Neonatally Induced Inactivation of the Vascular Cell Adhesion Molecule 1 Gene Impairs B Cell Localization and T Cell–Dependent Humoral Immune Response

Vascular cellular adhesion molecule (VCAM)-1 is a membrane-bound cellular adhesion molecule that mediates adhesive interactions between hematopoietic progenitor cells and stromal cells in the bone marrow (BM) and between leukocytes and endothelial as well as dendritic cells. Since VCAM-1–deficient mice die embryonically, conditional VCAM-1 mutant mice were generated to analyze the in vivo function of this adhesion molecule. Here we show that interferon-induced Cre-loxP–mediated deletion of the VCAM-1 gene after birth efficiently ablates expression of VCAM-1 in most tissues like, for example, BM, lymphoid organs, and lung, but not in brain. Induced VCAM-1 deficiency leads to a reduction of immature B cells in the BM and to an increase of these cells in peripheral blood but not in lymphoid organs. Mature recirculating B cells are reduced in the BM. In a migration assay, the number of mature B cells that appears in the BM after intravenous injection is decreased. In addition, the humoral immune response to a T cell–dependent antigen is impaired. VCAM-1 serves an important role for B cell localization and the T cell–dependent humoral immune response.

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Attenuation of Apoptosis Underlies B Lymphocyte Stimulator Enhancement of Humoral Immune Response

Journal of Experimental Medicine ◽

10.1084/jem.192.7.953 ◽

2000 ◽

Vol 192 (7) ◽

pp. 953-964 ◽

Cited By ~ 313

Author(s):

Richard K.G. Do ◽

Eunice Hatada ◽

Hayyoung Lee ◽

Michelle R. Tourigny ◽

David Hilbert ◽

...

Keyword(s):

Immune Response ◽

T Cell ◽

B Cells ◽

B Cell ◽

Cell Survival ◽

B Lymphocyte ◽

Humoral Immune ◽

B Cell Survival ◽

B Lymphocyte Stimulator

B lymphocyte stimulator (BLyS) is a newly identified monocyte-specific TNF family cytokine. It has been implicated in the development of autoimmunity, and functions as a potent costimulator with antiimmunoglobulin M in B cell proliferation in vitro. Here we demonstrate that BLyS prominently enhances the humoral responses to both T cell–independent and T cell–dependent antigens, primarily by attenuation of apoptosis as evidenced by the prolonged survival of antigen-activated B cells in vivo and in vitro. BLyS acts on primary splenic B cells autonomously, and directly cooperates with CD40 ligand (CD40L) in B cell activation in vitro by protecting replicating B cells from apoptosis. Moreover, although BLyS alone cannot activate the cell cycle, it is sufficient to prolong the survival of naive resting B cells in vitro. Attenuation of apoptosis by BLyS correlates with changes in the ratios between Bcl-2 family proteins in favor of cell survival, predominantly by reducing the proapoptotic Bak and increasing its prosurvival partners, Bcl-2 and Bcl-xL. In either resting or CD40L-activated B cells, the NF-κB transcription factors RelB and p50 are specifically activated, suggesting that they may mediate BLyS signals for B cell survival. Together, these results provide direct evidence for BLyS enhancement of both T cell–independent and T cell–dependent humoral immune responses, and imply a role for BLyS in the conservation of the B cell repertoire. The ability of BLyS to increase B cell survival indiscriminately, at either a resting or activated state, and to cooperate with CD40L, further suggests that attenuation of apoptosis underlies BLyS enhancement of polyclonal autoimmunity as well as the physiologic humoral immune response.

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A New Vaccine Paradigm To Break Tolerance with Potential Applications for the Immunotherapy of B Cell Lymphoma.

Blood ◽

10.1182/blood.v104.11.1411.1411 ◽

2004 ◽

Vol 104 (11) ◽

pp. 1411-1411

Author(s):

Ronald P. Taylor ◽

Emily C. Whipple ◽

Margaret A. Lindorfer ◽

Andrew H. Ditto ◽

Ryan S. Shanahan

Keyword(s):

