Fabienne Mackay

Publications of Fabienne Mackay

• Mutation of the BAFF furin cleavage site impairs B-cell homeostasis and antibody responses.

  Authors: Claudia Bossen, Aubry Tardivel, Laure Willen, Carrie A Fletcher, Mai Perroud, Friedrich Beermann, Antonius G Rolink, Martin L Scott, Fabienne Mackay, Pascal Schneider

  European journal of immunology. 03/2011; 41(3):787-97.

  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 proteolyticB-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.

• Y1 signalling has a critical role in allergic airway inflammation.

  Authors: Laurence Macia, Priya T Rao, Julie Wheway, Frederic Sierro, Fabienne Mackay, Herbert Herzog

  Immunology and cell biology. 03/2011; 89(8):882-8.

  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 inflammationAsthma 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.

• Analysis of microRNA turnover in mammalian cells following Dicer1 ablation.

  Authors: Michael P Gantier, Claire E McCoy, Irina Rusinova, Damien Saulep, Die Wang, Dakang Xu, Aaron T Irving, Mark A Behlke, Paul J Hertzog, Fabienne Mackay, Bryan R G Williams

  Nucleic acids research. 03/2011; 39(13):5692-703.

  Although microRNAs (miRNAs) are key regulators of gene expression, little is known of their overall persistence in the cell following processing. Characterization of such persistence is key to theAlthough microRNAs (miRNAs) are key regulators of gene expression, little is known of their overall persistence in the cell following processing. Characterization of such persistence is key to the full appreciation of their regulatory roles. Accordingly, we measured miRNA decay rates in mouse embryonic fibroblasts following loss of Dicer1 enzymatic activity. The results confirm the inherent stability of miRNAs, the intracellular levels of which were mostly affected by cell division. Using the decay rates of a panel of six miRNAs representative of the global trend of miRNA decay, we establish a mathematical model of miRNA turnover and determine an average miRNA half-life of 119 h (i.e. ∼5 days). In addition, we demonstrate that select miRNAs turnover more rapidly than others. This study constitutes, to our knowledge, the first in-depth characterization of miRNA decay in mammalian cells. Our findings indicate that miRNAs are up to 10× more stable than messenger RNA and support the existence of novel mechanism(s) controlling selective miRNA cellular concentration and function.

• Development of autoimmune nephritis in genetically asplenic and splenectomized BAFF transgenic mice.

  Authors: Carrie A Fletcher, Joanna R Groom, Blanche Woehl, Helen Leung, Charles Mackay, Fabienne Mackay

  Journal of autoimmunity. 01/2011; 36(2):125-34.

  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 resemblingB 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.

• B-cell stage and context-dependent requirements for survival signals from BAFF and the B-cell receptor.

  Authors: Fabienne Mackay, William A Figgett, Damien Saulep, Melanie Lepage, Margaret L Hibbs

  Immunological reviews. 09/2010; 237(1):205-25.

  One remarkable feature of the immune system is its capacity to maintain constant numbers of resting immune cells despite the complex nature of signals needed throughout development and maturation.One remarkable feature of the immune system is its capacity to maintain constant numbers of resting immune cells despite the complex nature of signals needed throughout development and maturation. For many years, B-cell survival was thought to rely solely on B-cell receptor (BCR) tonic signals that would trigger necessary basal survival pathways. The discovery of the tumor necrosis factor (TNF)-like ligand BAFF(B-cell activating factor belonging to the TNF family)/BLyS (B-lymphocyte stimulator) changed these views entirely, as BAFF-deficient mice lack most mature B cells, and treatment with BAFF inhibitors leads to their loss, establishing BAFF as an unappreciated key B-cell survival factor. BAFF-mediated survival signals have been mapped and signaling crosstalk with the BCR has been identified, explaining the need for both BCR- and BAFF-mediated signals for B-cell survival. However, this crosstalk only explains how BCR and BAFF signals cooperate to produce survival proteins and yet, inactivating pro-apoptotic factors such as FOXO proteins, which may be managed separately by BAFF and the BCR, has emerged as an equally important step for survival. In this review, we present new views on B-cell survival, at all stages of B-cell life, and suggest that, in most cases, survival results from the production of appropriate survival factors balanced with the adequate and timely degradation of pro-apoptotic proteins.

• Control systems and decision making for antibody production.

  Authors: Christopher C Goodnow, Carola G Vinuesa, Katrina L Randall, Fabienne Mackay, Robert Brink

  Nature immunology. 08/2010; 11(8):681-8.

