽  
Translational Inhibition

Abstract Therapeutic options for advanced B-cell acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL) are limited. Available treatments can also deplete T lymphocytes, leaving patients at risk of life-threatening infections. In the National Cancer Institute cell line screen, the structurally unique natural product silvestrol produces an unusual pattern of cytotoxicity that suggests activity in leukemia and selectivity for B cells. We investigated silvestrol efficacy using primary human B-leukemia cells, established B-leukemia cell lines, and animal models. In CLL cells, silvestrol LC50 (concentration lethal to 50%) is 6.9 nM at 72 hours. At this concentration, there is no difference in sensitivity of cells from patients with or without the del(17p13.1) abnormality. In isolated cells and whole blood, silvestrol is more cytotoxic toward B cells than T cells. Silvestrol causes early reduction in Mcl-1 expression due to translational inhibition with subsequent mitochondrial damage, as evidenced by reactive oxygen species generation and membrane depolarization. In vivo, silvestrol causes significant B-cell reduction in Eμ-Tcl-1 transgenic mice and significantly extends survival of 697 xenograft severe combined immunodeficient (SCID) mice without discernible toxicity. These data indicate silvestrol has efficacy against B cells in vitro and in vivo and identify translational inhibition as a potential therapeutic target in B-cell leukemias.

B-1239, a Novel Anti-BAFF-R Afucosylated Human Antibody, Promotes Potent Natural Killer Cell- Mediated Antibody Dependent Cellular Cytotoxicity In Chronic Lymphocytic Leukemia Cells In- Vitro and Depletion Of Circulating Leukemic CLL B Cells In-Vivo

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4185-4185 ◽  
Author(s):  
Emily M. McWilliams ◽  
Carolyn Cheney ◽  
Jeffrey A. Jones ◽  
Joseph M. M. Flynn ◽  
Kami Maddocks ◽  
...  
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Cytotoxic Activity ◽  
Natural Killer ◽  
Lymphocytic Leukemia ◽  
Cellular Cytotoxicity ◽  
Antibody Dependent Cellular Cytotoxicity

Abstract B-cell activating factor (BAFF) belongs to the TNF ligand superfamily of cytokines involved in B cell survival and maturation. BAFF is produced by diverse cell types including innate immune cells like monocytes and dendritic cells as well as T cells, activated B cells, and bone marrow stromal cells. BAFF binds to the BAFF receptor (BAFF-R) with high affinity compared to the other BAFF receptors, BCMA and TACI. While BAFF is known to regulate normal B-cell development and proliferation, it also contributes to survival in chronic lymphocytic leukemia (CLL). We observed expression of BAFF-R on virtually all B cells from CLL patients. B-CLL cells have strong up-regulation of BAFF and BAFF-R compared to normal healthy B cells. We describe here the in-vitro and in-vivo evaluation in CLL of B-1239, a fully human anti-BAFF-R monoclonal IgG1 antibody. B-1239 is devoid of fucose residues in its Fc domain, resulting in enhanced binding to FCgammaRIIIa activating receptor on Natural Killer (NK) cells. While B-1239 failed to induce direct or complement mediated cytotoxicity, binding of B-1239 to CLL cells resulted in enhanced antibody dependent cellular cytotoxicity (ADCC) with allogeneic or autologous NK effector cells in-vitro. Indeed, at a therapeutically relevant concentration of 10 ug/mL B-1239 shows more than 30% increased relative cytotoxic activity over current CLL antibody therapeutic Rituximab. Dilutions of B-1239 down to 0.01 ug/mL showed similar cytotoxicity to the 10 ug/mL concentration. At 0.0001 ug/mL B-1239 has a 40% cytotoxic effect on CLL cells in ADCC assays while antibody therapeutic controls, like Rituximab, show virtually no cytotoxic activity. Furthermore, B-1239 mediated antibody-dependent cellular phagocytosis (ADCP) by monocyte-derived macrophages and mediated activation of monocytes and macrophages as detected by TNF-alpha production. Consistent with the cross reactivity to murine BAFF-R, flow cytometric analysis revealed binding of B-1239 to CD5+CD19+ leukemic B cells from Eu-Tcl-1 transgenic mouse CLL cells. A single dose of B-1239 by i.v injection into Eu-Tcl-1 mice resulted in dramatic reduction in circulating CD5+CD19+ leukemic B cells in all three B-1239 injected mice. In contrast, we observed continued increase of leukemic CD5+CD19+ populations in the two vehicle treated mice. Ongoing studies are focused on determining how targeting BAFF-R on CLL B-cells depletes the leukemic population both in-vitro and in-vivo and the downstream effects of targeting through this receptor. Collectively, these results demonstrate that targeting BAFF-R on CLL cells provides a B-cell specific approach for rapid and robust depletion of leukemic CLL cells and provides evidence for a strong therapeutic advantage in BAFF-R targeted therapies in CLL. Disclosures: Huet: Novartis: Employment, Employment Related Perks Other. Gram:Novartis: Employment, Employment Related Perks Other. Baeck:Novartis: Employment, Employment Related Perks Other.

