bluuebunny/crossref_metadata_2025 huggingface dataset:
Exposure Reduction or Retaliation? The Effects of Domestic Violence Resources on Intimate-Partner Homicide
Authors: Dugan Laura , Nagin Daniel S. , Rosenfeld Richard
Published: December 2004

Rates of homicide involving intimate partners have declined substantially over the past 25 years in the United States, while public awareness of and policy responses to domestic violence have grown. To what extent has the social response to domestic violence contributed to the decline in intimate-partner homicide? We evaluate the relationship between intimate-partner homicide and domestic violence prevention resources in 48 large cities between 1976 and 1996. Controlling for other influences, several types of prevention resources are linked to lower levels of intimate-partner homicide, which we interpret in terms of their capacity to effectively reduce victims' exposure to abusive or violent partners. Other resources, however, are related to higher levels of homicide, suggesting a retaliation effect when interventions stimulate increased aggression without adequately reducing exposure. In light of other research on deficiencies in accessing and implementing prevention resources, our results suggest that too little exposure reduction in severely violent relationships may be worse than none at all.
B‐cell homeostasis, competition, resources, and positive selection by self‐antigens
Authors: Gaudin Emmanuelle , Rosado Manuela , Agenes Fabien , Mclean Angela , Freitas Antonio A.
Published: December 2004

Summary: In adult mice, the number of B lymphocytes remains constant under homeostatic control, in spite of the fact that B cells are produced continuously in numbers that largely exceed the number required to replenish the peripheral pools. It follows that each newly formed lymphocyte can only persist if another lymphocyte dies. In an immune system where the total number of cells is limited, cell survival is no longer a passive phenomenon but rather a continuous active process where each lymphocyte must compete with other lymphocytes to survive. Consequently, the number and the life expectancy of a B‐cell clone vary according to the presence or absence of competitor populations. This process of lymphocyte competition is likely controlled by a common need for resources that are in limited supply. The number of peripheral B‐cells varies according to the availability of B‐cell receptor (BCR) ligands. Indeed, it is possible to modify steady‐state B‐cell numbers by antigen manipulation. Moreover, conventional self‐reactive B cells can undergo positive selection. We showed that the fate of a self‐reactive B cell is determined by the quantity of self‐antigens, the number of antigen‐specific receptors engaged, and its overall antigen‐binding avidity rather than the affinity of individual BCRs.
B‐cell homeostasis: digital survival or analog growth?
Authors: Rathmell Jeffrey C.
Published: December 2004

Summary:  Maintenance of B‐lymphocyte homeostasis requires balanced cell production, death, and proliferation. To coordinate these processes, B cells are dependent on cell extrinsic signals. In lymphocyte development, precursor cells are dependent on Fms‐like tyrosine kinase ligand 3 (Flt3L), and pre‐B cells are dependent on the cytokine interleukin‐7. Transitional B cells require B‐lymphocyte stimulator (BLyS) for survival. Mature B cells require B‐cell receptor (BCR) signals and also remain sensitive to their microenvironment. An emerging model suggests that extrinsic signals do not regulate B‐cell survival through a digital mechanism where cells are simply instructed to survive or die. Instead, availability and competition for extrinsic signals regulates cellular physiology and metabolism in an analog fashion that then influences cell commitment to apoptosis or proliferation. Decreases in cellular metabolism may sensitize cells to activation and action of the pro‐apoptotic Bcl‐2 family members, Bak and Bax, and promote apoptosis. In contrast, increases in metabolism may predispose cells to proliferate. Analog control of cell physiology can, thus, be integrated with other inputs by individual cells to produce a fate decision for survival, proliferation, or apoptosis and prevent diseases of cell death, such as immunodeficiency, and cell activation and proliferation, such as autoimmunity or cancer.
Positive selection focuses the VH12 B‐cell repertoire towards a single B1 specificity with survival function
Authors: Wang Hongsheng , Clarke Stephen H.
Published: December 2004

Summary:  B cells of varying antigen specificities are consistently present in the unmanipulated repertoire. These B cells appear to belong to the marginal zone (MZ) and B1 B‐cell subsets and provide protection to the blood and lymph, respectively. Some are specific for self‐antigens, suggesting that they are selected based on specificity for self but have a protective role against foreign pathogens. One of these specificities is for phosphatidylcholine (PtC). Anti‐PtC B cells comprise 5–8% of the B1 repertoire and are protective against bacterial pathogens. In general, they are restricted to the expression of two VH/Vκ combinations, VH11/Vκ9 and VH12/Vκ4/5H. This review focuses on the differentiation of VH12 anti‐PtC B cells. They undergo a series of positive selection events beginning at the pre‐B‐cell stage that enriches for those with a VHCDR3 and L chain required for PtC binding and eliminating the majority of VH12 B cells that lack the ability to bind PtC. Thus, positive selection focuses the VH12 repertoire toward PtC, ensuring that anti‐PtC VH12 B cells are a significant component of the B1‐cell repertoire in all individuals.
Signaling in transitional type 2 B cells is critical for peripheral B‐cell development
Authors: Su Thomas T. , Guo Beichu , Wei Bo , Braun Jonathan , Rawlings David J.
Published: December 2004

Summary:  Splenic peripheral B‐cell development and the events regulating this functionally significant but relatively poorly defined developmental process have become a major focus in recent studies in B‐cell immunology. Following the exit from the bone marrow, peripheral B cells develop through transitional type 1 (T1) and transitional type 2 (T2) B‐cell stages. Emerging data suggest that the T2 subset is the immediate precursor of the mature B‐cell populations present in the spleen. In this review, we first elaborate on the evidence describing the unique properties of CD21hiCD24hiCD23hiIgMhiIgDhi T2 B cells. T2 cells uniquely activate a proliferative, pro‐survival, and differentiation program in response to B‐cell antigen receptor (BCR) engagement. The potential mechanisms leading to the differential BCR responsiveness of T1 versus T2 B cells are discussed. We also review evidence that distinguishes key BCR‐dependent signaling pathways operative in T2 and mature B cells. These signaling cascades include a protein kinase Cβ (PKCβ)‐dependent cell‐survival pathway and a second PKCβ‐independent pathway essential for BCR‐driven differentiation. