ORCID Profile
0000-0001-9276-8479
Current Organisations
Australian and New Zealand Society for Immunology Inc.
,
UNSW Sydney
,
Australian Institute of Company Directors
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Publisher: Wiley
Date: 13-04-2012
Publisher: Rockefeller University Press
Date: 31-03-2017
DOI: 10.1084/JEM.20161533
Abstract: Plasma cells (PCs) derived from germinal centers (GCs) secrete the high-affinity antibodies required for long-term serological immunity. Nevertheless, the process whereby GC B cells differentiate into PCs is uncharacterized, and the mechanism underlying the selective PC differentiation of only high-affinity GC B cells remains unknown. In this study, we show that differentiation into PCs is induced among a discrete subset of high-affinity B cells residing within the light zone of the GC. Initiation of differentiation required signals delivered upon engagement with intact antigen. Signals delivered by T follicular helper cells were not required to initiate differentiation but were essential to complete the differentiation process and drive migration of maturing PCs through the dark zone and out of the GC. This bipartite or two-signal mechanism has likely evolved to both sustain protective immunity and avoid autoantibody production.
Publisher: Elsevier BV
Date: 05-2015
DOI: 10.1016/J.IMMUNI.2015.04.010
Abstract: The mechanistic links between genetic variation and autoantibody production in autoimmune disease remain obscure. Autoimmune lymphoproliferative syndrome (ALPS) is caused by inactivating mutations in FAS or FASL, with autoantibodies thought to arise through failure of FAS-mediated removal of self-reactive germinal center (GC) B cells. Here we show that FAS is in fact not required for this process. Instead, FAS inactivation led to accumulation of a population of unconventional GC B cells that underwent somatic hypermutation, survived despite losing antigen reactivity, and differentiated into a large population of plasma cells that included autoantibody-secreting clones. IgE(+) plasma cell numbers, in particular, increased after FAS inactivation and a major cohort of ALPS-affected patients were found to have hyper-IgE. We propose that these previously unidentified cells, designated "rogue GC B cells," are a major driver of autoantibody production and provide a mechanistic explanation for the linked production of IgE and autoantibodies in autoimmune disease.
Publisher: Rockefeller University Press
Date: 04-01-2010
DOI: 10.1084/JEM.20091706
Abstract: Engagement of cytokine receptors by specific ligands activate Janus kinase–signal transducer and activator of transcription (STAT) signaling pathways. The exact roles of STATs in human lymphocyte behavior remain incompletely defined. Interleukin (IL)-21 activates STAT1 and STAT3 and has emerged as a potent regulator of B cell differentiation. We have studied patients with inactivating mutations in STAT1 or STAT3 to dissect their contribution to B cell function in vivo and in response to IL-21 in vitro. STAT3 mutations dramatically reduced the number of functional, antigen (Ag)-specific memory B cells and abolished the ability of IL-21 to induce naive B cells to differentiate into plasma cells (PCs). This resulted from impaired activation of the molecular machinery required for PC generation. In contrast, STAT1 deficiency had no effect on memory B cell formation in vivo or IL-21–induced immunoglobulin secretion in vitro. Thus, STAT3 plays a critical role in generating effector B cells from naive precursors in humans. STAT3-activating cytokines such as IL-21 thus underpin Ag-specific humoral immune responses and provide a mechanism for the functional antibody deficit in STAT3-deficient patients.
Publisher: Proceedings of the National Academy of Sciences
Date: 12-05-2014
Abstract: Antibodies are selected to bind microbial but not self-antigens, because binding to self would compete with binding microbes, shorten antibody half-life, and cause autoimmunity. Self-tolerance is actively acquired in part by discarding self-binding antibodies before the body is exposed to a microbe or vaccine. The experiments here provide evidence of an opposite mechanism, allowing antibodies that initially bind both foreign and self-antigens to acquire self/non-self discrimination during the course of an immune response through somatic hypermutation away from self-reactivity. In addition to selection for lower-affinity binding to self, antibody variants were selected with fewer binding sites available to bind self-antigen because most were occupied by N-linked carbohydrate, possibly explaining the frequent occurrence of N-linked glycosylation of antibody variable domains.