  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 keyThis 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.

• B-cell tolerance breakdown in Sjögren's syndrome: focus on BAFF.

  Authors: Marie-Michèle Varin, Laëtitia Le Pottier, Pierre Youinou, Damien Saulep, Fabienne Mackay, Jacques-Olivier Pers

  Autoimmunity reviews. 05/2010; 9(9):604-8.

  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 theSjögren'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.

• Dock8 mutations cripple B cell immunological synapses, germinal centers and long-lived antibody production.

  Authors: Katrina L Randall, Teresa Lambe, Andy Johnson, Bebhinn Treanor, Edyta Kucharska, Heather Domaschenz, Belinda Whittle, Lina E Tze, Anselm Enders, Tanya L Crockford [......] Fabienne Mackay, Elissa K Deenick, Stuart G Tangye, Tyani D Chan, Tahra Camidge, Robert Brink, Carola G Vinuesa, Facundo D Batista, Richard J Cornall, Christopher C Goodnow

  Nature immunology. 11/2009;

  To identify genes and mechanisms involved in humoral immunity, we did a mouse genetic screen for mutations that do not affect the first wave of antibody to immunization but disrupt responseTo identify genes and mechanisms involved in humoral immunity, we did a mouse genetic screen for mutations that do not affect the first wave of antibody to immunization but disrupt response maturation and persistence. The first two mutants identified had loss-of-function mutations in the gene encoding a previously obscure member of a family of Rho-Rac GTP-exchange factors, DOCK8. DOCK8-mutant B cells were unable to form marginal zone B cells or to persist in germinal centers and undergo affinity maturation. Dock8 mutations disrupted accumulation of the integrin ligand ICAM-1 in the B cell immunological synapse but did not alter other aspects of B cell antigen receptor signaling. Humoral immunodeficiency due to Dock8 mutation provides evidence that organization of the immunological synapse is critical for signaling the survival of B cell subsets required for long-lasting immunity.

• Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43.

  Authors: Kendle M Maslowski, Angelica T Vieira, Aylwin Ng, Jan Kranich, Frederic Sierro, Di Yu, Heidi C Schilter, Michael S Rolph, Fabienne Mackay, David Artis, Ramnik J Xavier, Mauro M Teixeira, Charles R Mackay

  Nature. 10/2009; 461(7268):1282-6.

  The immune system responds to pathogens by a variety of pattern recognition molecules such as the Toll-like receptors (TLRs), which promote recognition of dangerous foreign pathogens. However, recentThe immune system responds to pathogens by a variety of pattern recognition molecules such as the Toll-like receptors (TLRs), which promote recognition of dangerous foreign pathogens. However, recent evidence indicates that normal intestinal microbiota might also positively influence immune responses, and protect against the development of inflammatory diseases. One of these elements may be short-chain fatty acids (SCFAs), which are produced by fermentation of dietary fibre by intestinal microbiota. A feature of human ulcerative colitis and other colitic diseases is a change in 'healthy' microbiota such as Bifidobacterium and Bacteriodes, and a concurrent reduction in SCFAs. Moreover, increased intake of fermentable dietary fibre, or SCFAs, seems to be clinically beneficial in the treatment of colitis. SCFAs bind the G-protein-coupled receptor 43 (GPR43, also known as FFAR2), and here we show that SCFA-GPR43 interactions profoundly affect inflammatory responses. Stimulation of GPR43 by SCFAs was necessary for the normal resolution of certain inflammatory responses, because GPR43-deficient (Gpr43(-/-)) mice showed exacerbated or unresolving inflammation in models of colitis, arthritis and asthma. This seemed to relate to increased production of inflammatory mediators by Gpr43(-/-) immune cells, and increased immune cell recruitment. Germ-free mice, which are devoid of bacteria and express little or no SCFAs, showed a similar dysregulation of certain inflammatory responses. GPR43 binding of SCFAs potentially provides a molecular link between diet, gastrointestinal bacterial metabolism, and immune and inflammatory responses.

• Cracking the BAFF code.

  Authors: Fabienne Mackay, Pascal Schneider

  Nature reviews. Immunology. 08/2009; 9(7):491-502.

  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 BAFFThe 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.

• CD4+ CD25+ T cells control autoimmunity in the absence of B cells.

