ORCID Profile
0000-0002-6074-2693
Current Organisations
Novo Nordisk
,
Monash University
,
University of Melbourne
,
QIMR Bergoher Medical Reserach Institute
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Gene Expression (incl. Microarray and other genome-wide approaches) | Genomics | Systems Biology | Genetics
Expanding Knowledge in the Biological Sciences | Expanding Knowledge in the Medical and Health Sciences | Expanding Knowledge in Technology |
Publisher: Royal Society of Chemistry (RSC)
Date: 2022
DOI: 10.1039/D1SC06844J
Abstract: mRNA display generates vast datasets of protein binders. Bioinformatic clustering of the sequences combined with high throughput synthesis and analysis methods allow efficient prioritisation of hits for in vivo experiments.
Publisher: American Society for Clinical Investigation
Date: 15-07-2003
DOI: 10.1172/JCI18025
Publisher: Wiley
Date: 2019
DOI: 10.1002/CTI2.1090
Publisher: Rockefeller University Press
Date: 06-12-1999
Abstract: The cause of many autoimmune and inflammatory diseases is unresolved, although dysregulated production of tumor necrosis factor (TNF) family members appears to be important in many cases. BAFF, a new member of the TNF family, binds to B cells and costimulates their growth in vitro. Mice transgenic for BAFF have vastly increased numbers of mature B and effector T cells, and develop autoimmune-like manifestations such as the presence of high levels of rheumatoid factors, circulating immune complexes, anti–DNA autoantibodies, and immunoglobulin deposition in the kidneys. This phenotype is reminiscent of certain human autoimmune disorders and suggests that dysregulation of BAFF expression may be a critical element in the chain of events leading to autoimmunity.
Publisher: Elsevier BV
Date: 06-2007
DOI: 10.1016/J.COI.2007.04.008
Abstract: B-cell activation factor from the tumor necrosis factor family (BAFF) is a key survival factor during B-cell maturation -- a delicate immune checkpoint for B cells. Excessive BAFF production at this stage corrupts B-cell tolerance and leads to autoimmunity. Elevated serum BAFF levels have been detected in some patients suffering from various autoimmune conditions. The positive outcomes of currently ongoing clinical trials using BAFF-neutralising agents confirm that this factor plays a major pathological role in rheumatoid arthritis and in systemic lupus erythematosus. Almost a decade after its discovery, BAFF continues to occupy the main stage in Immunology, with more than one hundred BAFF-related articles published per year. In recent years, our understanding of cell signaling and autoimmune mechanisms in this system have seen major advances, refining new possibilities for therapeutic intervention.
Publisher: Wiley
Date: 27-02-2013
DOI: 10.1111/IMJ.12039
Abstract: The incidence and prevalence of autoimmune diseases such as rheumatoid arthritis, primary Sjögren syndrome, scleroderma and systemic lupus erythematosus (SLE) varies with geography and ethnicity. For ex le, SLE is reported to be more common in populations such as African-Caribbeans and Indigenous Australians (IA). As well as socio-economic status, variation in severity of disease may also show ethnic variability. The initial presentation of SLE in IA, in the context of a unique genetic background and distinctive environmental influences, is often florid with a recurring spectrum of clinical phenotypes. These clinical observations suggest a unique pathway for autoimmunity pathogenesis in this population. For instance, the high prevalence of bacterial infections in IA, particularly group A streptococcus, may be a potential explanation not only for increased incidence and prevalence of SLE but also the commonly florid acute disease presentation and propensity for rapidly progressive end organ threatening disease. This article will review the state of research in autoimmune disease of IA, consider key findings related to autoimmune disease in this population and propose a model potentially to explain the involvement of innate immunity and chronic infection in autoimmune disease pathogenesis. Ultimately, understanding of SLE at this level could affect management and result in personalised and targeted therapies to improve the health status of IA as well as better understanding of SLE pathogenesis per se.
Publisher: Wiley
Date: 2019
DOI: 10.1002/CTI2.1093
Publisher: Wiley
Date: 09-2006
Abstract: B cell-activating factor belonging to the TNF family (BAFF) is a B cell survival factor required for B cell maturation. BAFF transgenic (Tg) mice develop autoimmune disorders characterized by autoantibody production, which leads to nephritis and salivary gland destruction (sialadenitis), features reminiscent of systemic lupus erythematosus and Sjögren's syndrome (SS), respectively. Disease in BAFF Tg mice correlates with the expansion of the marginal zone (MZ) B cell compartment and the abnormal presence of MZ-like B cells in the blood, LN and inflamed salivary glands, suggesting a role for these cells in BAFF-induced autoimmunity. Lymphotoxin-beta (LTbeta)-deficient mice show disrupted splenic architecture, lack MZ B cells and some peripheral LN, and are unable to mount T cell-dependent immune responses. BAFF Tg mice lacking LTbeta (LTbetaDelta-BTg) retained these defects, yet still developed nephritis associated with the presence of B-1 B cells in the kidneys. However, in contrast to old BAFF Tg mice, aging LTbetaDelta-BTg mice no longer developed sialadenitis. Thus, autoimmune disorders in BAFF Tg mice are possibly events coordinated by MZ and B-1 B cells at separate anatomical sites.
Publisher: Public Library of Science (PLoS)
Date: 06-08-2012
Publisher: Wiley
Date: 08-03-2011
DOI: 10.1038/ICB.2011.6
Abstract: Asthma affects 300 million people worldwide, yet the mechanism behind this pathology has only been partially elucidated. The documented connection between psychological stress and airway inflammation strongly suggests the involvement of the nervous system and its secreted mediators, including neuropeptides, on allergic respiratory disease. In this study, we show that neuropeptide Y (NPY), a prominent neurotransmitter, which release is strongly upregulated during stress, exacerbates allergic airway inflammation (AAI) in mice, via its Y1 receptor. Our data indicate that the development of AAI was associated with elevated NPY expression in the lung and that lack of NPY-mediated signalling in NPYKO mice or its Y1 receptor in Y1KO mice significantly improved AAI. In vivo, eosinophilia in the bronchoalveolar fluid as well as circulating immunoglobulin E in response to AAI, were significantly reduced in NPY- and Y1-deficient compared with wild-type mice. These changes correlated with a blunting of the Th2 immune profile that is characteristic for AAI, as shown by the decreased release of interleukin-5 during ex vivo re-stimulation of T cells isolated from the thoracic draining lymph nodes of NPY- or Y1-deficient mice subjected to AAI. Taken together this study demonstrates that signalling through Y1-receptors emerges as a critical pathway for the development of airway inflammation and as such potentially opens novel avenues for therapeutic intervention in asthma.
Publisher: American Society for Clinical Investigation
Date: 04-2004
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2007
Publisher: Elsevier BV
Date: 2011
DOI: 10.1016/J.NEURON.2010.12.006
Abstract: The chemokine Cxcl12 binds Cxcr4 and Cxcr7 receptors to control cell migration in multiple biological contexts, including brain development, leukocyte trafficking, and tumorigenesis. Both receptors are expressed in the CNS, but how they cooperate during migration has not been elucidated. Here, we used the migration of cortical interneurons as a model to study this process. We found that Cxcr4 and Cxcr7 are coexpressed in migrating interneurons, and that Cxcr7 is essential for chemokine signaling. Intriguingly, this process does not exclusively involve Cxcr7, but most critically the modulation of Cxcr4 function. Thus, Cxcr7 is necessary to regulate Cxcr4 protein levels, thereby adapting chemokine responsiveness in migrating cells. This demonstrates that a chemokine receptor modulates the function of another chemokine receptor by controlling the amount of protein that is made available for signaling at the cell surface.
Publisher: Rockefeller University Press
Date: 03-12-2001
Abstract: B cells undergo a complex series of maturation and selection steps in the bone marrow and spleen during differentiation into mature immune effector cells. The tumor necrosis factor (TNF) family member B cell activating factor of the TNF family (BAFF) (BLyS/TALL-1) plays an important role in B cell homeostasis. BAFF and its close homologue a proliferation-inducing ligand (APRIL) have both been shown to interact with at least two receptors, B cell maturation antigen (BCMA) and transmembrane activator and cyclophilin ligand interactor (TACI), however their relative contribution in transducing BAFF signals in vivo remains unclear. To functionally inactivate both BAFF and APRIL, mice transgenic for a soluble form of TACI were generated. They display a developmental block of B cell maturation in the periphery, leading to a severe depletion of marginal zone and follicular B2 B cells, but not of peritoneal B1 B cells. In contrast, mice transgenic for a soluble form of BCMA, which binds APRIL, have no detectable B cell phenotype. This demonstrates a crucial role for BAFF in B cell maturation and strongly suggests that it signals via a BCMA-independent pathway and in an APRIL-dispensable way.
Publisher: Elsevier BV
Date: 03-2008
DOI: 10.1016/J.IMMUNI.2008.01.009
Abstract: Tumor necrosis factor receptor-associated factors 2 and 3 (TRAF2 and TRAF3) were shown to function in a cooperative and nonredundant manner to suppress nuclear factor-kappaB2 (NF-kappaB2) activation, gene expression, and survival in mature B cells. In the absence of this suppressive activity, B cells developed independently of the obligatory B cell survival factor, BAFF (B cell-activating factor of the tumor necrosis factor family). However, deletion of either TRAF2 or TRAF3 from the T cell lineage did not promote T cell survival, despite causing extensive NF-kappaB2 activation. This constitutive, lineage-specific suppression of B cell survival by TRAF2 and TRAF3 determines the requirement for BAFF to sustain B cell development in vivo. Binding of BAFF to BAFF receptor reversed TRAF2-TRAF3-mediated suppression of B cell survival by triggering the depletion of TRAF3 protein. This process was TRAF2 dependent, revealing dual roles for TRAF2 in regulating B cell homeostasis.