Publisher: Rockefeller University Press
Date: 29-10-2020
DOI: 10.1084/JEM.20191167
Abstract: The TNF superfamily ligand BAFF maintains the survival of naive B cells by signaling through its surface receptor, BAFFR. Activated B cells maintain expression of BAFFR after they differentiate into germinal center (GC) or memory B cells (MBCs). However, the functions of BAFFR in these antigen-experienced B cell populations remain unclear. Here, we show that B cell–intrinsic BAFFR does not play a significant role in the survival or function of GC B cells or in the generation of the somatically mutated MBCs derived from them. Instead, BAFF/BAFFR signaling was required to generate the unmutated, GC-independent MBCs that differentiate directly from activated B cell blasts early in the response. Furthermore, lification of BAFFR signaling in responding B cells did not affect GCs or the generation of GC-derived MBCs but greatly expanded the GC-independent MBC response. Although BAFF/BAFFR signaling specifically controlled the formation of the GC-independent MBC response, both types of MBCs required input from this pathway for optimal long-term survival.
Publisher: Springer New York
Date: 2015
DOI: 10.1007/978-1-4939-2498-1_9
Abstract: T cell-dependent B cell responses generate optimal antibodies to combat foreign antigens. Naïve B cells responding to antigen undergo a complex series of differentiation events and cell fate decisions to provide long-lived memory B cells and plasma cells. Historically, B cell biologists have been challenged by the task of investigating rare antigen-specific B cells in an in vivo setting such that their interactions with antigen, regulation and migration may be accurately tracked. We have developed the SW(HEL) experimental system capable of accurately monitoring B cells that interact with a protein antigen and then subsequently undergo isotype switching, somatic hypermutation, and affinity maturation within germinal centers (GC) to generate high-affinity antibodies. Here we provide a comprehensive description of the procedures involved in establishing and using the SW(HEL) system to assess B cell responses to a foreign antigen. This system can provide a valuable measure of the functional capabilities of T follicular helper cells, whose role is ultimately to support and shape long-term humoral immunity.
Publisher: Elsevier BV
Date: 09-2005
Publisher: Elsevier BV
Date: 11-2004
DOI: 10.1016/J.IMMUNI.2004.09.011
Abstract: To examine the role of the TNF-R superfamily signaling protein TRAF2 in mature B cell development and NF-kappaB activation, conditionally TRAF2-deficient mice were produced. B cells lacking TRAF2 expression in these mice possessed a selective survival advantage, accumulated in the lymph nodes and splenic marginal zone, were larger in size, and expressed increased levels of CD21/35. These TRAF2-deficient B cells could not proliferate or activate the canonical NF-kappaB pathway in response to CD40 ligation. By contrast, noncanonical NF-kappaB activation was constitutively hyperactive, with TRAF2-deficient B cells exhibiting close to maximal processing of NF-kappaB2 from p100 to p52 and high levels of constitutive p52 and RelB DNA binding activity. These findings establish TRAF2 as a multifunctional regulator of NF-kappaB activation that mediates activation of the canonical pathway but acts as a negative regulator of the noncanonical pathway. This dual functionality explains the contrasting roles of TRAF2 in B cell maturation and activation.