  Authors: Eliana Mariño, Jeanette Villanueva, Stacey Walters, David Liuwantara, Fabienne Mackay, Shane T Grey

  Diabetes. 04/2009;

  Objective. TNF-ligand family members BAFF and APRIL can exert powerful effects upon B cell activation and development, Th1-type immune responses and autoimmunity. We examined the effect of blockingObjective. TNF-ligand family members BAFF and APRIL can exert powerful effects upon B cell activation and development, Th1-type immune responses and autoimmunity. We examined the effect of blocking BAFF and APRIL upon the development of autoimmune diabetes. Research Design and Methods. Female NOD mice were administered BCMA-Fc from 9-15-weeks-of-age. Diabetes incidence, islet pathology, as well as T and B cell populations were examined. Results. 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-type cytokines IL-7, IL-15 and IL-17. Thus T cell activation was blunted with reduced B cells. However, BCMA-Fc treated mice still harboured detectable diabetogenic T cells; suggesting regulatory mechanisms contributed to diabetes prevention. Indeed, BCMA-Fc treated mice accumulated increased CD4+ CD25+ Tregs with age. CD4+ CD25+ cells were essential for maintaining euglycaemia as their depletion abrogated BCMA-Fc-mediated protection. BCMA-Fc did not directly effect Treg homeostasis as; CD4+ CD25+ Foxp3+ T cells did not express TACI or BR3 receptors; and, CD4+ CD25+ Foxp3+ T cell frequencies were equivalent in WT, BAFF(-/-), TACI(-/-), BCMA(-/-) and BR3(-/-) mice. Rather, B cell depletion resulted in CD4+ CD25+ T cell-mediated protection from diabetes; as anti-CD25 mAb treatment precipitated diabetes in both diabetes resistant NOD.muMT(-/-) and BCMA-Fc-treated mice. Conclusions. BAFF/APRIL blockade prevents diabetes. BCMA-Fc reduces B cells, subsequently blunting autoimmune activity and allowing endogenous regulatory mechanisms to preserve a pre-hyperglycaemic state.

• Increased CD4+Foxp3+ T cells in BAFF-transgenic mice suppress T cell effector responses.

  Authors: Stacey Walters, Kylie E Webster, Andrew Sutherland, Sandra Gardam, Joanna Groom, David Liuwantara, Eliana Mariño, Jessica Thaxton, Anita Weinberg, Fabienne Mackay, Robert Brink, Jonathon Sprent, Shane T Grey

  Journal of immunology (Baltimore, Md. : 1950). 02/2009; 182(2):793-801.

  The cytokine B cell activation factor of the TNF family (BAFF) is considered to perform a proinflammatory function. This paradigm is particularly true for B cell-dependent immune responses; howeverThe cytokine B cell activation factor of the TNF family (BAFF) is considered to perform a proinflammatory function. This paradigm is particularly true for B cell-dependent immune responses; however the exact role for BAFF in regulating T cell immunity is ill-defined. To directly assess the effect of BAFF upon T cells, we analyzed T cell-dependent immune responses in BAFF-transgenic (Tg) mice. We found that T cell responses in BAFF-Tg mice are profoundly compromised, as indicated by their acceptance of islet allografts and delayed skin graft rejection. However, purified BAFF-Tg effector T cells could reject islet allografts with a normal kinetic, suggesting that the altered response did not relate to a defect in T cell function per se. Rather, we found that BAFF-Tg mice harbored an increased number of peripheral CD4+Foxp3+ T cells. A large proportion of the BAFF-expanded CD4+CD25+Foxp3+ regulatory T cells (Tregs) were CD62LlowCD103high and ICAM-1high, a phenotype consistent with an ability to home to inflammatory sites and prevent T cell effector responses. Indeed, depletion of the endogenous BAFF-Tg Tregs allowed allograft rejection to proceed, demonstrating that the increased Tregs were responsible for preventing alloimmunity. The ability of BAFF to promote Treg expansion was not T cell intrinsic, as Tregs did not express high levels of BAFF receptor 3, nor did excessive BAFF trigger NF-kappaB2 processing in Tregs. In contrast, we found that BAFF engendered Treg expansion through an indirect, B cell-dependent mechanism. Thus, under certain conditions, BAFF can play a surprising anti-inflammatory role in T cell biology by promoting the expansion of Treg cells.

• TRAF2 and TRAF3 signal adapters act cooperatively to control the maturation and survival signals delivered to B cells by the BAFF receptor.

  Authors: Sandra Gardam, Frederic Sierro, Antony Basten, Fabienne Mackay, Robert Brink

  Immunity. 04/2008; 28(3):391-401.