Publisher: Wiley
Date: 09-2021
DOI: 10.1002/RAI2.12010
Abstract: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by extraordinary heterogeneity, due to the complex pathogenesis and erse manifestations. Stratification of patients for therapy and prognosis represents a major challenge to manage SLE. Conventional biomarkers for disease diagnosis and activity assessment provide very limited insight into immunological pathogenesis and therapeutic response rates. The advancement of “omics” technologies including genomics, transcriptomics, proteomics, and metabolomics has constituted an unprecedented opportunity to characterize the immunopathological landscape in in idual patients with SLE. Indeed, genomic studies reveal a subset of SLE patients carrying one or more functional single nucleotide polymorphisms (SNPs) underlying immune dysregulation while transcriptomic studies have revealed subgroups in SLE patients showing distinct signatures for Type I interferon (TI‐IFN) pathway activation or aberrant differentiation of B cells into plasma cells. This review will summarize results from the latest studies using omics technology to understand SLE heterogeneity. In addition, we propose that the application of artificial intelligence, such as by machine learning‐based nonlinear dimensionality reduction method uniform manifold approximation and projection (UMAP) can further strengthen the analysis of omics big data. The combination of new technology and novel analysis pipeline can lead to breakthroughs in stratifying SLE patients for a better monitoring of disease activity and more precise design of treatment regime, not only for conventional immunosuppression but also novel immunotherapies targeting B‐cell activating factor (BAFF), TI‐IFN, and interleukin 2 (IL‐2).
Publisher: Elsevier BV
Date: 02-2014
Publisher: Elsevier BV
Date: 03-2011
DOI: 10.1016/J.JAUT.2010.12.002
Abstract: B cell activating factor belonging to the TNF family (BAFF or BLyS) is a critical B cell survival factor essential for B cell maturation. BAFF transgenic (Tg) mice develop autoimmunity resembling Systemic Lupus Erythematosus (SLE) in a T cell-independent but toll-like receptor (TLR) signalling-dependent manner, requiring TLR-induced innate B cell-derived pro-inflammatory autoantibody deposition in the kidneys. Importantly, neutralizing BAFF in the clinic shows efficacy in patients with SLE, confirming its critical role in the progression of this disease in both humans and mouse models. The specific B cell types that produce autoantibodies in BAFF Tg mice are TLR-activated innate marginal zone (MZ) B cells and B1 cells, but not follicular B cells. Interestingly, in BAFF Tg mice MZ-like B cells infiltrate salivary glands whereas B1 B cells infiltrate the kidneys. To ascertain the relevance of B1 and MZ-like B cells in the development of nephritis in BAFF Tg mice, we generated genetically asplenic as well as splenectomized BAFF Tg animals. BAFF Tg mice born without a spleen lack MZ B cells, have very reduced B1a B cell numbers but a normal B1b B cell compartment. Loss of these B cell subsets failed to protect BAFF Tg mice against nephritis indicating that B1b B cells are an important subset for the development of autoimmune nephritis in BAFF Tg mice. Thus the spleen is dispensable for the development of autoimmune nephritis in BAFF Tg mice and points toward a pathogenic role for innate B1 B cells. Identifying similar innate B cells in humans may offer the possibility of more targeted B cell therapies.
Publisher: Wiley
Date: 08-1997
Abstract: To compare the function of the tumor necrosis factor (TNF) and lymphotoxin (LT)alpha/beta systems in the mature immune system, these two pathways were blocked with soluble receptor-immunoglobulin (R-Ig) fusion proteins in normal adult mice. Inhibition of LT alpha/beta signaling using LT betaR-Ig or a blocking monoclonal antibody against murine LT beta had profound effects. The spleen lacked discrete B cell follicles and the marginal zone was altered. Less marked changes were detected in lymph nodes. LT alpha/beta inhibition also prevented germinal center formation in the spleen and impaired Ig production in response to sheep red blood cells (SRBC) immunization. These results show that the LT alpha/beta system is required for the maintenance of splenic architecture and normal immune responses, and not simply for the development of peripheral immune organs during ontogeny. In contrast, inhibition of the TNF/LT alpha pathway with TNF-R55-Ig did not affect the splenic architecture or the anti-SRBC response. Splenic defects and impaired antibody responses are seen in TNF-deficient mice, suggesting that TNF is important during development. Therefore relative to TNF, the LT system has the dominant influence on splenic organization and anti-SRBC Ig formation in the adult mouse.
Publisher: Wiley
Date: 16-10-2012
Publisher: Springer Science and Business Media LLC
Date: 07-2009
DOI: 10.1038/NRI2572
Abstract: The tumour necrosis factor (TNF) family members B cell activating factor (BAFF) and APRIL (a proliferation-inducing ligand) are crucial survival factors for peripheral B cells. An excess of BAFF leads to the development of autoimmune disorders in animal models, and high levels of BAFF have been detected in the serum of patients with various autoimmune conditions. In this Review, we consider the possibility that in mice autoimmunity induced by BAFF is linked to T cell-independent B cell activation rather than to a severe breakdown of B cell tolerance. We also outline the mechanisms of BAFF signalling, the impact of ligand oligomerization on receptor activation and the progress of BAFF-depleting agents in the clinical setting.
Publisher: Research Square Platform LLC
Date: 26-07-2023
DOI: 10.21203/RS.3.RS-3183670/V1
Abstract: Chronic Lymphocytic Leukemia (CLL) is the most common leukemia in adults, characterized by the expansion of CD19 + CD5 + B cells. The origin of CLL remains debated, with one model suggesting that CLL cells carrying mutations in the variable regions of immunoglobulin are derived from post-germinal center B cells, whereas unmutated CLL cells originate from CD5 + mature B cell precursors. The cytokines BAFF and APRIL each play a significant role in CLL cell survival and accumulation, but their involvement in disease initiation is unclear. Using the TCL1-transgenic (Tg) model, we have demonstrated that BAFF, but not, APRIL is needed for the initiation and dissemination of CLL. In the absence of BAFF or its receptor BAFF-R, expression of the TCL1 transgene increases CLL cell numbers in the peritoneal cavity but does not allow dissemination into the periphery. BAFF binding to BAFF-R is not required for the survival of peritoneal CLL cells but for the expression of tumor-promoting genes, likely allowing peritoneal CLL cells to disseminate to other sites to drive CLL. Our findings unveil BAFF as an unrecognized tumor-promoting cytokine in CLL. Combining current CLL therapies with BAFF inhibition may offer dual benefits: reducing peripheral tumor burden and suppressing transformed CLL cell output.
Publisher: Elsevier BV
Date: 2001
Publisher: American Diabetes Association
Date: 31-03-2009
DOI: 10.2337/DB08-1504
Abstract: Tumor necrosis factor ligand family members B-cell–activating factor (BAFF) and a proliferation-inducing ligand (APRIL) can exert powerful effects on B-cell activation and development, type 1 T-helper cell (Th1) immune responses, and autoimmunity. We examined the effect of blocking BAFF and APRIL on the development of autoimmune diabetes. Female NOD mice were administered B-cell maturation antigen (BCMA)-Fc from 9 to 15 weeks of age. Diabetes incidence, islet pathology, and T- and B-cell populations were examined. BCMA-Fc treatment reduced the severity of insulitis and prevented diabetes development in NOD mice. BCMA-Fc–treated mice showed reduced follicular, marginal-zone, and T2MZ B-cells. B-cell reduction was accompanied by decreased frequencies of pathogenic CD4+CD40+ T-cells and reduced Th1 cytokines IL-7, IL-15, and IL-17. Thus, T-cell activation was blunted with reduced B-cells. However, BCMA-Fc–treated mice still harbored detectable diabetogenic T-cells, suggesting that regulatory mechanisms contributed to diabetes prevention. Indeed, BCMA-Fc–treated mice accumulated increased CD4+CD25+ regulatory T-cells (Tregs) with age. CD4+CD25+ cells were essential for maintaining euglycemia because their depletion abrogated BCMA-Fc–mediated protection. BCMA-Fc did not directly affect Treg homeostasis given that CD4+CD25+Foxp3+ T-cells did not express TACI or BR3 receptors and that CD4+CD25+Foxp3+ T-cell frequencies were equivalent in wild-type, BAFF−/−, TACI−/−, BCMA−/−, and BR3−/− mice. Rather, B-cell depletion resulted in CD4+CD25+ T-cell–mediated protection from diabetes because anti-CD25 monoclonal antibody treatment precipitated diabetes in both diabetes-resistant NOD.μMT−/− and BCMA-Fc–treated mice. BAFF/APRIL blockade prevents diabetes. BCMA-Fc reduces B-cells, subsequently blunting autoimmune activity and allowing endogenous regulatory mechanisms to preserve a prehyperglycemic state.
Publisher: Wiley
Date: 07-2012
DOI: 10.1002/DMRR.2302
Abstract: Obesity and type 2 diabetes mellitus are characterized by insulin resistance and 'low-grade inflammation' however, the pathophysiological link is poorly understood. To determine the relative contribution of obesity and insulin resistance to systemic 'inflammation', this study comprehensively characterized circulating immune cells in different grades of obesity. Immune cell phenotypes and activation status were analysed by flow cytometry cross-sectionally in morbidly obese (n = 16, body mass index (BMI) 42.2 ± 5.4 kg/m2), overweight (n = 13, BMI 27.4 ± 1.6 kg/m2) and normal weight (n = 12, BMI 22.5 ± 1.9 kg/m2) subjects. Obese, but not overweight subjects, had increased activation marker expression on neutrophils, monocytes, T-lymphocytes and polarization of T helper cells towards a pro-inflammatory type 1-phenotype (Th1). Th1 numbers correlated positively with the degree of insulin resistance (homeostasis model assessment, p < 0.05). Lymphocytes from obese subjects showed reduced insulin-stimulated AKT-phosphorylation in vitro. Supra-physiological insulin concentrations did not affect T-cell differentiation, which under normal circumstances would promote an anti-inflammatory T helper type 2-phenotype. These results show that morbid obesity is characterized by circulating immune cells that are activated and insulin resistant, with the T-cell balance polarized towards a pro-inflammatory Th1 phenotype. The loss of insulin-induced suppression of inflammatory phenotypes in circulating immune cells could contribute to the systemic and adipose tissue inflammation found in morbid obesity.
Publisher: Cold Spring Harbor Laboratory
Date: 24-05-2019
DOI: 10.1101/647719
Abstract: Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease that is difficult to treat. There is currently no optimal stratification of patients with SLE, and thus responses to available treatments are unpredictable. Here, we developed a new stratification scheme for patients with SLE, based on the whole-blood transcriptomes of patients with SLE. We applied machine learning approaches to RNA-sequencing (RNA-seq) datasets to stratify patients with SLE into four distinct clusters based on their gene expression profiles. A meta-analysis on two recently published whole-blood RNA-seq datasets was carried out and an additional similar dataset of 30 patients with SLE and 29 healthy donors was contributed in this research 141 patients with SLE and 51 healthy donors were analysed in total. Examination of SLE clusters, as opposed to unstratified SLE patients, revealed underappreciated differences in the pattern of expression of disease-related genes relative to clinical presentation. Moreover, gene signatures correlated to flare activity were successfully identified. Given that disease heterogeneity has confounded research studies and clinical trials, our approach addresses current unmet medical needs and provides a greater understanding of SLE heterogeneity in humans. Stratification of patients based on gene expression signatures may be a valuable strategy to harness disease heterogeneity and identify patient populations that may be at an increased risk of disease symptoms. Further, this approach can be used to understand the variability in responsiveness to therapeutics, thereby improving the design of clinical trials and advancing personalised therapy.