scholarly journals Antigen receptor nonresponsiveness in chronic lymphocytic leukemia B cells

Blood ◽  
1995 ◽  
Vol 86 (3) ◽  
pp. 1090-1071 ◽  
Author(s):  
AC Lankester ◽  
GM van Schijndel ◽  
CE van der Schoot ◽  
MH van Oers ◽  
CJ van Noesel ◽  
...  
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Functional Properties ◽  
Antigen Receptor ◽  
Lymphocytic Leukemia ◽  
Cross Linking ◽  
Cell Stage

Abstract B chronic lymphocytic leukemia (B-CLL) are clonal populations of mIgM+ or mIgM+/mIgD+ CD5+ B cells that appear to be arrested in the follicular mantle-zone B-cell stage. Functional analyses have shown two groups of B-CLL that can be distinguished based on their capacity to proliferate in response to B-cell antigen receptor complex (BCR) cross- linking. To investigate the molecular basis for this phenomenon, we have analyzed both architecture and functional properties of BCR complexes on these two groups of B-CLL. Both groups were found to express structurally similar BCR. However, protein tyrosine kinase (PTK) activity associated with and specific for BCR constituents was strongly diminished in nonresponsive B-CLL. Moreover, the PTK-dependent assembly of Shc/Grb2 complexes, which may couple the BCR to p21ras, was absent in these B-CLL. Finally, of all PTKs tested, the expression of PTK syk was found to be considerably lower in nonresponsive B-CLL. Thus, absence of mitogenic responses upon BCR cross-linking in particular B-CLL was found to be strictly correlated with diminished induction of BCR-associated PTK activity and lower levels of PTK syk. Because nonresponsive B-CLL closely resembles tolerant autoreactive B cells both functionally and biochemically, distinction between B-CLL with respect to functional properties in vitro may be determined by differences in antigen encounter in vivo.

scholarly journals Antigen receptor nonresponsiveness in chronic lymphocytic leukemia B cells

Blood ◽  
1995 ◽  
Vol 86 (3) ◽  
pp. 1090-1071 ◽  
Author(s):  
AC Lankester ◽  
GM van Schijndel ◽  
CE van der Schoot ◽  
MH van Oers ◽  
CJ van Noesel ◽  
...  
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Functional Properties ◽  
Antigen Receptor ◽  
Lymphocytic Leukemia ◽  
Cross Linking ◽  
Cell Stage

B chronic lymphocytic leukemia (B-CLL) are clonal populations of mIgM+ or mIgM+/mIgD+ CD5+ B cells that appear to be arrested in the follicular mantle-zone B-cell stage. Functional analyses have shown two groups of B-CLL that can be distinguished based on their capacity to proliferate in response to B-cell antigen receptor complex (BCR) cross- linking. To investigate the molecular basis for this phenomenon, we have analyzed both architecture and functional properties of BCR complexes on these two groups of B-CLL. Both groups were found to express structurally similar BCR. However, protein tyrosine kinase (PTK) activity associated with and specific for BCR constituents was strongly diminished in nonresponsive B-CLL. Moreover, the PTK-dependent assembly of Shc/Grb2 complexes, which may couple the BCR to p21ras, was absent in these B-CLL. Finally, of all PTKs tested, the expression of PTK syk was found to be considerably lower in nonresponsive B-CLL. Thus, absence of mitogenic responses upon BCR cross-linking in particular B-CLL was found to be strictly correlated with diminished induction of BCR-associated PTK activity and lower levels of PTK syk. Because nonresponsive B-CLL closely resembles tolerant autoreactive B cells both functionally and biochemically, distinction between B-CLL with respect to functional properties in vitro may be determined by differences in antigen encounter in vivo.