Publisher: Springer Science and Business Media LLC
Date: 08-11-2009
DOI: 10.1038/NI.1820
Publisher: The American Association of Immunologists
Date: 12-2015
Abstract: The selection of affinity-matured Ab-producing B cells is supported by interactions with T follicular helper (Tfh) cells. In addition to cell surface–expressed molecules, cytokines produced by Tfh cells, such as IL-21 and IL-4, provide B cell helper signals. In this study, we analyze how the fitness of Th cells can influence Ab responses. To do this, we used a model in which IL-21R–sufficient (wild-type [WT]) and –deficient (Il21r−/−) Ag-specific Tfh cells were used to help immunodeficient Il21r−/− B cells following T-dependent immunization. Il21r−/− B cells that had received help from WT Tfh cells, but not from Il21r−/− Tfh cells, generated affinity-matured Ab upon recall immunization. This effect was dependent on IL-4 produced in the primary response and associated with an increased fraction of memory B cells. Il21r−/− Tfh cells were distinguished from WT Tfh cells by a decreased frequency, reduced conjugate formation with B cells, increased expression of programmed cell death 1, and reduced production of IL-4. IL-21 also influenced responsiveness to IL-4 because expression of both membrane IL-4R and the IL-4–neutralizing soluble (s)IL-4R were reduced in Il21r−/− mice. Furthermore, the concentration of sIL-4R was found to correlate inversely with the amount of IgE in sera, such that the highest IgE levels were observed in Il21r−/− mice with the least sIL-4R. Taken together, these findings underscore the important collaboration between IL-4 and IL-21 in shaping T-dependent Ab responses.
Publisher: The American Association of Immunologists
Date: 09-2009
Abstract: To optimize the initial wave of Ab production against T-dependent Ags, primary B cell clones with the highest Ag affinity are selected to generate the largest extrafollicular plasmablast (PB) responses. The mechanism behind this remains undefined, primarily due to the difficulty of analyzing low frequency Ag-specific B cells during the earliest phases of the immune response when key differentiation decisions are made. In this study, a high resolution in vivo mouse model was used to characterize in detail the first 6 days of a T-dependent B cell response and to identify the steps at which initial Ag affinity has a major impact. Ag-specific B cells proliferated within splenic follicles from days 1.0 to 3.0 before undergoing a dynamic phase of multilineage differentiation (days 3.0–4.0) that generated switched and unswitched populations of germinal center B cells, early memory B cells, and extrafollicular PBs. PB differentiation was marked by synchronous up-regulation of CXCR4 and down-regulation of CXCR5 and the adoption of a unique BCRhigh phenotype by unswitched PBs. Differences in Ag affinity of & -fold did not markedly affect the early stages of the response, including the differentiation and extrafollicular migration of PBs. However, high affinity PBs underwent significantly greater expansion within the splenic bridging channels and red pulp, due to both increased proliferation and decreased apoptosis. Extrafollicular PBs maintained class II MHC, but not IL-21R expression, and interacted directly with Ag-specific extrafollicular Th cells, suggesting that IL-21-independent T cell help may drive extrafollicular PB expansion in responses to foreign Ag.
Publisher: Wiley
Date: 19-08-2010
Publisher: Rockefeller University Press
Date: 09-10-2006
DOI: 10.1084/JEM.20061254
Abstract: A hallmark of T cell–dependent immune responses is the progressive increase in the ability of serum antibodies to bind antigen and provide immune protection. Affinity maturation of the antibody response is thought to be connected with the preferential survival of germinal centre (GC) B cells that have acquired increased affinity for antigen via somatic hypermutation of their immunoglobulin genes. However, the mechanisms that drive affinity maturation remain obscure because of the difficulty in tracking the affinity-based selection of GC B cells and their differentiation into plasma cells. We describe a powerful new model that allows these processes to be followed as they occur in vivo. In contrast to evidence from in vitro systems, responding GC B cells do not undergo plasma cell differentiation stochastically. Rather, only GC B cells that have acquired high affinity for the immunizing antigen form plasma cells. Affinity maturation is therefore driven by a tightly controlled mechanism that ensures only antibodies with the greatest possibility of neutralizing foreign antigen are produced. Because the body can sustain only limited numbers of plasma cells, this “quality control” over plasma cell differentiation is likely critical for establishing effective humoral immunity.