Publisher: American Diabetes Association
Date: 15-11-2012
DOI: 10.2337/DB12-0156
Abstract: Recruitment of activated immune cells into white adipose tissue (WAT) is linked to the development of insulin resistance and obesity, but the mechanism behind this is unclear. Here, we demonstrate that Y1 receptor signaling in immune cells controls inflammation and insulin resistance in obesity. Selective deletion of Y1 receptors in the hematopoietic compartment of mice leads to insulin resistance and inflammation in WAT under high fat–fed conditions. This is accompanied by decreased mRNA expression of the anti-inflammatory marker adiponectin in WAT and an increase of the proinflammatory monocyte chemoattractant protein-1 (MCP-1). In vitro, activated Y1-deficient intraperitoneal macrophages display an increased inflammatory response, with exacerbated secretion of MCP-1 and tumor necrosis factor, whereas addition of neuropeptide Y to wild-type macrophages attenuates the release of these cytokines, this effect being blocked by Y1 but not Y2 receptor antagonism. Importantly, treatment of adipocytes with the supernatant of activated Y1-deficient macrophages causes insulin resistance, as demonstrated by decreased insulin-induced phosphorylation of the insulin receptor and Akt as well as decreased expression of insulin receptor substrate 1. Thus, Y1 signaling in hematopoietic-derived cells such as macrophages is critical for the control of inflammation and insulin resistance in obesity.
Publisher: The Company of Biologists
Date: 05-2014
DOI: 10.1242/DEV.104224
Abstract: The CXCL12/CXCR4 signaling pathway is involved in the development of numerous neuronal and non-neuronal structures. Recent work established that the atypical second CXCL12 receptor, CXCR7, is essential for the proper migration of interneuron precursors in the developing cerebral cortex. Two CXCR7-mediated functions were proposed in this process: direct modulation of β-arrestin-mediated signaling cascades and CXCL12 scavenging to regulate local chemokine availability and ensure responsiveness of the CXCL12/CXCR4 pathway in interneurons. Neither of these functions has been proven in the embryonic brain. Here, we demonstrate that migrating interneurons efficiently sequester CXCL12 through CXCR7. CXCR7 ablation causes excessive phosphorylation and downregulation of CXCR4 throughout the cortex in mice expressing CXCL12, but not in CXCL12-deficient animals. Cxcl12−/− mice lack activated CXCR4 in embryonic brain lysates and display a similar interneuron positioning defect as Cxcr4−/−, Cxcr7−/− and Cxcl12−/− Cxcr7−/− animals. Thus, CXCL12 is the only CXCR4-activating ligand in the embryonic brain and deletion of one of the CXCL12 receptors is sufficient to generate a migration phenotype that corresponds to the CXCL12-deficient pathway. Our findings imply that interfering with the CXCL12-scavenging activity of CXCR7 causes loss of CXCR4 function as a consequence of excessive CXCL12-mediated CXCR4 activation and degradation.
Publisher: Society for Neuroscience
Date: 30-10-2013
DOI: 10.1523/JNEUROSCI.0857-13.2013
Abstract: Gonadotropin-releasing hormone (GnRH) neurons are neuroendocrine cells, located in the hypothalamus, that play an essential role in mammalian reproduction. These neurons originate in the nasal placode and migrate during embryonic development, in association with olfactory/vomeronasal nerves, first in the nose, then through the cribriform plate to enter the forebrain, before settling in the hypothalamus. One of the molecules required for their early migration in the nose is the chemokine CXCL12, which is expressed in the embryonic nasal mesenchyme in an increasing ventral to dorsal gradient, presumably guiding GnRH neurons toward the forebrain. Mice lacking CXCR4, the receptor for CXCL12, exhibit defective GnRH cell movement and a significant reduction in their number, suggesting that CXCL12/CXCR4 signaling is important in the migration and survival of these neurons. Here, we investigated the role of the more recently identified second CXCL12 receptor, CXCR7, in GnRH neuron development. We demonstrate that CXCR7 is expressed along the migratory path of GnRH neurons in the nasal cavity and, although not expressed by GnRH neurons, it affects their migration as indicated by the ectopic accumulation of these cells in the nasal compartment in CXCR7 −/− mice. Absence of CXCR7 caused abnormal accumulation of CXCL12-RFP at CXCR4-positive sites in the nasal area of CXCL12-RFP-transgenic mice and excessive CXCL12-dependent intracellular clustering of CXCR4 in GnRH neurons, suggesting internalization. These findings imply that CXCR7 regulates CXCL12 availability by acting as a scavenger along the migratory path of GnRH neurons and, thus, influences the migration of these cells in a noncell-autonomous manner.
Publisher: Elsevier BV
Date: 10-2006
DOI: 10.1016/J.SMIM.2006.04.005
Abstract: BAFF is a key factor controlling B cell survival and maturation and its over-expression promotes B cell-mediated autoimmune disorders and participates in the progression of B cell lymphomas. Yet, BAFF and a related ligand APRIL are expressed by T lymphocytes and modulate their functions. BAFF and APRIL promote T cell activation and survival. BAFF over-expression in transgenic (Tg) mice enhances T helper 1 (Thl)-driven delayed-type hypersensitivity (DTH), but inhibits T helper 2 (Th2) cell-mediated allergic airway inflammation in mice. Some of these effects are also dependent on BAFF-induced modification of the B cell compartment. Therefore, direct BAFF/APRIL signalling in T cells and/or T cell modulation in response to a BAFF-modified B cell compartment may play an important role in inflammation and immunomodulation.
Publisher: Rockefeller University Press
Date: 06-04-1998
Abstract: The transfer of lymphocytes into severe combined immunodeficiency (SCID) mice induces a series of histological changes in the spleen, including the appearance of mature follicular dendritic cells (FDCs). Studies were undertaken to clarify the role of lymphotoxin (LT) in this process. The results show that SCID mice have a small and partially differentiated white pulp containing marginal zone and interdigitating dendritic cells, but lacking FDCs. Transferred spleen cells can segregate into T and B cell areas shortly after their injection to SCID mice. This ability is dependent on signaling through LT-β receptor (LT-βR), since blocking ligand–receptor interaction in recipient SCID mice ablates the capacity of the transferred cells to segregate. A week after lymphocyte transfer, host-derived FDCs appeared in the reconstituted SCID mice. This induction of FDCs is dependent on LT-βR signaling by B cells since LT-α−/− B cells are incapable of inducing development of FDCs in SCID mice, even after cotransfer of LT-α+/+ T cells. Therefore, LT plays at least two discrete roles in splenic organization. First, it appears that LT induces the differentiation of the white pulp to create sites for lymphocyte segregation. Second, LT expression by B cells drives the maturation of FDCs and the organization of B cell follicles.
Publisher: Elsevier
Date: 2006
Publisher: Elsevier BV
Date: 12-2002
DOI: 10.1016/S0952-7915(02)00407-7
Abstract: Over two decades of research have increased the interest in factors from the tumor necrosis factor family. The vast majority of these factors are powerful modulators of critical immune functions and participate in pathogenic mechanisms leading to autoimmune disease. This field constantly evolves with the addition of new family members and the discovery of their function. During the past few years several additional factors from this family, such as BAFF, RANKL, TRAIL and GITRL, have emerged with novel functions that regulate both T and B cell immune tolerance and participate in tissue destruction in autoimmunity. These new findings revealed exciting innovative strategies for the treatment of autoimmune diseases.
Publisher: Humana Press
Date: 2010
Publisher: Springer Science and Business Media LLC
Date: 24-02-2020
Publisher: Springer Science and Business Media LLC
Date: 08-11-2009
DOI: 10.1038/NI.1820
Publisher: Springer Science and Business Media LLC
Date: 2013
DOI: 10.1186/AR4277
Publisher: Wiley
Date: 30-06-2006
Abstract: B cell-activating factor belonging to the TNF family (BAFF) and its receptor BAFF-R play critical roles in the maturation and survival of conventional peripheral B cells. However, they appeared to be dispensable for the generation and maintenance of CD5(+) B-1 cells as BAFF(-/-) and BAFF-R(-/-) mice have normal B-1 cell populations. Hence, it is presently unclear if B-1 cells are responsive to BAFF and if BAFF regulates some aspects of B-1 cell function. We show here that BAFF-R and transmembrane activator and CAML interactor (TACI) are the major receptors expressed by B-1 cells. Specifically, we show that BAFF treatment of B-1 cells leads to increased NF-kappaB p100 processing and CD21/CD35 expression. Interestingly, toll-like receptor (TLR) engagement of B-1 cells augmented the surface expression of BAFF receptors and rendered them responsive to BAFF costimulation, as evidenced by their increased proliferation, expression of cell surface activation markers and secretion of the pro-inflammatory cytokine IL-6 and the anti-inflammatory cytokine IL-10. This costimulatory effect is achieved primarily through BAFF-R as BAFF failed to costimulate B-1 cells obtained from A/WySnJ mice which have defective BAFF-R signaling. Thus, as TLR are innate immune receptors and B-1 cells are "innate-like" lymphocytes, our data provide evidence that BAFF plays a role in innate immunity.
Publisher: Elsevier BV
Date: 07-1998
DOI: 10.1016/S1074-7613(00)80589-0
Abstract: We investigated lymphotoxin (LT) and TNF function in lymph node genesis and cellular organization by manipulating LTbeta-R and TNF-R signaling. Lymph nodes developed in LTalpha-/- mice treated in utero with agonist anti-LTbeta-R monoclonal antibody. Thus, LTbeta-R signaling mediates lymph node genesis. Surprisingly, mucosal lymph nodes that can develop independently of LTalphabeta/LTbeta-R interaction were generated. Normal mice treated in utero with LTbeta-R-Ig and TNF-R55-Ig or anti-TNF lacked all lymph nodes, indicating that TNF signaling contributes to lymph node genesis. Lymph nodes generated in LTalpha-/- mice had disrupted cellular organization. Therefore, LTbeta-R signaling during gestation is not sufficient to establish normal cellular microarchitecture. We conclude that LT and TNF play critical roles in the genesis and cellular organization of lymph nodes.