Flow Cytometry ◽

Immune Response ◽

B Cells ◽

B Cell ◽

Humoral Immune Response ◽

Critical Role ◽

B Cell Lymphoma ◽

Breakdown Product ◽

Humoral Immune ◽

Mouse Igg2a

Abstract Complement (C) plays a critical role in the immune response by opsonizing immune complexes (IC) and thymus-independent type 2 antigens with C3 breakdown product C3dg. We investigated the in vivo fate and handling in mice of anti-CR1/CR2 mAb 7G6. We used this rat IgG mAb as a surrogate for C3dg-opsonized IC; mAb 7G6 binds to CR1/CR2 with high affinity, blocks C3dg binding and saturates mouse B cell CR2 at inputs of only 2 ug. RIA, flow cytometry, and fluorescence immunohistochemistry were used to examine the disposition of 0.5–2 ug quantities of mAb 7G6 infused i.v. in mice. The mAb binds to circulating B cells and in the spleen binds preferentially to marginal zone (MZ) B cells. However, within 24 h MZ B cells relocate and transfer the mAb to regions rich in follicular dendritic cells (FDC). Localization of intact antigen to FDC should induce a substantial immune response, and therefore we immunized mice and monkeys i.v. with low doses (1–20 ug/kg) of prototype antigens constructed with anti-CR1/2 mAb 7G6 or anti-CR2 mAb HB135, respectively. We observed a strong immune response characterized by early development of IgG antibodies and long-lasting immunity extending out to at least one year. We applied our immunization paradigm to mouse IgG idiotypes, based on i.v. infusion of mouse IgG2a mAbs which were cross-linked with mAb 7G6. The purpose of these experiments was to determine if tolerance can be broken in order to develop a more powerful vaccine strategy to induce a cytotoxic humoral immune response to malignant B cells based on targeting the idiotype of immunoglobulin molecules expressed on their surfaces. I.V. immunization with the constructs indeed generated a mouse IgG1 immune response to two different mouse IgG2a mAbs, as demonstrated by ELISA. The immune response was idiotype specific, but some anti-isotype antibodies were also detected. Moreover, sera from immunized mice immunoprecipitated the specific radiolabeled mouse mAbs in the presence of 7.5% polyethylene glycol. This humoral immune response was also demonstrable in flow cytometry assays in which IgG1 in sera of immunized mice bound to erythrocytes opsonized with bispecific mAb constructs consisting of the IgG2a mAb crosslinked with an anti-CR1 mAb. The present approach, based on coupling the targeted immunoglobulin to an anti-CR2 mAb for delivery to FDC, may lead to a more effective immunotherapeutic vaccine compared to methods currently in clinical trials which require use of glutaraldehyde to effect crosslinking of the targeted immunoglobulin to KLH.

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Wiskott-Aldrich syndrome protein deficiency leads to reduced B-cell adhesion, migration, and homing, and a delayed humoral immune response

Blood ◽

10.1182/blood-2004-03-1003 ◽

2005 ◽

Vol 105 (3) ◽

pp. 1144-1152 ◽

Cited By ~ 91

Author(s):

Lisa Westerberg ◽

Malin Larsson ◽

Samantha J. Hardy ◽

Carmen Fernández ◽

Adrian J. Thrasher ◽

...

Keyword(s):

Immune Response ◽

B Cells ◽

B Cell ◽

Humoral Immune Response ◽

Wiskott Aldrich Syndrome ◽

Humoral Immune ◽

Germinal Center Reaction ◽

Syndrome Protein ◽

Deficient Mice

Abstract The Wiskott-Aldrich syndrome protein (WASp) is mutated in the severe immunodeficiency disease Wiskott-Aldrich syndrome (WAS). The function of B cells and the physiologic alterations in WAS remain unclear. We show that B cells from WAS patients exhibited decreased motility and had reduced capacity to migrate, adhere homotypically, and form long protrusions after in vitro culture. WASp-deficient murine B cells also migrated less well to chemokines. Upon antigen challenge, WASp-deficient mice mounted a reduced and delayed humoral immune response to both T-cell–dependent and –independent antigens. This was at least in part due to deficient migration and homing of B cells. In addition, the germinal center reaction was reduced in WASp-deficient mice. Thus, WASp is crucial for optimal B-cell responses and plays a pivotal role in the primary humoral immune response.

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Humoral Immune Response in Mice Over-expressing or Deficient in Growth Hormone

Experimental Biology and Medicine ◽

10.1177/153537020222700719 ◽

2002 ◽

Vol 227 (7) ◽

pp. 535-544 ◽

Cited By ~ 17

Author(s):

Mary A. Hall ◽

Andrzej Bartke ◽

John M. Martinko

Keyword(s):