Publisher: Wiley
Date: 20-11-2007
Abstract: Burnet's original description of the clonal selection hypothesis of antibody production included many prescient predictions of how 'lymphocytes carrying reactive sites' for foreign antigens might respond during immune responses. Somatic mutation, plasma cell differentiation and transition into memory cells were all described as potential fates for the 'variety of descendents' derived from proliferative expansion of antigen-reactive clones. After 50 years much is known about the molecular controls that drive these various processes. Comparatively little insight has been gained, however, into why particular daughter cells progress down one response pathway versus another. In this article, we briefly describe the evolution of the genetic technologies that now allow us to visualize the very processes predicted by Burnet. An in-depth description of the recently developed SW(HEL) mouse model and its utility for tracking in vivo B-cell responses to various forms of hen-egg lysozyme (HEL) is also provided. Recent data obtained with this system indicate that antigen-dependent variables play a critical role in regulating the differentiation of responding B cells into antibody-secreting plasma cells.
Publisher: Rockefeller University Press
Date: 10-04-2006
DOI: 10.1084/JEM.20060087
Abstract: B cells responding to T-dependent antigen either differentiate rapidly into extrafollicular plasma cells or enter germinal centers and undergo somatic hypermutation and affinity maturation. However, the physiological cues that direct B cell differentiation down one pathway versus the other are unknown. Here we show that the strength of the initial interaction between B cell receptor (BCR) and antigen is a primary determinant of this decision. B cells expressing a defined BCR specificity for hen egg lysozyme (HEL) were challenged with sheep red blood cell conjugates of a series of recombinant mutant HEL proteins engineered to bind this BCR over a 10,000-fold affinity range. Decreasing either initial BCR affinity or antigen density was found to selectively remove the extrafollicular plasma cell response but leave the germinal center response intact. Moreover, analysis of competing B cells revealed that high affinity specificities are more prevalent in the extrafollicular plasma cell versus the germinal center B cell response. Thus, the effectiveness of early T-dependent antibody responses is optimized by preferentially steering B cells reactive against either high affinity or abundant epitopes toward extrafollicular plasma cell differentiation. Conversely, responding clones with weaker antigen reactivity are primarily directed to germinal centers where they undergo affinity maturation.
Publisher: Elsevier BV
Date: 11-2012
DOI: 10.1016/J.IMMUNI.2012.07.017
Abstract: Secondary ersification of the B cell repertoire by immunoglobulin gene somatic hypermutation in the germinal center (GC) is essential for providing the high-affinity antibody specificities required for long-term humoral immunity. While the risk to self-tolerance posed by inadvertent generation of self-reactive GC B cells has long been recognized, it has not previously been possible to identify such cells and study their fate. In the current study, self-reactive B cells generated de novo in the GC failed to survive when their target self-antigen was either expressed ubiquitously or specifically in cells proximal to the GC microenvironment. By contrast, GC B cells that recognized rare or tissue-specific self-antigens were not eliminated, and could instead undergo positive selection by cross-reactive foreign antigen and produce plasma cells secreting high-affinity autoantibodies. These findings demonstrate the incomplete nature of GC self-tolerance and may explain the frequent association of cross-reactive, organ-specific autoantibodies with postinfectious autoimmune disease.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 13-04-2018
Abstract: Antibodies distinguish foreign epitopes from closely related self-antigens by poorly understood mechanisms. In mice, Burnett et al. found that a proportion of B cells could cross-react with similar foreign and self-antigens (see the Perspective by Kara and Nussenzweig). Challenge with self-antigen resulted in anergy (i.e., a lack of immune response), which was reversed by exposure to high-density foreign antigen. Mutations that decreased self-affinity were rapidly selected for, whereas selection for epistatic mutations that enhanced foreign reactivity took longer. Self-reactivity, rather than being an impediment to immunization, resulted in higher affinities against a foreign immunogen. Science , this issue p. 223 see also p. 152
Publisher: Springer Science and Business Media LLC
Date: 07-2010
DOI: 10.1038/NI0710-644A
Location: Australia
No related grants have been discovered for Tyani Chan.