Regulation of B cell growth and differentiation via CD21 and CD40

Axcrona, Karol; Gray, David; Leanderson, Tomas

doi:10.1002/eji.1830260936

Cited by 24 publications

(16 citation statements)

References 32 publications

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“…Ligation of CD40 enhances immunity by inducing proliferation, germinal center formation, and class switch recombination; however, CD40 signal transduction also inhibits differentiation of B cells and reduces Ig secretion by B-cell hybridomas. 24,[29][30][31][32][33] Furthermore, sustained CD40 signaling in germinal center B cells selects for memory cell formation by inhibiting differentiation of ASCs. 6,24,25,34 The findings that sCD40L represses autoantibody production during innate immune responses expands our understanding of the pleiotropic nature of CD40L by identifying that CD40/CD40L interactions are important in more than T-dependent immune responses.…”

Section: Discussionmentioning

confidence: 99%

Macrophages prevent the differentiation of autoreactive B cells by secreting CD40 ligand and interleukin-6

Kilmon¹,

Wagner²,

Garland³

et al. 2007

Blood

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Activation of the innate immune system promotes polyclonal antibody secretion to eliminate invading pathogens. Inherent in this process is the potential to activate autoreactive B cells and induce autoimmunity. We showed previously that TLRstimulated dendritic cells and macrophages regulate B cell tolerance to Smith antigen, in part through the secretion of interleukin-6 (IL-6). In this manuscript, we show that neutralization of IL-6 fails to abrogate macrophage-mediated repression and identify soluble CD40 ligand IntroductionRecognition of microorganisms by Toll-like receptors (TLRs) promotes inflammation and stimulates the innate immune system to produce antibody, responses that are beneficial in clearing infections. However, TLR ligation of autoreactive B cells can lead to transient or persistent autoimmunity. 1 Studies of rheumatoid factorspecific B cells show that immune complexes containing TLR and B-cell receptor (BCR) ligands induce proliferation of autoreactive B cells. [2][3][4] Likewise, anti-double-stranded DNA (dsDNA)-specific B cells proliferate in response to BCRmediated internalization of chromatin. 5 Because most nuclear self-antigens contain BCR and TLR ligands, these findings suggest that stimulation of autoreactive B cells through the BCR and/or TLR activates some autoreactive B cells.During T-dependent immune responses, CD40 stimulation induces B-cell proliferation, increases the expression of costimulatory molecules, and promotes germinal center formation leading to high affinity, class-switched antibodies. Continuous exposure to CD40 ligand (CD40L) promotes the formation of memory cells by blocking B lymphocyte-induced maturation protein-1 (Blimp-1) expression and arresting plasma cell differentiation. 6 CD40/CD40L interactions also regulate autoreactive B cells that encounter activated CD4 ϩ T H cells. 7 Hen egg lysozyme (HEL)-specific B cells that have been continuously exposed to self-antigen up-regulate Fas in response to CD40L stimulation. Subsequent encounter with an activated HEL-specific T cell induces Fasdependent B-cell apoptosis, thereby preventing autoimmunity. Thus, persistent exposure to self-antigen modulates Fas and CD40 to induce apoptosis or prevent terminal differentiation.We recently identified a mechanism of tolerance that regulates autoreactive B cells during innate immune responses. In response to lipopolysaccharide (LPS), dendritic cells (DCs) and macrophages (M⌽s) regulate HEL-, p-azophenylarsonate (Ars)-and low-affinity (2-12H/V8), Smith antigen (Sm)-specific B cells through the secretion of interleukin-6 (IL-6). 8 Regulation of immunoglobulin (Ig) secretion is selective in that chronically antigen-experienced (anergic) B cells are repressed, whereas transiently stimulated naive B cells are not. This indicates that tolerance within the B-cell compartment extends beyond antigeninduced receptor desensitization and that persistent BCR ligation affects other receptors. Herein, we report that in addition to IL-6, M⌽s secrete soluble CD40L (sCD40L), which selectively r...

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Section: Discussionmentioning

confidence: 99%

Macrophages prevent the differentiation of autoreactive B cells by secreting CD40 ligand and interleukin-6

Kilmon¹,

Wagner²,

Garland³

et al. 2007

Blood

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“…Introduction CD40-CD154 system in thrombosis and inflammation CD40, a member of the tumor necrosis factor (TNF) receptor superfamily, [1,2] is constitutively expressed on the surface of resting and activated platelets, vascular endothelial cells (ECs), melanoma and carcinoma cell types [3,4]. Its ligand, CD154 (CD40 Ligand), plays several roles in immune activation, the most prominent being immunoglobulin class switching [5][6][7][8].…”

mentioning

confidence: 99%

Deficiencies in the CD40 and CD154 receptor-ligand system reduce experimental lung metastasis

Ingersoll

Walker

Meyer

et al. 2009

Clin Exp Metastasis

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It is established that experimental metastasis requires platelet activity. CD154 expressed on and released from activated platelets induces an inflammatory response in endothelial cells and monocytes, including tissue factor production. CD154 has also been shown to activate platelets in vitro and promote thrombus stability in vivo. These CD154 effects may be mediated, at least in part, by CD40 signaling on platelets and vascular endothelial cells. We have previously demonstrated prolonged bleeding and PFA-100 closure times in mice deficient for Cd154 or its receptor Cd40. In the present study, we hypothesized that Cd40 and Cd154 promote lung tumor formation in experimental metastasis in mice. We created mice doubly deficient in Cd40 and Cd154 (Dbl KO) and found them to be both fertile and viable. Injected tumor cells seeded poorly in mice deficient in Cd40 or Cd154, as well as Dbl KO, compared to wild-type mice. We sought to determine whether blood-borne Cd40 versus endothelial Cd40 contribute differentially to reduced experimental lung metastasis, as observed in Cd40 deficient mice. By bone marrow transplantation, we created mice deficient for Cd40 either in the blood compartment but not in the endothelium, or vice versa. We found that mice deficient in blood compartment Cd40 had fewer lung nodules compared to wild-type mice and mice deficient in endothelial Cd40. Our findings suggest an important contribution of the Cd40-Cd154 pathway to experimental lung metastasis. Furthermore, the data points to a selective role for peripheral blood cell Cd40 in this process.

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“…While LPS activation of mouse B cells induces proliferation and differentiation, activation through CD40 causes proliferation only. The effect of CD40 signaling in conjunction with LPS is less clear, but it may inhibit differentiation as indicated by reduced Ig secretion [25]. Our results therefore suggest that the induction of E2A requires not only proliferation but also differentiation.…”

Section: Discussionmentioning

confidence: 69%

Post-transcriptional regulation of E2A proteins via lipopolysaccharide and CD40 signaling

Meyer

Mufti

2000

Eur. J. Immunol.

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Regulation of B cell growth and differentiation via CD21 and CD40

Cited by 24 publications

References 32 publications

Macrophages prevent the differentiation of autoreactive B cells by secreting CD40 ligand and interleukin-6

Macrophages prevent the differentiation of autoreactive B cells by secreting CD40 ligand and interleukin-6

Deficiencies in the CD40 and CD154 receptor-ligand system reduce experimental lung metastasis

Post-transcriptional regulation of E2A proteins via lipopolysaccharide and CD40 signaling

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