Publisher: Elsevier BV
Date: 07-2010
DOI: 10.1016/J.AUTREV.2010.05.006
Abstract: Sjögren's syndrome (SS) is an autoimmune epithelitis hallmarked by a destruction of epithelial cells, the subsequent lymphocytic infiltration of exocrine glands and their ensuing dryness. Given the prominent role currently assigned to B cells in SS, it is not surprising that the B cell activating factor belonging to the Tumor Necrosis Factor family (BAFF) is involved in its pathogenesis. When overexpressed, this cytokine leads to self-reactive B cells emergence at the transitional B-cell stage. BAFF overexpression that has been observed in SS, is associated with B-cell tolerance breakdown and autoantibody production. Furthermore, BAFF is responsible for the abnormal distribution of B cells subsets and B-cell hyperactivity described in the blood. In the salivary glands, a minority of B-cell clusters represent ectopic germinal center cells, while the majority manifest features consistent with transitional type 2 (T2) and marginal-zone (MZ)-like B cells. Interestingly, both types of B-cell cluster include autoreactive B cells and BAFF is associated with expansion of T2 B cells and MZ-like B cells in the salivary glands. Finally, BAFF plays a major role in B-cell repopulation after their depletion by rituximab in SS.
Publisher: Public Library of Science (PLoS)
Date: 09-12-2013
Publisher: Wiley
Date: 29-05-2012
DOI: 10.1002/IUB.1046
Abstract: In November 2009, Human Genome Sciences and Glaxo-Smith Kline [HGS (Rockville, Maryland) and GSK, respectively] announced that Belimumab, a neutralizing antibody to the tumour necrosis factor (TNF)-like ligand, B-cell activating factor (BAFF belonging to the TNF family, also named BLyS), met the primary endpoints in two phase III clinical trials in systemic lupus erythematosus (SLE, lupus). In March 2011, Belimumab was approved by the US Federal Drug Agency for treatment of SLE patients this was followed in May with approval by the European Medicines Agency for use in the European Union. This is an exciting development as it is the first successful late-stage clinical trial in SLE in over 40 years. In the light of this breakthrough, we review the key data and research outcomes and examine how blocking BAFF in patients with SLE significantly improves clinical outcomes.
Publisher: Rockefeller University Press
Date: 14-06-2004
DOI: 10.1084/JEM.20031942
Abstract: Dendritic cell (DC) activation by nucleic acid–containing immunoglobulin (Ig)G complexes has been implicated in systemic lupus erythematosus (SLE) pathogenesis. However, the mechanisms responsible for activation and subsequent disease induction are not completely understood. Here we show that murine DCs are much more effectively activated by immune complexes that contain IgG bound to chromatin than by immune complexes that contain foreign protein. Activation by these chromatin immune complexes occurs by two distinct pathways. One pathway involves dual engagement of the Fc receptor FcγRIII and Toll-like receptor (TLR)9, whereas the other is TLR9 independent. Furthermore, there is a characteristic cytokine profile elicited by the chromatin immune complexes that distinguishes this response from that of conventional TLR ligands, notably the induction of BAFF and the lack of induction of interleukin 12. The data establish a critical role for self-antigen in DC activation and explain how the innate immune system might drive the adaptive immune response in SLE.
Publisher: Elsevier BV
Date: 02-2007
DOI: 10.1016/J.PEPTIDES.2006.09.030
Abstract: Growing evidence suggests that the neuropeptide Y (NPY) system plays an important role in the immune system. Yet, little is known about the expression of NPY and receptors in the immune system. Moreover, original contradicting results have confused the picture and h ered a clear understanding of its role in the immune system. The use of Y(1) receptor-deficient mice, combined with advanced methods to investigate immune functions, have provided the solution to the problem raised by previous disparities. From results obtained using Y(1)-deficient mice (Y(1)(-/-)), we uncovered a bimodal role for Y(1) on immune cells. Y(1) expression on antigen-presenting cells (APC) is essential for their function as T cell priming elements. Conversely, Y(1) signaling in T cells plays a regulatory role without which T cells are hyper-responsive. The opposite role of Y(1) on APC and T cells has reconciled previous disparities by showing that signaling via Y(1) protects against inflammation by inhibiting T cell responses, whereas Y(1)(-/-) mice are protected in the same inflammatory models due to defective APCs.
Publisher: Springer Science and Business Media LLC
Date: 03-02-2013
DOI: 10.1038/NI.2527
Publisher: Elsevier BV
Date: 09-2013
DOI: 10.1016/J.IMMUNI.2013.05.019
Abstract: Activation-induced cell death (AICD) plays a critical role in immune homeostasis and tolerance. In T-cell-dependent humoral responses, AICD of B cells is initiated by Fas ligand (FasL) on T cells, stimulating the Fas receptor on B cells. In contrast, T-cell-independent B cell responses involve innate-type B lymphocytes, such as marginal zone (MZ) B cells, and little is known about the mechanisms that control AICD during innate B cell responses to Toll-like receptor (TLR) activation. Here, we show that MZ B cells undergo AICD in response to TLR4 activation in vivo. The transmembrane activator, calcium modulator, and cyclophilin ligand interactor (TACI) receptor and TLR4 cooperate to upregulate expression of both FasL and Fas on MZ B cells and also to repress inhibitors of Fas-induced apoptosis signaling. These findings demonstrate an unappreciated role for TACI and its ligands in the regulation of AICD during T-cell-independent B cell responses.
Publisher: Rockefeller University Press
Date: 03-07-2000
Abstract: The tumor necrosis factor (TNF) family member B cell activating factor (BAFF) binds B cells and enhances B cell receptor–triggered proliferation. We find that B cell maturation antigen (BCMA), a predicted member of the TNF receptor family expressed primarily in mature B cells, is a receptor for BAFF. Although BCMA was previously localized to the Golgi apparatus, BCMA was found to be expressed on the surface of transfected cells and tonsillar B cells. A soluble form of BCMA, which inhibited the binding of BAFF to a B cell line, induced a dramatic decrease in the number of peripheral B cells when administered in vivo. Moreover, culturing splenic cells in the presence of BAFF increased survival of a percentage of the B cells. These results are consistent with a role for BAFF in maintaining homeostasis of the B cell population.
Publisher: BMJ
Date: 24-11-2013
DOI: 10.1136/ANNRHEUMDIS-2012-202545
Abstract: The introduction of biologics, especially tumour necrosis factor (TNF) inhibitors, has revolutionized the management of chronic inflammatory diseases. However, at least one third of patients with these diseases, receiving TNF inhibitors either do not respond to treatment, or lose initial responsiveness. For a significant proportion, improvement of clinical response is achieved after switching to another anti-TNF drug, suggesting a basis for failure unrelated to the therapeutic target itself. A likely explanation for this is immunogenicity, as all biologics are potentially immunogenic, and the resulting anti-drug antibodies (ADAb) can theoretically decrease the efficacy of biologics and/or induce adverse events. Indeed, in these chronic inflammatory diseases, many studies have now established correlations between ADAb formation, low serum drug levels, and the failure or loss of response to anti-TNF antibodies. This article will review key findings related to ADAb, and propose a model wherein monitoring of drug levels and ADAb may be a predictive tool leading to a better choice of biologics. Such an approach could improve chronic inflammatory disease management toward a personalized and more cost-effective approach.
Publisher: Rockefeller University Press
Date: 20-11-2000
Abstract: B cell maturation is a very selective process that requires finely tuned differentiation and survival signals. B cell activation factor from the TNF family (BAFF) is a TNF family member that binds to B cells and potentiates B cell receptor (BCR)-mediated proliferation. A role for BAFF in B cell survival was suggested by the observation of reduced peripheral B cell numbers in mice treated with reagents blocking BAFF, and high Bcl-2 levels detected in B cells from BAFF transgenic (Tg) mice. We tested in vitro the survival effect of BAFF on lymphocytes derived from primary and secondary lymphoid organs. BAFF induced survival of a subset of splenic immature B cells, referred to as transitional type 2 (T2) B cells. BAFF treatment allowed T2 B cells to survive and differentiate into mature B cells in response to signals through the BCR. The T2 and the marginal zone (MZ) B cell compartments were particularly enlarged in BAFF Tg mice. Immature transitional B cells are targets for negative selection, a feature thought to promote self-tolerance. These findings support a model in which excessive BAFF-mediated survival of peripheral immature B cells contributes to the emergence and maturation of autoreactive B cells, skewed towards the MZ compartment. This work provides new clues on mechanisms regulating B cell maturation and tolerance.
Publisher: The Endocrine Society
Date: 2007
DOI: 10.1210/EN.2006-0686
Abstract: Hyperglycemia in critical illness is a common complication and a strong independent risk factor for morbidity and death. Intensive insulin therapy decreases this risk by up to 50%. It is unclear to what extent this benefit is due to reversal of glucotoxicity or to a direct effect of insulin, because antiinflammatory effects of insulin have already been described, but the underlying mechanisms are still poorly understood. The insulin receptor is expressed on resting neutrophils, monocytes, and B cells, but is not detectable on T cells. However, significant up-regulation of insulin receptor expression is observed on activated T cells, which suggests an important role during T cell activation. Exogenous insulin in vitro induced a shift in T cell differentiation toward a T helper type 2 (Th2)-type response, decreasing the T helper type 1 to Th2 ratio by 36%. This result correlated with a corresponding change in cytokine secretion, with the interferon-γ to IL-4 ratio being decreased by 33%. These changes were associated with increased Th2-promoting ERK phosphorylation in the presence of insulin. Thus, we demonstrate for the first time that insulin treatment influences T cell differentiation promoting a shift toward a Th2-type response. This effect of insulin in changing T cell polarization may contribute to its antiinflammatory role not only in sepsis, but also in chronic inflammation associated with obesity and type 2 diabetes.