Growth Hormone ◽

Immune Response ◽

T Cell ◽

B Cell ◽

Humoral Immune Response ◽

Cell Populations ◽

Cell Numbers ◽

Humoral Immune ◽

Immune Parameters ◽

Th2 Cell

Effects of growth hormone (GH) levels on the humoral immune response were investigated in metallothionein I (MT)-bovine (b) GH-transgenic (tg) and GH-deficient Ames dwarf (Prop1 dt–/–) mice. Four-month-old mice were given primary and secondary injections of either normal saline or tetanus toxoid (TT) to induce specific antibody (Ab) production. MT-bGH-tg mice with high peripheral levels of bGH produced less TT-specific Ab than normal nontransgenic (Ntg) littermates, df, or nondwarf (Ndf) control mice. Titers reached maximum levels at 3–4 weeks postprimary immunization (PPI) and declined gradually through 24 weeks PPI in all groups of mice. Peripheral CD4+ and CD8+ T cell populations were significantly lower in tg than in Ntg, df, or Ndf mice. No significant differences were found in B cell numbers between tg, Ntg, or df mice. T helper 2 (Th2) cell populations were significantly greater in df mice compared to Ntg control mice. No significant differences were found in CD4+:CD8+ T cell ratios, interleukin (IL)-4 concentrations or interferon (IFN)-γ levels between tg, Ntg, df, and Ndf mice. No patterns of significant sexual dimorphism were found for any of the immune parameters studied. Elevated levels of corticosterone were investigated as a possible immunosuppressant mechanism responsible for low Ab responses in the tg mice. Ab production was not enhanced by decreasing corticosterone in tg mice. Thus, high endogenous GH levels inhibit specific Ab production and peripheral T cell populations but not peripheral B cell numbers, Th2 cell populations, or IL-4 or IFN-gamma production. Elevated corticosterone levels do not appear to be responsible for suppressed humoral immune responses. Low levels of endogenous GH do not inhibit specific Ab production but may contribute to increased peripheral Th2 cell numbers.

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Dissection of the signalling mechanisms underlying FcγRIIB-mediated apoptosis of mature B-cells

Biochemical Society Transactions ◽

10.1042/bst0320973 ◽

2004 ◽

Vol 32 (6) ◽

pp. 973-975 ◽

Cited By ~ 10

Author(s):

N.A. Carter ◽

M.M. Harnett

Keyword(s):

Immune Response ◽

B Cells ◽

B Cell ◽

Humoral Immune Response ◽

Feedback Inhibition ◽

Growth Arrest ◽

B Cell Antigen Receptor ◽

Mitochondrial Potential ◽

Humoral Immune ◽

Affinity Receptor

The low-affinity receptor for IgG, FcγRIIB, negatively regulates BCR (B-cell antigen receptor)-mediated proliferative signalling and thus plays an important role in feedback inhibition of the humoral immune response. Whereas crosslinking of BCR on mature B-cells results in proliferation, co-ligation of FcγRIIB results in growth arrest and apoptosis. We have now investigated the signals underlying FcγRIIB-driven apoptosis and found this to be dependent on disruption of mitochondrial potential (Δψ), involve the pro-apoptotic Bcl-2 family members, Bid and Bad, and be caspase-independent.

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Humoral and cellular immune responses to SARS CoV-2 vaccination in Persons with Multiple Sclerosis and NMOSD patients receiving immunomodulatory treatments

10.1101/2021.12.22.21268127 ◽

2021 ◽

Author(s):

Henry Bock ◽

Thomas Juretzek ◽

Robert Handreka ◽

Johanna Ruhnau ◽

Karl Reuner ◽

...

Keyword(s):

Multiple Sclerosis ◽

Immune Response ◽

T Cell ◽

Immune Responses ◽

B Cell ◽

Humoral Immune Response ◽

Humoral Immune ◽

Cell Responses ◽

Cellular Immune Responses ◽

Cellular Immune

Abstract Background: Vaccination against SARS CoV-2 results in excellent personal protection against a severe course of COVID19. In persons with Multiple Sclerosis (PwMS) vaccination efficacy may be reduced by immunomodulatory medications. Objective: To assess the vaccination induced cellular and humoral immune response in PwMS receiving disease modifiying therapies. Methods: In a monocentric observational study on PwMS and patients with Neuromyelitis optica we quantified the cellular and humoral immune responses to SARS CoV-2. Results: PwMS receiving Glatirameracetate, Interferon-beta, Dimethylfumarate, Cladribine or Natalalizumab had intact humoral and cellular immune responses following vaccination against SARS CoV-2. B-cell depleting therapies reduced B-cell responses but did not affect T cell responses. S1P inhibitors strongly reduced humoral and cellular immune responses. There was a good agreement between the Interferon gamma release assay and the T-SPOT assay used to measure viral antigen induced T-cell responses. Conclusion: This study demonstrates that S1P inhibitors impair the cellular and humoral immune response in SARS CoV-2 vaccination, whereas patients receiving B-cell depleting therapies mount an intact cellular immune response. These data can support clinicians in counselling their PwMS and NMOSD patients during the COVID 19 pandemic.

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