Elaine Bell

Bio: Elaine Bell is an academic researcher. The author has contributed to research in topics: Innate immune system & T cell. The author has an hindex of 6, co-authored 137 publications receiving 159 citations.

TWEAK and TNF: Yin and Yang in innate immunity

Abstract: could be a result of aberrant homing to the bone marrow or an inability to lodge in the endosteal niche. CaRdeficient fetal-liver LSK cells were found to express normal amounts of cell-surface molecules involved in homing to the bone marrow, and they were found to enter the bone marrow as efficiently as wild-type fetal-liver cells. By contrast, CaR-deficient fetal-liver cells were markedly impaired in their ability to bind the extracellular-matrix component collagen type I and showed reduced ability to physically associate with the endosteal surface. These data indicate that expression of CaR by HSCs is required for their lodgement in the endosteal niche. These results provide a mechanism for HSC engraftment in the bone marrow during ontogeny and, as the authors suggest, have important implications for stem-cell transplantation therapies. Karen Honey

Endothelial cells as sentinels

Abstract: saccharide (LPS) shed from Gram­ negative bacteria is recognized by Toll­like receptor 4 (TLR4) on cells such as tissue macrophages, leading to the recruitment of neutrophils to the site of infection, which is a hallmark of the innate immune response. Now, Andonegui and colleagues show that endothelial cells, rather than macro­ phages, are the key sentinel cells for detecting infection by Gram­negative bacteria and recruiting neutrophils to peripheral tissues. Endothelial cells can express TLR4 and receptors for tumour necrosis factor and interleukin­1β (cytokines that are released by macro phages after the detection of bacteria), so they can detect and respond to LPS directly or indirectly. To test the role of TLR4 on endo­ thelial cells in detecting LPS and initiating innate immune responses, the authors generated mice in which TLR4 was expressed exclusively on endothelium (EndotheliumTLR4 mice). Intravital microscopy showed that local administration of LPS into muscle resulted in the activation of endothelial cell TLR4 and the recruit­ ment of neutrophils. By contrast, EndotheliumTLR4 mice could not respond to intratracheal administra­ tion of LPS, suggesting that activation of the endothelium alone was not sufficient to recruit neutrophils into the alveoli, where a barrier exists between the microvasculature and the site of LPS administration. Systemic administration of LPS in both wild­type and EndotheliumTLR4 mice resulted in a reduction in the number of circulating neutro phils, which were sequestered in the lungs but did not migrate into the alveoli or lung parenchyma. In wild­type mice the sequestered neutrophils stayed in the lungs, but in EndotheliumTLR4 mice the neutrophils were released back into the circulation after 24 hours. When wild­type mice were infected intraperitoneally with the Gram­negative bacterium Escherichia coli, bacteria were detectable in the lungs in 30 minutes. Half of the wild­type mice died in 48 hours; the surviving mice cleared bacteria from the lungs in 70 hours and from the peritoneum in a week. By contrast, EndotheliumTLR4 mice all survived the infection and cleared peritoneal bacteria in 48 hours. So, infection that results in prolonged pulmonary sequestration of neutro­ phils in wild­type mice prevents neutrophils from migrating to the primary site of infection. These results show that TLR4­ expressing endothelial cells are sufficient for intravascular detection of bacteria but that bone marrow­ derived cells are required to detect bacteria at barrier­protected sites such as the lungs. This work has implications for understanding sepsis, which results in the death of 30–40% of patients, primarily owing to lung failure. Elaine Bell