Distinctive features of “nurselike” cells that differentiate in the context of chronic lymphocytic leukemia

Blood ◽  
2002 ◽  
Vol 99 (3) ◽  
pp. 1030-1037 ◽  
Author(s):  
Nobuhiro Tsukada ◽  
Jan A. Burger ◽  
Nathan J. Zvaifler ◽  
Thomas J. Kipps
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Mononuclear Cells ◽  
Cell Types ◽  
Lymphocytic Leukemia ◽  
Blood Monocytes ◽  
Hla Dq ◽  
Blood Mononuclear Cells

Abstract A subset of blood mononuclear cells from patients with chronic lymphocytic leukemia (CLL) can differentiate in vitro into “nurselike” cells (NLCs) that can protect CLL cells from apoptosis. NLCs express cytoplasmic vimentin and stromal-derived factor 1 (SDF-1). NLCs also express CD14, as well as CD11b, CD33, CD40, CD45RO, CD68, CD80, CD86, HLA-DQ, and HLA-DR, but not CD1a, CD2, CD3, CD11c, CD19, CD45RA, CD83, CD106, or CD154. Consistent with this phenotype, NLCs failed to differentiate from blood mononuclear cells that were depleted of CD14+ cells or from isolated CD19+cells. CD14+ blood cells of healthy donors could differentiate into cells with the morphology and phenotype of NLCs when cultured in direct contact with CLL B cells, but not with normal B cells. Despite expressing antigens in common with blood monocytes, monocyte-derived dendritic cells, and macrophages, NLCs expressed significantly higher levels of CD68 than these other cell types. Consistent with the notion that NLCs are present in vivo, CD14+ splenocytes from CLL patients have NLC morphology and express significantly higher levels of CD68 than CD14+splenocytes from persons without known B-cell malignancy. These findings indicate that although NLCs may differentiate from blood monocytes, they probably represent a distinctive hematopoietic cell type that exists in vivo, differentiates from hematopoietic CD14+ cells in the context of CLL, and in turn protect CLL cells from apoptosis via a mechanism that is independent of CD106 (vascular cell adhesion molecule-1). The interaction between CLL cells and NLCs may represent a novel target for therapy of patients with this disease.

Chronic lymphocytic leukemia: revelations from the B-cell receptor

Blood ◽  
2004 ◽  
Vol 103 (12) ◽  
pp. 4389-4395 ◽  
Author(s):  
Freda K. Stevenson ◽  
Federico Caligaris-Cappio
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Cell Of Origin ◽  
Regulatory B Cell ◽  
V Genes

Abstract The finding that chronic lymphocytic leukemia (CLL) consists of 2 clinical subsets, distinguished by the incidence of somatic mutations in the immunoglobulin (Ig) variable region (V) genes, has clearly linked prognosis to biology. Antigen encounter by the cell of origin is indicated in both subsets by selective but distinct expression of V genes, with evidence for continuing stimulation after transformation. The key to distinctive tumor behavior likely relates to the differential ability of the B-cell receptor (BCR) to respond. Both subsets may be undergoing low-level signaling in vivo, although analysis of blood cells limits knowledge of critical events in the tissue microenvironment. Analysis of signal competence in vitro reveals that unmutated CLL generally continues to respond, whereas mutated CLL is anergized. Differential responsiveness may reflect the increased ability of post-germinal center B cells to be triggered by antigen, leading to long-term anergy. This could minimize cell division in mutated CLL and account for prognostic differences. Unifying features of CLL include low responsiveness, expression of CD25, and production of immunosuppressive cytokines. These properties are reminiscent of regulatory T cells and suggest that the cell of origin of CLL might be a regulatory B cell. Continuing regulatory activity, mediated via autoantigen, could suppress Ig production and lead to disease-associated hypogammaglobulinemia. (Blood. 2004;103:4389-4395)

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