  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,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.

• Marginal-zone B-cells of nonobese diabetic mice expand with diabetes onset, invade the pancreatic lymph nodes, and present autoantigen to diabetogenic T-cells.

  Authors: Eliana Mariño, Marcel Batten, Joanna Groom, Stacey Walters, David Liuwantara, Fabienne Mackay, Shane T Grey

  Diabetes. 03/2008; 57(2):395-404.

  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 connectOBJECTIVE: 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 approximately 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, approximately 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 Vbeta4(+) 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 beta-cell self-constituents.

• TACI, unlike BAFF-R, is solely activated by oligomeric BAFF and APRIL to support survival of activated B cells and plasmablasts.

  Authors: Claudia Bossen, Teresa G Cachero, Aubry Tardivel, Karine Ingold, Laure Willen, Max Dobles, Martin L Scott, Aris Maquelin, Elodie Belnoue, Claire-Anne Siegrist, Stéphane Chevrier, Hans Acha-Orbea, Helen Leung, Fabienne Mackay, Jürg Tschopp, Pascal Schneider

  Blood. 03/2008; 111(3):1004-12.

  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 comparedThe 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.

• B cells flying solo.

  Authors: Joanna Groom, Fabienne Mackay

  Immunology and cell biology. 02/2008; 86(1):40-6.

  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 maySystemic 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.

• Disrupted cardiac development but normal hematopoiesis in mice deficient in the second CXCL12/SDF-1 receptor, CXCR7.

  Authors: Frederic Sierro, Christine Biben, Laura Martínez-Muñoz, Mario Mellado, Richard M Ransohoff, Meizhang Li, Blanche Woehl, Helen Leung, Joanna Groom, Marcel Batten, Richard P Harvey, Carlos Martínez-A, Charles R Mackay, Fabienne Mackay

  Proceedings of the National Academy of Sciences of the United States of America. 10/2007; 104(37):14759-64.

  Chemotactic cytokines (chemokines) attract immune cells, although their original evolutionary role may relate more closely with embryonic development. We noted differential expression of theChemotactic 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.

• An important role for B-cell activation factor and B cells in the pathogenesis of Sjögren's syndrome.

  Authors: Fabienne Mackay, Joanna R Groom, Stuart G Tangye

  Current opinion in rheumatology. 10/2007; 19(5):406-13.

  PURPOSE OF REVIEW: This review provides an update on the specific, strong association between dysregulated production of the cytokine B-cell activation factor and Sjögren's syndrome, and offers newPURPOSE OF REVIEW: This review provides an update on the specific, strong association between dysregulated production of the cytokine B-cell activation factor and Sjögren's syndrome, and offers new perspectives on potential pathogenic mechanisms. RECENT FINDINGS: Excess B-cell activation factor in mice triggers Sjögren's syndrome-like symptoms, and elevated serum B-cell activation factor in humans correlates with Sjögren's syndrome. B-cell activation factor is produced locally by activated monocytes, T cells and dendritic cells, and by epithelial cells and infiltrating B cells. Moreover, recent data in humans suggest that the innate immune system plays a role as an initiator of immune disorders in inflamed tissues. SUMMARY: Recent data have demonstrated the critical role of B-cell activation factor and B cells in the pathogenesis of Sjögren's syndrome, and its association with B lymphomas. Moreover, B-cell depleting treatments have confirmed the critical role of B cells in Sjögren's syndrome. Excess B-cell activation factor possibly corrupts B-cell tolerance and allows the emergence of self-reactive B cells that efficiently present antigen to T cells. In addition, B-cell activation factor may stimulate T-cell independent activation of B cells via Toll-like receptors; this recently identified mechanism could also play a separate, detrimental role in autoimmunity.

• BAFF and MyD88 signals promote a lupuslike disease independent of T cells.

  Authors: Joanna R Groom, Carrie A Fletcher, Stacey N Walters, Shane T Grey, Sally V Watt, Mathew J Sweet, Mark J Smyth, Charles R Mackay, Fabienne Mackay

  The Journal of experimental medicine. 09/2007; 204(8):1959-71.

  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 cellSystemic 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.

• B cells and the BAFF/APRIL axis: fast-forward on autoimmunity and signaling.

  Authors: Fabienne Mackay, Pablo A Silveira, Robert Brink

  Current opinion in immunology. 07/2007; 19(3):327-36.

  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 thisB-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.