Innate immunity: TLR4 signalling

Abstract: among TLRs in its ability to activate two distinct signalling pathways — one pathway is activated by the adaptors TIRAP (Toll/interleukin-1receptor (TIR)-domain-containing adaptor protein) and MyD88, which leads to the induction of pro-inflammatory cytokines, and the second pathway is activated by the adaptors TRIF (TIR-domaincontaining adaptor protein inducing interferon-β) and TRAM (TRIFrelated adaptor molecule), which leads to the induction of type I interferons. Until now, it had been believed that these two signalling pathways were activated simultaneously at the plasma membrane. Now, a study from Ruslan Medzhitov’s laboratory shows that the two signalling pathways are induced sequentially and that the TRAM–TRIF pathway is only operational from early endosomes following endocytosis of TLR4. The authors found it puzzling that TLR4 is the only known TLR capable of inducing the production of type I interferons from the plasma membrane so they decided to take a closer look at TLR4 signalling. First, they assessed the subcellular localization of tagged TLR4 and found that it localized to both the plasma membrane and endosomal vesicles. They found that lipopolysaccharideinduced TLR4 internalization was disrupted in the presence of a specific inhibitor of dynamin — a GTPase that regulates the endocytosis of ‘pinched-off ’ invaginations of the plasma membrane. Disruption of endocytosis abolished the TRAM– TRIF-dependent phosphorylation of interferon-regulatory factor 3 (IRF3), a component of the pathway that leads to the production of type I interferons, whereas TIRAP–MyD88-dependent signalling proceeded normally. Next, a deletional analysis of TRAM showed that the first 20 amino acids constituted the minimum signal for TRAM localization to both the plasma membrane and endosomes, but the first 7 amino acids were sufficient to allow TRAM to localize specifically to endosomes. These 20 amino acids constitute a bipartite localization domain — consisting of a myristoylation motif (the first 7 amino acids) and a polybasic domain — that is commonly found in other proteins that shuttle between the plasma membrane and endosomes. Mutational analysis showed that the myristoylation motif is necessary for endosomal localization but both parts of the bipartite motif are required for plasma-membrane targeting. A TRAM transgene of which the protein product resided specifically on endosomes retained the ability to signal the production of type I interferons. This study supports a model whereby ligand engagement of TLR4 at the plasma membrane induces the TIRAP–MyD88 pathway. TLR4 is then endocytosed into endosomes to engage the TRAM–TRIF pathway. These results also confirm that TRAM, similar to TIRAP, is a ‘sorting’ adaptor that defines the location of subcellular TLR signalling, and that receptors that induce the production of type I interferons all signal from intracellular compartments. Elaine Bell

Back in fashion

Abstract: Sex is good for you! Recreational sex — sex with no procreational purpose — might have a positive role in conception. Research from the University of Adelaide in South Australia shows that plenty of sex with the same man — even a year before conception — can increase the chance of a healthy pregnancy, reducing the risk of miscarriage, still births and pre-eclampsia. An article in New Scientist discusses that these fertility problems might occur due to “the reluctance of the mother’s immune system to accept the fetus and placenta”, which both express foreign proteins from the father’s genes. “Sex, early and often, and with the intended father, may help overcome that reluctance”. As a report from ABC NewsOnline explains, “The more accustomed the woman’s immune system is to the man’s sperm, the less likely her body will be to reject the fetus”. Repeated exposure to the man’s semen, and the foreign proteins it contains, might help the mother-to-be to develop tolerance to them. Gustaaf Deekker from the University of Adelaide said, “If there’s repeated exposure to that signal, then eventually when the woman conceives, her [immune] cells will say ‘we know that guy, he’s been around a long time, we’ll allow the pregnancy to continue’”. The Adelaide group has also identified the cytokine transforming growth factor (TGF)-β as a component of semen, which they believe is also important for tolerance, and might represent a new treatment for women who repeatedly suffer pregnancy failures. Jenny Buckland IN THE NEWS

Phagocytosis of apoptotic cells in homeostasis.

Abstract: Human bodies collectively turn over about 200 billion to 300 billion cells every day. Such turnover is an integral part of embryonic and postnatal development, as well as routine tissue homeostasis. This process involves the induction of programmed cell death in specific cells within the tissues and the specific recognition and removal of dying cells by a clearance 'crew' composed of professional, non-professional and specialized phagocytes. In the past few years, considerable progress has been made in identifying many features of apoptotic cell clearance. Some of these new observations challenge the way dying cells themselves are viewed, as well as how healthy cells interact with and respond to dying cells. Here we focus on the homeostatic removal of apoptotic cells in tissues.

The role of JAK-STAT signaling pathway and its regulators in the fate of T helper cells

Abstract: The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway plays critical roles in orchestrating of immune system, especially cytokine receptors and they can modulate the polarization of T helper cells. This pathway is regulated by an array of regulator proteins, including Suppressors of Cytokine Signaling (SOCS), Protein Inhibitors of Activated STATs (PIAS) and Protein Tyrosine Phosphatases (PTPs) determining the initiation, duration and termination of the signaling cascades. Dysregulation of the JAK-STAT pathway in T helper cells may result in various immune disorders. In this review, we represent how the JAK-STAT pathway is generally regulated and then in Th cell subsets in more detail. Finally, we introduce novel targeted strategies as promising therapeutic approaches in the treatment of immune disorders. Studies are ongoing for identifying the other regulators of the JAK-STAT pathway and designing innovative therapeutic strategies. Therefore, further investigation is needed.