Publisher: Springer Science and Business Media LLC
Date: 07-2002
DOI: 10.1038/NRI844
Publisher: Elsevier BV
Date: 06-2008
DOI: 10.1016/J.CYTOGFR.2008.04.006
Abstract: BAFF is a B cell survival factor that binds to three receptors BAFF-R, TACI and BCMA. BAFF-R is the receptor triggering naïve B cell survival and maturation while BCMA supports the survival of plasma cells in the bone marrow. Excessive BAFF production leads to autoimmunity, presumably as the consequence of inappropriate survival of self-reactive B cells. The function of TACI has been more elusive with TACI(-/-) mice revealing two sides of this receptor, a positive one driving T cell-independent immune responses and a negative one down-regulating B cell activation and expansion. Recent work has revealed that the regulation of TACI expression is intimately linked to the activation of innate receptors on B cells and that TACI signalling in response to multimeric BAFF and APRIL provides positive signals to plasmablasts. How TACI negatively regulates B cells remains elusive but may involve an indirect control of BAFF levels. The discovery of TACI mutations associated with common variable immunodeficiency (CVID) in humans not only reinforces its important role for humoral responses but also suggests a more complex role than first anticipated from knockout animals. TACI is emerging as an unusual TNF receptor-like molecule with a sophisticated mode of action.
Publisher: Elsevier BV
Date: 12-2006
DOI: 10.1016/J.PHARMTHERA.2006.06.002
Abstract: In an effort to develop more effective treatments for inflammatory diseases, immunologists have targeted numerous molecular pathways, but with limited success. Notable exceptions are anti-TNF agents, which have proved efficacious in a proportion of rheumatoid arthritis (RA) patients. Another TNF family member, termed BAFF ("B cell-activating factor belonging to the TNF family"), plays a central role in autoimmune diseases, as well as in B cell maturation, survival, and T cell activation. Agents that block BAFF have proven to be highly effective in the treatment of certain autoimmune conditions in mice. In addition, phase II data in human clinical trials for RA appear very promising. BAFF is also a survival factor for certain B cell lymphomas. Despite the relatively recent identification of BAFF, this molecule has provided considerable new insight into B cell homeostasis and immune function, and represents an important new molecular target for treatment of autoimmune diseases and lymphomas.
Publisher: Rockefeller University Press
Date: 05-1993
Abstract: Tumor necrosis factor alpha (TNF-alpha) is a pleiotropic cytokine triggering cell responses through two distinct membrane receptors. Stimulation of leukocyte adhesion to the endothelium is one of the many TNF-alpha activities and is explained by the upregulation of adhesion molecules on the endothelial cell surface. Human umbilical vein endothelial cells (HUVEC) were isolated, cultured, and demonstrated to express both TNF receptor types, TNF-R55 and TNF-R75. Cell adhesion to HUVEC was studied using the HL60, U937, and MOLT-4 cell lines. HUVEC were activated by either TNF-alpha, binding to both TNF-R55 and TNF-R75, and by receptor type-specific agonists, binding exclusively to TNF-R55 or to TNF-R75. The TNF-alpha-induced cell adhesion to HUVEC was found to be controlled almost exclusively by TNF-R55. This finding correlated with the exclusive activity of TNF-R55 in the TNF-alpha-dependent regulation of the expression of the intercellular adhesion molecule type 1 (ICAM-1), E-selectin, and vascular cell adhesion molecule type 1 (VCAM-1). The CD44 adhesion molecule in HUVEC was also found to be upregulated through TNF-R55. However, both TNF-R55 and TNF-R75 upregulate alpha 2 integrin expression in HUVEC. The predominant role of TNF-R55 in TNF-alpha-induced adhesion in HUVEC may correlate with its specific control of NF-kappa B activation, since kappa B elements are known to be present in ICAM-1, E-selectin, and VCAM-1 gene regulatory sequences.
Publisher: Springer Science and Business Media LLC
Date: 07-2000
DOI: 10.1038/77401
Publisher: American Diabetes Association
Date: 02-2008
DOI: 10.2337/DB07-0589
Abstract: OBJECTIVE—B-cells are important for disease pathogenesis in the nonobese diabetic (NOD) mouse model of type 1 diabetes. Recent studies demonstrate that marginal-zone B-cells (MZBs), which connect innate with adaptive immune responses, are increased in NOD mice. However, beyond this, the contribution of different B-cell subsets to diabetes pathogenesis is poorly understood. RESEARCH DESIGN AND METHODS—To better understand the role of different B-cell subsets in the etiology of type 1 diabetes, we have examined the MZB compartment in NOD mice, with respect to their number, distribution, and function. RESULTS—We demonstrate that splenic MZB numbers in female NOD mice undergo a marked, approximately threefold expansion between ∼12 and 16 weeks of age, coincident with the onset of frank diabetes. Functionally, NOD MZBs are hyperresponsive to toll-like receptor 9 ligation and CD40 ligation, as well as sphingosine-1-phosphate–dependent chemotactic cues, suggesting an increased sensitivity to selective innate- and activation-induced stimuli. Intriguingly, at 16 weeks of age, ∼80% of female NOD mice present with MZB-like cells in the pancreatic lymph node (PLN). These MZB-like cells express major histocompatibility complex class II and high levels of CD80 and CD86, and their presence in the PLN is associated with an increased frequency of activated Vβ4+ CD4+ T-cells. Significantly, we demonstrate that purified MZBs are able to present the autoantigen insulin to diabetogenic T-cells. CONCLUSIONS—These data are consistent with MZBs contributing to the pathogenesis of type 1 diabetes as antigen-presenting cells. By integrating innate-derived inflammatory signals with the activation of autoreactive T-cells, MZBs may help to direct T-cell responses against β-cell self-constituents.
Publisher: Proceedings of the National Academy of Sciences
Date: 11-09-2007
Abstract: Chemotactic cytokines (chemokines) attract immune cells, although their original evolutionary role may relate more closely with embryonic development. We noted differential expression of the chemokine receptor CXCR7 (RDC-1) on marginal zone B cells, a cell type associated with autoimmune diseases. We generated Cxcr7 −/− mice but found that CXCR7 deficiency had little effect on B cell composition. However, most Cxcr7 −/− mice died at birth with ventricular septal defects and semilunar heart valve malformation. Conditional deletion of Cxcr7 in endothelium, using Tie2-Cre transgenic mice, recapitulated this phenotype. Gene profiling of Cxcr7 −/− heart valve leaflets revealed a defect in the expression of factors essential for valve formation, vessel protection, or endothelial cell growth and survival. We confirmed that the principal chemokine ligand for CXCR7 was CXCL12/SDF-1, which also binds CXCR4. CXCL12 did not induce signaling through CXCR7 however, CXCR7 formed functional heterodimers with CXCR4 and enhanced CXCL12-induced signaling. Our results reveal a specialized role for CXCR7 in endothelial biology and valve development and highlight the distinct developmental role of evolutionary conserved chemokine receptors such as CXCR7 and CXCR4.
Publisher: Springer Science and Business Media LLC
Date: 28-10-2019
DOI: 10.1038/S41467-019-12711-7
Abstract: AspH is an endoplasmic reticulum (ER) membrane-anchored 2-oxoglutarate oxygenase whose C-terminal oxygenase and tetratricopeptide repeat (TPR) domains present in the ER lumen. AspH catalyses hydroxylation of asparaginyl- and aspartyl-residues in epidermal growth factor-like domains (EGFDs). Here we report crystal structures of human AspH, with and without substrate, that reveal substantial conformational changes of the oxygenase and TPR domains during substrate binding. Fe(II)-binding by AspH is unusual, employing only two Fe(II)-binding ligands (His679/His725). Most EGFD structures adopt an established fold with a conserved Cys1–3, 2–4, 5–6 disulfide bonding pattern an unexpected Cys3–4 disulfide bonding pattern is observed in AspH-EGFD substrate complexes, the catalytic relevance of which is supported by studies involving stable cyclic peptide substrate analogues and by effects of Ca(II) ions on activity. The results have implications for EGFD disulfide pattern processing in the ER and will enable medicinal chemistry efforts targeting human 2OG oxygenases.
Publisher: Wiley
Date: 15-10-2003
Publisher: Radcliffe Media Media Ltd
Date: 19-04-2023
DOI: 10.15420/AER.2022.33
Abstract: Over the past decade there has been an interest in understanding the role of gut microbiota in the pathogenesis of AF. A number of studies have linked the gut microbiota to the occurrence of traditional AF risk factors such as hypertension and obesity. However, it remains unclear whether gut dysbiosis has a direct effect on arrhythmogenesis in AF. This article describes the current understanding of the effect of gut dysbiosis and associated metabolites on AF. In addition, current therapeutic strategies and future directions are discussed.
Publisher: Wiley
Date: 02-2004
Abstract: The TNF family ligand B cell-activating factor (BAFF, BLyS, TALL-1) is an essential factor for B cell development. BAFF binds to three receptors, BAFF-R, transmembrane activator and CAML interactor (TACI), and B cell maturation antigen (BCMA), but only BAFF-R is required for successful survival and maturation of splenic B cells. To test whether the effect of BAFF is due to the up-regulation of anti-apoptotic factors, TACI-Ig-transgenic mice, in which BAFF function is inhibited, were crossed with transgenic mice expressing FLICE-inhibitory protein (FLIP) or Bcl-2 in the B cell compartment. FLIP expression did not rescue B cells, while enforced Bcl-2 expression restored peripheral B cells and the ability to mount T-dependent antibody responses. However, many B cells retained immaturity markers and failed to express normal amounts of CD21. Marginal zone B cells were not restored and the T-independent IgG3, but not IgM, response was impaired in the TACI-IgxBcl-2 mice. These results suggest that BAFF is required not only to inhibit apoptosis of maturating B cells, but also to promote differentiation events, in particular those leading to the generation of marginal zone B cells.
Publisher: American Society of Hematology
Date: 02-2008
DOI: 10.1182/BLOOD-2007-09-110874
Abstract: The cytokine BAFF binds to the receptors TACI, BCMA, and BAFF-R on B cells, whereas APRIL binds to TACI and BCMA only. The signaling properties of soluble trimeric BAFF (BAFF 3-mer) were compared with those of higher-order BAFF oligomers. All forms of BAFF bound BAFF-R and TACI, and elicited BAFF-R–dependent signals in primary B cells. In contrast, signaling through TACI in mature B cells or plasmablasts was only achieved by higher-order BAFF and APRIL oligomers, all of which were also po-tent activators of a multimerization-dependent reporter signaling pathway. These results indicate that, although BAFF-R and TACI can provide B cells with similar signals, only BAFF-R, but not TACI, can respond to soluble BAFF 3-mer, which is the main form of BAFF found in circulation. BAFF 60-mer, an efficient TACI agonist, was also detected in plasma of BAFF transgenic and nontransgenic mice and was more than 100-fold more active than BAFF 3-mer for the activation of multimerization-dependent signals. TACI supported survival of activated B cells and plasmablasts in vitro, providing a rational basis to explain the immunoglobulin deficiency reported in TACI-deficient persons.
