BLyS BINDS TO B CELLS WITH HIGH AFFINITY AND INDUCES ACTIVATION OF THE TRANSCRIPTION FACTORS NF-κB AND ELF-1

Kanakaraj, Palanisamy; Migone, Thi‐Sau; Nardelli, Bernardetta; Ullrich, Stephen J.; Li, Yuling; Olsen, Henrik S.; Salcedo, Theodora W.; Kaufman, Thomas M.; Cochrane, E.V.; Gan, Yuxiang; Hilbert, David M.; Giri, Judith G.

doi:10.1006/cyto.2000.0793

Cited by 46 publications

(17 citation statements)

References 33 publications

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“…How these large oligomers would interact with their receptors has yet to be elucidated. These results are not consistent with two other reports that found that BLyS exists only as a trimer and not as an oligomer (4,21).…”

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confidence: 99%

BLyS and APRIL Form Biologically Active Heterotrimers That Are Expressed in Patients with Systemic Immune-Based Rheumatic Diseases

Roschke

Sosnovtseva

Ward

et al. 2002

The Journal of Immunology

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243

179

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BLyS and APRIL are two members of the TNF superfamily that are secreted by activated myeloid cells and have costimulatory activity on B cells. BLyS and APRIL share two receptors, TACI and BCMA, whereas a third receptor, BAFF-R, specifically binds BLyS. Both BLyS and APRIL have been described as homotrimeric molecules, a feature common to members of the TNF superfamily. In this study, we show that APRIL and BLyS can form active heterotrimeric molecules when coexpressed and that circulating heterotrimers are present in serum samples from patients with systemic immune-based rheumatic diseases. These findings raise the possibility that active BLyS/APRIL heterotrimers may play a role in rheumatic and other autoimmune diseases and that other members of the TNF ligand superfamily may also form active soluble heterotrimers.

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confidence: 99%

BLyS and APRIL Form Biologically Active Heterotrimers That Are Expressed in Patients with Systemic Immune-Based Rheumatic Diseases

Roschke

Sosnovtseva

Ward

et al. 2002

The Journal of Immunology

Self Cite

243

179

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“…The significant reduction in B cell numbers is likely due to defective BR3-mediated survival signaling, which at least in part involves the activation of NF-B. In this regard, early studies of BAFF function in primary B cells revealed that BR3-mediated signaling activates the alternative NF-B pathway, as evidenced by IkB kinase (IKK) ␣-dependent processing of p100 to p52 (23,(63)(64)(65). Additionally, processing of p100 is impaired in B cells from A/WySnJ mice, confirming a role for BR3 signaling in the regulation of alternative NF-B activity in response to BAFF (64).…”

Section: Discussionmentioning

confidence: 99%

Absence of Mature Peripheral B Cell Populations in Mice with Concomitant Defects in B Cell Receptor and BAFF-R Signaling

Hoek

Carlesso

Clark

et al. 2009

The Journal of Immunology

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Generation of mature B lymphocytes from early (T1) and late transitional (T2) precursors requires cooperative signaling through BCR and B cell-activating factor receptor 3 (BR3). Recent studies have shown that BCR signaling positively regulates NF-κB2, suggesting BCR regulation of BR3 signaling. To investigate the significance of signal integration from BCR and BR3 in B cell development and function, we crossed Btk-deficient mice (btk−/−), which are developmentally blocked between the T2 and the mature follicular B cell stage as a result of a partial defect in BCR signaling, and A/WySnJ mice, which possess a mutant BR3 defective in propagating intracellular signals that results in a severely reduced peripheral B cell compartment, although all B cell subsets are present in relatively normal ratios. A/WySnJ × btk−/− mice display a B cell-autonomous defect, resulting in a developmental block at an earlier stage (T1) than either mutation alone, leading to the loss of mature splenic follicular and marginal zone B cells, as well as the loss of peritoneal B1 and B2 cell populations. The competence of the double mutant T1 B cells to respond to TLR4 and CD40 survival and activation signals is further attenuated compared with single mutations as evidenced by severely reduced humoral immune responses in vivo and proliferation in response to anti-IgM, LPS, and anti-CD40 stimulation in vitro. Thus, BCR and BR3 independently and in concert regulate the survival, differentiation, and function of all B cell populations at and beyond T1, earliest transitional stage.

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“…The finding that IKK␣ is required for the processing of NF-B 2 (178) may partially explain this defect since NF-B 2 Ϫ/Ϫ mice have approximately 10% of normal B-cell numbers (27,58). In mice which lack both NF-B 1 and NF-B 2 , B-cell maturation is blocked at the immature stage, although it is not known if this is due to a cell autonomous defect (60) or whether factors like the TNF superfamily member BlyS, which activate NF-B (107) and are important in the control of B-cell homeostasis, are dysregulated in these mice. Marginal zone B cells represent a subset of B cells localized in the marginal sinuses of the spleen and are thought to be the one of the first immune cells that interact with blood-borne pathogens and so may represent a link between innate and adaptive immunity.…”

Section: Developmentmentioning

confidence: 99%

NF-κB Family of Transcription Factors: Central Regulators of Innate and Adaptive Immune Functions

2002

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SUMMARY Transcription factors of the Rel/NF-κB family are activated in response to signals that lead to cell growth, differentiation, and apoptosis, and these proteins are critical elements involved in the regulation of immune responses. The conservation of this family of transcription factors in many phyla and their association with antimicrobial responses indicate their central role in the regulation of innate immunity. This is illustrated by the association of homologues of NF-κB, and their regulatory proteins, with resistance to infection in insects and plants (M. S. Dushay, B. Asling, and D. Hultmark, Proc. Natl. Acad. Sci. USA 93:10343-10347, 1996; D. Hultmark, Trends Genet. 9:178-183, 1993; J. Ryals et al., Plant Cell 9:425-439, 1997). The aim of this review is to provide a background on the biology of NF-κB and to highlight areas of the innate and adaptive immune response in which these transcription factors have a key regulatory function and to review what is currently known about their roles in resistance to infection, the host-pathogen interaction, and development of human disease.

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BLyS BINDS TO B CELLS WITH HIGH AFFINITY AND INDUCES ACTIVATION OF THE TRANSCRIPTION FACTORS NF-κB AND ELF-1

Cited by 46 publications

References 33 publications

BLyS and APRIL Form Biologically Active Heterotrimers That Are Expressed in Patients with Systemic Immune-Based Rheumatic Diseases

BLyS and APRIL Form Biologically Active Heterotrimers That Are Expressed in Patients with Systemic Immune-Based Rheumatic Diseases

Absence of Mature Peripheral B Cell Populations in Mice with Concomitant Defects in B Cell Receptor and BAFF-R Signaling

NF-κB Family of Transcription Factors: Central Regulators of Innate and Adaptive Immune Functions

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