Type I/II cytokines, JAKs, and new strategies for treating autoimmune diseases

Abstract: Cytokines are major drivers of autoimmunity, and biologic agents targeting cytokines have revolutionized the treatment of immune-mediated diseases. Despite the effectiveness of these drugs, they do not induce complete remission in all patients, prompting the development of alternative strategies - including targeting of intracellular signal transduction pathways downstream of cytokines. Many cytokines that bind type I and type II cytokine receptors are critical regulators of immune-mediated diseases and employ the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathway to exert their effect. Pharmacological inhibition of JAKs blocks the actions of type I/II cytokines, and within the past 3 years therapeutic JAK inhibitors, or Jakinibs, have become available to rheumatologists. Jakinibs have proven effective for the treatment of rheumatoid arthritis and other inflammatory diseases. Adverse effects of these agents are largely related to their mode of action and include infections and hyperlipidemia. Jakinibs are currently being investigated for a number of new indications, and second-generation selective Jakinibs are being developed and tested. Targeting STATs could be a future avenue for the treatment of rheumatologic diseases, although substantial challenges remain. Nonetheless, the ability to therapeutically target intracellular signalling pathways has already created a new paradigm for the treatment of rheumatologic disease.

Chitins and chitosans as immunoadjuvants and non-allergenic drug carriers.

Abstract: Due to the fact that some individuals are allergic to crustaceans, the presumed relationship between allergy and the presence of chitin in crustaceans has been investigated. In vivo, chitin is part of complex structures with other organic and inorganic compounds: in arthropods chitin is covalently linked to proteins and tanned by quinones, in fungi it is covalently linked to glucans, while in bacteria chitin is diversely combined according to Gram(+/-) classification. On the other hand, isolated, purified chitin is a plain polysaccharide that, at the nano level, presents itself as a highly associated structure, recently refined in terms of regularity, nature of bonds, crystallinity degree and unusual colloidal behavior. Chitins and modified chitins exert a number of beneficial actions, i.e., (i) they stimulate macrophages by interacting with receptors on the macrophage surface that mediate the internalization of chitin particles to be degraded by lysozyme and N-acetyl-beta-glucosaminidase (such as Nod-like, Toll-like, lectin, Dectin-1, leukotriene 134 and mannose receptors); (ii) the macrophages produce cytokines and other compounds that confer non-specific host resistance against bacterial and viral infections, and anti-tumor activity; (iii) chitin is a strong Th1 adjuvant that up-regulates Th1 immunity induced by heat-killed Mycobacterium bovis, while down- regulating Th2 immunity induced by mycobacterial protein; (iv) direct intranasal application of chitin microparticles into the lung was also able to significantly down-regulate allergic response to Dermatophagoids pteronyssinus and Aspergillus fumigatus in a murine model of allergy; (v) chitin microparticles had a beneficial effect in preventing and treating histopathologic changes in the airways of asthmatic mice; (vi) authors support the fact that chitin depresses the development of adaptive type 2 allergic responses. Since the expression of chitinases, chitrotriosidase and chitinase-like proteins is greatly amplified during many infections and diseases, the common feature of chitinase-like proteins and chitinase activity in all organisms appears to be the biochemical defense of the host. Unfortunately, conceptual and methodological errors are present in certain recent articles dealing with chitin and allergy, i.e., (1) omitted consideration of mammalian chitinase and/or chitotriosidase secretion, accompanied by inactive chitinase-like proteins, as an ancestral defensive means against invasion, capable to prevent the insurgence of allergy; (2) omitted consideration of the fact that the mammalian organism recognizes more promptly the secreted water soluble chitinase produced by a pathogen, rather than the insoluble and well protected chitin within the pathogen itself; (3) superficial and incomplete reports and investigations on chitin as an allergen, without mentioning the potent allergen from crustacean flesh, tropomyosine; (4) limited perception of the importance of the chemical/biochemical characteristics of the isolated chitin or chitosan for the replication of experiments and optimization of results; and (5) lack of interdisciplinarity. There is quite a large body of knowledge today on the use of chitosans as biomaterials, and more specifically as drug carriers for a variety of applications: the delivery routes being the same as those adopted for the immunological studies. Said articles, that devote attention to the safety and biocompatibility aspects, never reported intolerance or allergy in individuals and animals, even when the quantities of chitosan used in single experiments were quite large. Therefore, it is concluded that crab, shrimp, prawn and lobster chitins, as well as chitosans of all grades, once purified, should not be considered as "crustacean derivatives", because the isolation procedures have removed proteins, fats and other contaminants to such an extent as to allow them to be classified as chemicals regardless of their origin.

Slaying the Seven-Headed Dragon: The Quest for Gender Change in Academia

Abstract: In this article we propose a multi-level distinction between gender inequality practices and gender equality practices to come to better understanding of the slow pace of gender change in academia. Gender inequality resembles an unbeatable seven-headed dragon that has a multitude of faces in different social contexts. Based on an empirical study on the recruitment and selection of full professors in three academic fields in The Netherlands we discuss practices that should bring about gender equality and show how these interact with gender inequality practices. We argue that the multitude of gender inequality practices are ineffectively countered by gender equality practices because the latter lack teeth, especially in traditional masculine academic environments.