Publisher: Rockefeller University Press
Date: 24-12-2013
DOI: 10.1084/JEM.20121076
Abstract: Druggable proteins required for B lymphocyte survival and immune responses are an emerging source of new treatments for autoimmunity and lymphoid malignancy. In this study, we show that mice with an inactivating mutation in the intramembrane protease signal peptide peptidase–like 2A (SPPL2A) unexpectedly exhibit profound humoral immunodeficiency and lack mature B cell subsets, mirroring deficiency of the cytokine B cell–activating factor (BAFF). Accumulation of Sppl2a-deficient B cells was rescued by overexpression of the BAFF-induced survival protein B cell lymphoma 2 (BCL2) but not BAFF and was distinguished by low surface BAFF receptor and IgM and IgD B cell receptors. CD8-negative dendritic cells were also greatly decreased. SPPL2A deficiency blocked the proteolytic processing of CD74 MHC II invariant chain in both cell types, causing dramatic build-up of the p8 product of Cathepsin S and interfering with earlier steps in CD74 endosomal retention and processing. The findings illuminate an important role for the final step in the CD74–MHC II pathway and a new target for protease inhibitor treatment of B cell diseases.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 19-05-2000
DOI: 10.1126/SCIENCE.288.5469.1257
Abstract: In scrapie-infected mice, prions are found associated with splenic but not circulating B and T lymphocytes and in the stroma, which contains follicular dendritic cells (FDCs). Formation and maintenance of mature FDCs require the presence of B cells expressing membrane-bound lymphotoxin-α/β. Treatment of mice with soluble lymphotoxin-β receptor results in the disappearance of mature FDCs from the spleen. We show that this treatment abolishes splenic prion accumulation and retards neuroinvasion after intraperitoneal scrapie inoculation. These data provide evidence that FDCs are the principal sites for prion replication in the spleen.
Publisher: Springer Science and Business Media LLC
Date: 11-03-2014
Abstract: Systemic lupus erythematosus (SLE) is characterized by multisystem immune-mediated injury in the setting of autoimmunity to nuclear antigens. The clinical heterogeneity of SLE, the absence of universally agreed clinical trial end points, and the paucity of validated therapeutic targets have, historically, contributed to a lack of novel treatments for SLE. However, in 2011, a therapeutic monoclonal antibody that neutralizes the cytokine TNF ligand superfamily member 13B (also known as B-cell-activating factor of the TNF family [BAFF]), belimumab, became the first targeted therapy for SLE to have efficacy in a randomized clinical trial. Because of its specificity, the efficacy of belimumab provides an opportunity to increase understanding of SLE pathophysiology. Although belimumab depletes B cells, this effect is not as powerful as that of other B-cell-directed therapies that have not been proven efficacious in randomized clinical trials. In this article, therefore, we review results suggesting that neutralizing BAFF can have effects on the immune system other than depletion of B cells. We also identify aspects of the BAFF system for which data in relation to SLE are still missing, and we suggest studies to investigate the pathogenesis of SLE and ways to refine anti-BAFF therapies. The role of a related cytokine, TNF ligand superfamily member 13 (also known as a proliferation-inducing ligand [APRIL]) in SLE is much less well understood, and hence this review focuses on BAFF.
Publisher: Elsevier BV
Date: 12-1998
DOI: 10.1016/S0016-5085(98)70025-3
Abstract: Membrane lymphotoxin (LT) alpha/beta, a member of the tumor necrosis factor (TNF) family of immune regulatory molecules, is involved both in the development of secondary lymphoid tissues and the maintenance of organized lymphoid tissues in the adult. Defects observed in the mucosal immune system in animals with a genetically disrupted LTalpha/beta pathway coupled with the expression of LTalpha/beta in activated T cells motivated an examination of the importance of this pathway in experimental colitis. Soluble LTbeta receptor (LTbetaR) immunoglobulin fusion protein was used to inhibit the LTalpha/beta/light axis in two independent rodent models of colitis: CD45RBhi CD4(+)-reconstituted SCID mice and bone marrow-transplanted tg26 mice (BM --> tg26). Treatment with LTbetaR immunoglobulin attenuated the development of both the clinical and histological manifestations of the disease in these two murine models of colitis. Given the success of TNF inhibitors in the treatment of human Crohn's disease, the effects of LTbetaR immunoglobulin have been compared with antibody to TNF in the BM --> tg26 model, and both treatments were equally efficacious. The LT pathway plays a role in the development of colitis as important as that of the TNF system and, therefore, represents a potential novel intervention point for the treatment of inflammatory bowel disease.
Publisher: Wiley
Date: 02-2011
Abstract: B-cell-activating factor of the TNF family (BAFF)/BLyS contributes to B-cell homeostasis and function in the periphery. BAFF is expressed as a membrane-bound protein or released by proteolytic cleavage, but the functional importance of this processing event is poorly understood. Mice expressing BAFF with a mutated furin consensus cleavage site, i.e. furin-mutant BAFF (fmBAFF), were not different from BAFF-deficient mice with regard to their B-cell populations and responses to immunization. It is however noteworthy that an alternative processing event releases some soluble BAFF in fmBAFF mice. Mild overexpression (∼ 5-fold) of fmBAFF alone generated intermediate levels of B cells without improving humoral responses to immunization. Processed BAFF was however important for B-cell homeostasis, as peripheral B-cell populations and antibody responses were readily restored by administration of soluble BAFF trimers in BAFF-deficient mice. However, the rescue of CD23 expression in B cells of BAFF-deficient mice required both soluble BAFF trimers and fmBAFF, or a polymeric form of soluble BAFF (BAFF 60-mer). These results point to a predominant role of processed BAFF for B-cell homeostasis and function, and indicate possible accessory roles for membrane-bound BAFF.
Publisher: Springer Science and Business Media LLC
Date: 09-1998
DOI: 10.1038/25630
Publisher: Wiley
Date: 10-01-2012
DOI: 10.1038/ICB.2011.111
Abstract: Recently, the B cell has emerged as a cornerstone of systemic lupus erythematosus (SLE) pathogenesis. This has been highlighted by studies of the cytokine B-cell-activating factor of the tumour necrosis factor (TNF) family (BAFF), a crucial factor regulating B-cell maturation, survival and function. Overexpression of BAFF in mice leads to the development of an SLE-like disease, independent of T cells but instead relying on innate immunity mechanisms. Moreover, BAFF has been shown to be elevated in the serum of patients suffering from autoimmune conditions, especially SLE, and may correlate with disease activity. These findings challenge the previous notion that T:B-cell collaboration is the sole driver of SLE. In recent years, controlled trials have for the first time tested targeted therapeutics for SLE. However, agents designed to target B cells failed to meet primary endpoints in clinical trials in SLE, suggesting that a more complex role for B cells in SLE awaited elucidation. By contrast, on 9 March 2011, the US Food and Drug Administration approved belimumab, a fully human anti-BAFF monoclonal antibody, as a new B-cell-specific treatment for SLE. This article will review over 10 years of research on the BAFF system, key findings that led to this recent positive clinical outcome and propose a model potentially explaining why this B-cell-specific therapy has yielded positive results in clinical trials. We will also review promising therapies presently in clinical trials targeting innate immunity, which are likely to revolutionize SLE management towards a personalized and targeted therapy approach.
Publisher: Annual Reviews
Date: 04-2003
DOI: 10.1146/ANNUREV.IMMUNOL.21.120601.141152
Abstract: BAFF, a member of the TNF family, is a fundamental survival factor for transitional and mature B cells. BAFF overexpression leads to an expanded B cell compartment and autoimmunity in mice, and elevated amounts of BAFF can be found in the serum of autoimmune patients. APRIL is a related factor that shares receptors with BAFF yet appears to play a different biological role. The BAFF system provides not only potential insight into the development of autoreactive B cells but a relatively simple paradigm to begin considering the balancing act between survival, growth, and death that affects all cells.
Publisher: Rockefeller University Press
Date: 30-07-2007
DOI: 10.1084/JEM.20062567
Abstract: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by the production of autoantibodies. However, the underlying cause of disease appears to relate to defects in T cell tolerance or T cell help to B cells. Transgenic (Tg) mice overexpressing the cytokine B cell–activating factor of the tumor necrosis factor family (BAFF) develop an autoimmune disorder similar to SLE and show impaired B cell tolerance and altered T cell differentiation. We generated BAFF Tg mice that were completely deficient in T cells, and, surprisingly, these mice developed an SLE-like disease indistinguishable from that of BAFF Tg mice. Autoimmunity in BAFF Tg mice did, however, require B cell–intrinsic signals through the Toll-like receptor (TLR)–associated signaling adaptor MyD88, which controlled the production of proinflammatory autoantibody isotypes. TLR7/9 activation strongly up-regulated expression of transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), which is a receptor for BAFF involved in B cell responses to T cell–independent antigens. Moreover, BAFF enhanced TLR7/9 expression on B cells and TLR-mediated production of autoantibodies. Therefore, autoimmunity in BAFF Tg mice results from altered B cell tolerance, but requires TLR signaling and is independent of T cell help. It is possible that SLE patients with elevated levels of BAFF show a similar basis for disease.
Publisher: SAGE Publications
Date: 11-07-2013
Abstract: The objective of this study is to determine whether serum concentrations of B cell activating factor from the tumour necrosis factor family (BAFF) and/or a proliferation-inducing ligand (APRIL) are associated with clinical manifestations of systemic lupus erythematosus (SLE). BAFF and APRIL concentrations were quantified using a commercial ELISA in serum s les obtained at the time of clinical assessment in 98 patients, and on 245 s les from 75 of these patients followed prospectively. Serum BAFF was significantly increased, and APRIL decreased, in patients with either renal or central nervous system (CNS) lupus. In contrast, in cross-sectional analysis, there was no correlation between disease activity (SLEDAI-2k) and serum BAFF or APRIL. In longitudinal follow-up, there was no association between changes in serum BAFF or APRIL and changes in SLEDAI-2k, or between baseline serum BAFF or APRIL and subsequent changes in SLEDAI-2k. However, between-visit changes in BAFF were significantly different in patients with increases in SLEDAI-2k ≥ 4, compared to patients whose SLEDAI-2k did not change. Although neither serum BAFF nor APRIL correlated with disease activity in the overall population, elevated serum BAFF and reduced APRIL may be markers of renal and CNS disease in SLE patients.
