A subset of anti‐CD21 antibodies promote the rescue of germinal center B cells from apoptosis

Bonnefoy, Jean‐Yves; Henchoz, Sybille; Hardie, Deborah; Holder, Michelle J.; Gordon, John

doi:10.1002/eji.1830230432

Cited by 109 publications

(45 citation statements)

References 25 publications

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“…Of greatest relevance to the present work, Bonnefoy et al (69) reported that in vitro engagement of CD21 on human germinal center B cells promoted cell viability via a Bcl-2-dependent mechanism (70). Additionally, Roberts and Snow (23) noted that engagement of CD19 on LPSactivated murine B cells promoted both increased Bcl-2 expression and increased proliferation.…”

Section: Discussionmentioning

confidence: 58%

Role of Complement-Binding CD21/CD19/CD81 in Enhancing Human B Cell Protection from Fas-Mediated Apoptosis

Mongini

Jackson

Tolani

et al. 2003

The Journal of Immunology

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Defective expression of Fas leads to B cell autoimmunity, indicating the importance of this apoptotic pathway in eliminating autoreactive B cells. However, B cells with anti-self specificities occasionally escape such regulation in individuals with intact Fas, suggesting ways of precluding this apoptosis. Here, we examine whether coligation of the B cell Ag receptor (BCR) with the complement (C3)-binding CD21/CD19/CD81 costimulatory complex can enhance the escape of human B cells from Fas-induced death. This was warranted given that BCR-initiated signals induce resistance to Fas apoptosis, some (albeit not all) BCR-triggered events are amplified by coligation of BCR and the co-stimulatory complex, and several self Ags targeted in autoimmune diseases effectively activate complement. Using a set of affinity-diverse surrogate Ags (receptor-specific mAb:dextran conjugates) with varying capacity to engage CD21, it was established that BCR:CD21 coligation lowers the BCR engagement necessary for inducing protection from Fas apoptosis. Enhanced protection was associated with altered expression of several molecules known to regulate Fas apoptosis, suggesting a unique molecular model for how BCR:CD21 coligation augments protection. BCR:CD21 coligation impairs the generation of active fragments of caspase-8 via dampened expression of membrane Fas and augmented expression of FLIPL. This, in turn, diminishes the generation of cells that would be directly triggered to apoptosis via caspase-8 cleavage of caspase 3 (type I cells). Any attempt to use the mitochondrial apoptotic protease-activating factor 1 (Apaf-1)-dependent pathway for apoptosis (as type II cells) is further blocked because BCR:CD21 coligation promotes up-regulation of the mitochondrial antiapoptotic molecule, Bcl-2.

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Section: Discussionmentioning

confidence: 58%

Role of Complement-Binding CD21/CD19/CD81 in Enhancing Human B Cell Protection from Fas-Mediated Apoptosis

Mongini

Jackson

Tolani

et al. 2003

The Journal of Immunology

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“…CD23 is an immunoregulatory protein found both on cell membranes and as a soluble protein. CD23 interacts with CR2 to increase production of IgE in the presence of IL-4 (3), rescue germinal-center B cells from apoptosis (24), provide T cell-activating signals by B cell APCs (25), and promote T-B cell adhesion (26).…”

Section: H Uman Complement Receptor (Cr)mentioning

confidence: 99%

Characterization of Human Complement Receptor Type 2 (CR2/CD21) as a Receptor for IFN-α: A Potential Role in Systemic Lupus Erythematosus

Asokan

Hua

Young

et al. 2006

The Journal of Immunology

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Human complement receptor type 2 (CR2/CD21) is a B lymphocyte membrane glycoprotein that plays a central role in the immune responses to foreign Ags as well as the development of autoimmunity to nuclear Ags in systemic lupus erythematosus. In addition to these three well-characterized ligands, C3d/iC3b, EBV-gp350, and CD23, a previous study has identified CR2 as a potential receptor for IFN-α. IFN-α, a multifunctional cytokine important in the innate immune system, has recently been proposed to play a major pathogenic role in the development of systemic lupus erythematosus in humans and mice. In this study, we have shown using surface plasmon resonance and ELISA approaches that CR2 will bind IFN-α in the same affinity range as the other three well-characterized ligands studied in parallel. In addition, we show that IFN-α interacts with short consensus repeat domains 1 and 2 in a region that serves as the ligand binding site for C3d/iC3b, EBV-gp350, and CD23. Finally, we show that treatment of purified human peripheral blood B cells with the inhibitory anti-CR2 mAb 171 diminishes the induction of IFN-α-responsive genes. Thus, IFN-α represents a fourth class of extracellular ligands for CR2 and interacts with the same domain as the other three ligands. Defining the role of CR2 as compared with the well-characterized type 1 IFN-α receptor 1 and 2 in mediating innate immune and autoimmune roles of this cytokine should provide additional insights into the biologic roles of this interaction.

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“…Interaction of CD21 with CD23 on B-cells is believed to additionally protect B-cells from apoptosis (Bonnefoy et al, 1993). However, the function of CD21 on most other cell types remains unknown.…”

Section: Introductionmentioning

confidence: 99%

EBV attachment stimulates FHOS/FHOD1 redistribution and co-aggregation with CD21: formin interactions with the cytoplasmic domain of human CD21

Gill

Roecklein‐Canfield

Sage

et al. 2004

Journal of Cell Science

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CD21 is a multifunctional receptor for Epstein-Barr virus (EBV), for C3dg and for CD23. Upon engagement of immune complexes CD21 modulates immunoreceptor signaling, linking innate and adaptive immune responses. The mechanisms enabling CD21 to independently relay information between the exterior and interior of the cell, however, remain unresolved. We show that formin homologue overexpressed in spleen (FHOS/FHOD1) binds the cytoplasmic domain of human CD21 through its C terminus. When expressed in cells, EGFP-FHOS localizes to the cytoplasm and accumulates with actin in membrane protrusions. Plasma membrane aggregation, redistribution and co-localization of both proteins are stimulated when EBV (ligand) binds CD21. Though widely expressed, FHOS RNA is most abundant in the littoral cell, a major constituent of the red pulp of human spleen believed to function in antigen filtration. Formins are molecular scaffolds that nucleate actin by a pathway distinct from Arp2/3 complex, linking signal transduction to actin reorganization and gene transcription. Thus, ligand stimulation of FHOS-CD21 interaction may transmit signals through promotion of cytoskeletal rearrangement. Moreover, formin recruitment to sites of actin assembly initiated by immunoreceptors could be a general mechanism whereby co-receptors such as CD21 modulate intracellular signaling.

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A subset of anti‐CD21 antibodies promote the rescue of germinal center B cells from apoptosis

Cited by 109 publications

References 25 publications

Role of Complement-Binding CD21/CD19/CD81 in Enhancing Human B Cell Protection from Fas-Mediated Apoptosis

Role of Complement-Binding CD21/CD19/CD81 in Enhancing Human B Cell Protection from Fas-Mediated Apoptosis

Characterization of Human Complement Receptor Type 2 (CR2/CD21) as a Receptor for IFN-α: A Potential Role in Systemic Lupus Erythematosus

EBV attachment stimulates FHOS/FHOD1 redistribution and co-aggregation with CD21: formin interactions with the cytoplasmic domain of human CD21

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