Publisher: Royal Society of Chemistry (RSC)
Date: 2018
DOI: 10.1039/C8SC00286J
Abstract: Tight, non-active site binding cyclic peptides are promising affinity reagents for studying proteins and their interactions.
Publisher: Rockefeller University Press
Date: 03-1996
Abstract: Surface lymphotoxin (LT) is a heteromeric complex of LT-alpha and LT-beta chains that binds to the LT-beta receptor (LT-beta-R), a member of the tumor necrosis factor (TNF) family of receptors. The biological function of this receptor-ligand system is poorly characterized. Since signaling through other members of this receptor family can induce cell death, e.g., the TNF and Fas receptors, it is important to determine if similar signaling events can be communicated via the LT-beta-R. A soluble form of the surface complex was produced by coexpression of LT-alpha and a converted form of LT-beta wherein the normally type II LT-beta membrane protein was changed to a type I secreted form. Recombinant LT-alpha 1/beta 2 was cytotoxic to the human adenocarcinoma cell lines HT-29, WiDr, MDA-MB-468, and HT-3 when added with the synergizing agent interferon (IFN) gamma. When immobilized on a plastic surface, anti-LT-beta-R monoclonal antibodies (mAbs) induced the death of these cells, demonstrating direct signaling via the LT-beta-R. Anti-LT-beta-R mAbs were also identified that inhibited ligand-induced cell death, whereas others were found to potentiate the activity of the ligand when added in solution. The human WiDr adenocarcinoma line forms solid tumors in immunocompromised mice, and treatment with an anti-LT-beta-R antibody combined with human IFN-gamma arrested tumor growth. The delineation of a biological signaling event mediated by the LT-beta-R opens a window for further studies on its immunological role, and furthermore, activation of the LT-beta-R may have an application in tumor therapy.
Publisher: Elsevier BV
Date: 03-2002
Publisher: Elsevier BV
Date: 05-2005
DOI: 10.1016/J.MOLIMM.2004.06.041
Abstract: B cell activating factor belonging to the TNF family (BAFF) and a proliferation-inducing ligand (APRIL) are two members of the TNF ligand superfamily. Studies of BAFF, APRIL and their receptors have highlighted the importance of this ligand/receptor system in regulating B cell homeostasis, tolerance and malignancy. Neutralizing BAFF can inhibit disease progression in animal models of autoimmunity, possibly by reducing survival of autoreactive B cells. In addition, BAFF inhibitors also prevent B lymphoma cell survival and may be useful for the treatment of lymphoid cancers. Recent work suggests that BAFF is also important for T cell activation and differentiation, an aspect that may be critical for the progression of certain autoimmune diseases. Therefore, targeting the BAFF/APRIL system may protect against autoimmunity and lymphoid cancers through the inhibition of pathogenic B and T cell functions.
Publisher: Elsevier BV
Date: 06-2013
Publisher: Bentham Science Publishers Ltd.
Date: 09-2007
DOI: 10.2174/156802607782341046
Abstract: Growing evidence suggests that neuropeptide Y (NPY) plays an important role in the immune system. NPY is produced by the central and peripheral nervous system but also by immune cells in response to activation. NPY has pleiotropic effects on both the innate and adaptive arms of the immune system, with effects ranging from the modulation of cell migration to macrophage, T helper (Th) cell cytokine release, and antibody production. Subsequent studies have confirmed the importance of this system in immunity in particular via the demonstration that Y1, a receptor for NPY, plays a fundamental role in autoimmunity and inflammation using Y1-deficient animals. Furthermore, clinical studies have suggested a role for NPY in other immune disorders such as asthma and arthritis. This review provides the latest information on the role of NPY and Y1 in the immune system, and discusses the potential new opportunities of this work for the development of a new generation of immuno-modulatory treatments of autoimmune and inflammatory diseases.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2022
Abstract: IL-33 is an activator of innate lymphoid cells 2 (ILC2s) in innate immunity and allergic inflammation and drives ILC2 expansion. High levels of B cell activating factor (BAFF), which plays a central role in B cell proliferation and differentiation, cause excess antibody production, including IgA. Using an animal model of IgA glomerulonephritis, a transgenic mouse that expresses excessive BAFF, the authors found that IL-33 exacerbates IgA glomerulonephritis, appearing to do so through expansion of ILC2 cells that drive an increase in IgA production and the development of kidney disease. They confirmed the role of ILC2s in exacerbating disease in a mouse model of IgA glomerulonephritis in transfer and depletion experiments. Their findings suggest that evaluation of IL-33 and ILC2s as potential mediators of IgA nephropathy in humans is warranted. The cytokine IL-33 is an activator of innate lymphoid cells 2 (ILC2s) in innate immunity and allergic inflammation. B cell activating factor (BAFF) plays a central role in B cell proliferation and differentiation, and high levels of this protein cause excess antibody production, including IgA. BAFF-transgenic mice overexpress BAFF and spontaneously develop glomerulonephritis that resembles human IgA nephropathy. We administered IL-33 or PBS to wild-type and BAFF-transgenic mice. After treating Rag1-deficient mice with IL-33, with or without anti-CD90.2 to preferentially deplete ILC2s, we isolated splenocytes, which were adoptively transferred into BAFF-transgenic mice. BAFF-transgenic mice treated with IL-33 developed more severe kidney dysfunction and proteinuria, glomerular sclerosis, tubulointerstitial damage, and glomerular deposition of IgA and C3. Compared with wild-type mice, BAFF-transgenic mice exhibited increases of CD19 + B cells in spleen and kidney and ILC2s in kidney and intestine, which were further increased by administration of IL-33. Administering IL-33 to wild-type mice had no effect on kidney function or histology, nor did it alter the number of ILC2s in spleen, kidney, or intestine. To understand the role of ILC2s, splenocytes were transferred from IL-33–treated Rag1-deficient mice into BAFF-transgenic mice. Glomerulonephritis and IgA deposition were exacerbated by transfer of IL-33–stimulated Rag1-deficient splenocytes, but not by ILC2 (anti-CD90.2)–depleted splenocytes. Wild-type mice infused with IL-33–treated Rag1-deficient splenocytes showed no change in kidney function or ILC2 numbers or distribution. IL-33–expanded ILC2s exacerbated IgA glomerulonephritis in a mouse model. These findings indicate that IL-33 and ILC2s warrant evaluation as possible mediators of human IgA nephropathy.
Publisher: Springer Science and Business Media LLC
Date: 19-07-2013
DOI: 10.1038/NI0813-877C
Publisher: American Association for the Advancement of Science (AAAS)
Date: 13-11-2012
DOI: 10.1126/SCISIGNAL.2003113
Abstract: Antibody-producing B cells require CD37-dependent integrin signaling for long-term survival.
Publisher: Springer Science and Business Media LLC
Date: 19-04-2011
DOI: 10.1038/NI0511-367
Publisher: Elsevier BV
Date: 08-2004
Publisher: Springer Science and Business Media LLC
Date: 20-07-2010
DOI: 10.1038/NI.1900
Abstract: This paper synthesizes recent progress toward understanding the integrated control systems and fail-safes that guide the quality and quantity of antibody produced by B cells. We focus on four key decisions: (1) the choice between proliferation or death in perifollicular B cells in the first 3 days after antigen encounter (2) differentiation of proliferating perifollicular B cells into extrafollicular plasma cells or germinal center B cells (3) positive selection of B cell antigen receptor (BCR) affinity for foreign antigen versus negative selection of BCR affinity for self antigen in germinal center B cells and (4) survival versus death of antibody-secreting plasma cells. Understanding the engineering of these control systems represents a challenging future step for treating disorders of antibody production in autoimmunity, allergy and immunodeficiency.
Publisher: Springer Science and Business Media LLC
Date: 17-09-2006
DOI: 10.1038/NBT1248
Abstract: Complement component C5a binds C5a receptor (C5aR) and facilitates leukocyte chemotaxis and release of inflammatory mediators. We used neutrophils from human C5aR knock-in mice, in which the mouse C5aR coding region was replaced with that of human C5aR, to immunize wild-type mice and to generate high-affinity antagonist monoclonal antibodies (mAbs) to human C5aR. These mAbs blocked neutrophil migration to C5a in vitro and, at low doses, both prevented and reversed inflammatory arthritis in the murine K/BxN model. Of approximately 40 mAbs generated to C5aR, all potent inhibitors recognized a small region of the second extracellular loop that seems to be critical for regulation of receptor activity. Human C5aR knock-in mice not only facilitated production of high-affinity mAbs against an important human therapeutic target but were also useful in preclinical validation of the potency of these antagonists. This strategy should be applicable to other important mAb therapeutics.
Publisher: American Association for Cancer Research (AACR)
Date: 10-2006
DOI: 10.1158/0008-5472.CAN-06-0217
Abstract: The lymphotoxin-β receptor (LTβR) is a tumor necrosis factor receptor family member critical for the development and maintenance of various lymphoid microenvironments. Herein, we show that agonistic anti-LTβR monoclonal antibody (mAb) CBE11 inhibited tumor growth in xenograft models and potentiated tumor responses to chemotherapeutic agents. In a syngeneic colon carcinoma tumor model, treatment of the tumor-bearing mice with an agonistic antibody against murine LTβR caused increased lymphocyte infiltration and necrosis of the tumor. A pattern of differential gene expression predictive of cellular and xenograft response to LTβR activation was identified in a panel of colon carcinoma cell lines and when applied to a panel of clinical colorectal tumor s les indicated 35% likelihood a tumor response to CBE11. Consistent with this estimate, CBE11 decreased tumor size and/or improved long-term animal survival with two of six independent orthotopic xenografts prepared from surgical colorectal carcinoma s les. Targeting of LTβR with agonistic mAbs offers a novel approach to the treatment of colorectal and potentially other types of cancers. (Cancer Res 2006 66(19): 9617-24)
Publisher: Elsevier BV
Date: 06-2004
Publisher: Rockefeller University Press
Date: 11-1996
Abstract: For more than a decade, the biological roles and the apparent redundancy of the cytokines tumor necrosis factor (TNF) and lymphotoxin (LT) have been debated. LT alpha exists in its soluble form as a homotrimer, which like TNF only binds the TNF receptors, TNF-R55 or TNF-R75. The cell surface form of LT exists as a heteromer of LT alpha and LT beta subunits and this complex specifically binds the LT beta receptor (LT beta-R). To discriminate the functions of the LT and TNF systems, soluble LT beta-R-immunoglobulin (Ig) or TNF-R-Ig fusion proteins were introduced into embryonic circulation by injecting pregnant mice. Exposure to LT beta-R-Ig during gestation disrupted lymph node development and splenic architecture in the progeny indicating that both effects are mediated by the surface LT alpha/beta complex. These data are the first to identify a cell surface ligand involved in immune organ morphogenesis. Moreover, they unambiguously discriminate the functions of the various TNF/LT ligands, provide a unique model to study compartmentalization of immune responses and illustrate the generic utility of receptor-Ig fusion proteins for dissecting/ordering ontogenetic events in the absence of genetic modifications.
Publisher: Wiley
Date: 28-06-2005
DOI: 10.1002/ART.21138
Abstract: To determine whether overexpression of BAFF can accelerate the development of systemic lupus erythematosus-associated end-organ disease in hosts with an underlying autoimmune diathesis. We introduced a BAFF transgene (Tg) into autoimmune-prone B6.Sle1 and B6.Nba2 mice and evaluated these mice for serologic autoimmunity and renal pathology. B6.Sle1.BAFF and B6.Nba2.BAFF mice, but not non-Tg littermates, frequently developed severe glomerular pathology by 3 months of age. Age-matched B6.BAFF mice, despite renal Ig deposits and increases in B cells and Ig production similar to those in B6.Sle1.BAFF and B6.Nba2.BAFF mice, did not develop glomerular pathology. In B6.Sle1.BAFF and B6.Nba2.BAFF mice, severity of glomerular disease did not obligately correlate with circulating levels of IgG anti-chromatin and/or anti-double-stranded DNA antibodies or with amounts of these autoantibodies deposited in the kidneys. Even in mice with severe glomerular disease, renal tubulointerstitial infiltrates were very limited, and increased proteinuria was not detected. BAFF-driven effects on glomerular pathology may be mediated, at least in part, by autoantibodies with specificities other than chromatin and/or by autoantibody-independent means. There is an uncoupling of BAFF-driven precocious glomerular pathology from concomitant development of clinically apparent renal disease, strongly suggesting that BAFF overexpression works in concert with other factors to promote overt renal disease.
Publisher: Springer Science and Business Media LLC
Date: 10-2009
DOI: 10.1038/NATURE08530
Publisher: Rockefeller University Press
Date: 05-12-2005
DOI: 10.1084/JEM.20051971
Abstract: Psychological conditions, including stress, compromise immune defenses. Although this concept is not novel, the molecular mechanism behind it remains unclear. Neuropeptide Y (NPY) in the central nervous system is a major regulator of numerous physiological functions, including stress. Postganglionic sympathetic nerves innervating lymphoid organs release NPY, which together with other peptides activate five Y receptors (Y1, Y2, Y4, Y5, and y6). Using Y1-deficient (Y1−/−) mice, we showed that Y1−/− T cells are hyperresponsive to activation and trigger severe colitis after transfer into lymphopenic mice. Thus, signaling through Y1 receptor on T cells inhibits T cell activation and controls the magnitude of T cell responses. Paradoxically, Y1−/− mice were resistant to T helper type 1 (Th1) cell–mediated inflammatory responses and showed reduced levels of the Th1 cell–promoting cytokine interleukin 12 and reduced interferon γ production. This defect was due to functionally impaired antigen-presenting cells (APCs), and consequently, Y1−/− mice had reduced numbers of effector T cells. These results demonstrate a fundamental bimodal role for the Y1 receptor in the immune system, serving as a strong negative regulator on T cells as well as a key activator of APC function. Our findings uncover a sophisticated molecular mechanism regulating immune cell functions that can lead to stress-induced immunosuppression.
Publisher: Oxford University Press (OUP)
Date: 28-03-2011
DOI: 10.1093/NAR/GKR148
Publisher: Elsevier BV
Date: 10-2006
Publisher: Elsevier BV
Date: 06-2003
DOI: 10.1016/S1359-6101(03)00023-6
Abstract: B cell activating factor belonging to the TNF family (BAFF) and apoptosis-inducing ligand (APRIL) are two related members of the TNF ligand superfamily. Although they share two receptors, TACI and BCMA, transgenic and knockout mice in this system reveal that their functions are not redundant. BAFF is a critical survival/maturation factor for peripheral B cells and this activity is mediated through a BAFF-specific receptor, BAFF-R. Overexpression of BAFF has been linked to autoimmune disease and aspects of B cell neoplasia. APRIL appears to play a role in T-independent type II antigen responses and T cell survival, but can also induce proliferation/survival of non-lymphoid cells. Elevated expression of APRIL has been found in some tumor cell lines and in tumor tissue libraries. Therapies designed to inhibit the BAFF and APRIL pathways holds great promise for the future.
Publisher: Rockefeller University Press
Date: 07-06-1999
Abstract: Members of the tumor necrosis factor (TNF) family induce pleiotropic biological responses, including cell growth, differentiation, and even death. Here we describe a novel member of the TNF family, designated BAFF (for B cell activating factor belonging to the TNF family), which is expressed by T cells and dendritic cells. Human BAFF was mapped to chromosome 13q32-34. Membrane-bound BAFF was processed and secreted through the action of a protease whose specificity matches that of the furin family of proprotein convertases. The expression of BAFF receptor appeared to be restricted to B cells. Both membrane-bound and soluble BAFF induced proliferation of anti-immunoglobulin M–stimulated peripheral blood B lymphocytes. Moreover, increased amounts of immunoglobulins were found in supernatants of germinal center–like B cells costimulated with BAFF. These results suggest that BAFF plays an important role as costimulator of B cell proliferation and function.
Publisher: Hindawi Limited
Date: 2001
DOI: 10.1155/2001/79823
Abstract: It has not been established whether an endogenous superantigen (SAg) expressed on B cells can induce germinal centers (GCs). An interesting model is that of mammary tumor virus encoded viral SAgs, which induce vigorous T cell proliferation and are predominantly expressed on activated B cells. We have used this model to analyze the possibility that direct stimulation of Mtv7 + DBA/2 B cells by vSAg-responsive (Vβ6 + ) BALB/c T cells can give rise to GCs. Injection of BALB/c SCID mice iv with 2 × 10 6 DBA/2 B cells, together with LPS, followed by 2 × 10 6 BALB/c T cells induces numerous large splenic GCs within 3–5 days. The GCs are still large on day 7, but are very much reduced by day 10. B cell activation with LPS is needed for this effect. These GCs form in spite of the apparent absence of follicular dendritic cells (FDCs) as judged by staining for several FDC surface markers. Control mice receiving either BALB/c T or DBA/2 B cells + LPS alone or DBA/2 T + B cells + LPS fail to exhibit any GCs on days 3–7. Numerous small clusters of PNA + cells, but few large GCs are observed when TNF-R(p55)-Ig is also injected, whereas LTβR-Ig treatment impeded the formation of aggregations of these cells even further, leaving scattered PNA+ single cells and very small clumps throughout the white pulp of the spleens. Anti-TNFα had no effect. These results suggest that endogenous vSAg mediated GC formation is independent of antigen trapping by FDCs.
Publisher: Proceedings of the National Academy of Sciences
Date: 05-08-2008
Abstract: BAFF-R-dependent activation of the alternative NF-κB pathway plays an essential role in mature B cell survival. Mutations leading to overexpression of NIK and deletion of the TRAF3 gene are implicated in human multiple myeloma. We show that overexpression of NIK in mouse B lymphocytes lifies alternative NF-κB activation and peripheral B cell numbers in a BAFF-R-dependent manner, whereas uncoupling NIK from TRAF3-mediated control causes maximal p100 processing and dramatic hyperplasia of BAFF-R-independent B cells. NIK controls alternative NF-κB signaling by increasing the protein levels of its negative regulator TRAF3 in a dose-dependent fashion. This mechanism keeps NIK protein levels below detection even when they cause B cell hyperplasia, so that contributions of NIK to B cell pathologies can easily be overlooked.
Publisher: Springer Science and Business Media LLC
Date: 09-2004
DOI: 10.1038/NATURE02955
Publisher: Wiley
Date: 2008
Abstract: Systemic autoimmunity such as systemic lupus erythematosus (SLE) is associated with the loss of B-cell tolerance, B-cell dysregulation and autoantibody production. While some autoantibodies may contribute to the pathology seen with SLE, numerous studies have shown that dysregulation of T-cell function is another critical aspect driving disease. The positive results obtained in clinical trials using T-cell- or B-cell-specific treatments have suggested that cooperation between T and B cells probably underlies disease progression in many patients. A similar cooperative mechanism seemed to explain SLE developing in mice overexpressing the B-cell-activating factor from the tumor necrosis factor family (BAFF). However, surprisingly, T-cell-deficient BAFF transgenic (Tg) mice develop SLE similar to T-cell-sufficient BAFF Tg mice, and the disease was linked to innate activation of B cells and production of proinflammatory autoantibody isotypes. In conclusion, dysregulated innate activation of B cells alone can drive disease independently of T cells, and as such this aspect represents a new pathogenic mechanism in autoimmunity.
Publisher: Wiley
Date: 08-10-2022
DOI: 10.1111/IMCB.12585
Abstract: The role of B‐cell–activating factor (BAFF) in B‐lymphocyte biology has been comprehensively studied, but its contributions to innate immunity remain unclear. Natural killer (NK) cells form the first line of defense against viruses and tumors, and have been shown to be defective in patients with systemic lupus erythematosus (SLE). The link between BAFF and NK cells in the development and progression of SLE remains unstudied. By assessing NK cell numbers in wild‐type (WT), BAFF −/− (BAFF deficient), BAFF‐R −/− (BAFF receptor deficient), TACI −/− (transmembrane activator and calcium modulator and cyclophilin ligand interactor deficient), BCMA −/− (B‐cell maturation antigen deficient) and BAFF transgenic (Tg) mice, we observed that BAFF signaling through BAFF‐R was essential for sustaining NK cell numbers in the spleen. However, according to the cell surface expression of CD27 and CD11b on NK cells, we found that BAFF was dispensable for NK cell maturation. Ex vivo and in vivo models showed that NK cells from BAFF −/− and BAFF Tg mice produced interferon‐γ and killed tumor cells at a level similar to that in WT mice. Finally, we established that NK cells do not express receptors that interact with BAFF in the steady state or in the BAFF Tg mouse model of SLE. Our findings demonstrate that BAFF has an indirect effect on NK cell homeostasis and no effect on NK cell function.
Publisher: Public Library of Science (PLoS)
Date: 04-01-2012
Start Date: 2014
End Date: 07-2016
Amount: $560,000.00
Funder: Australian Research Council
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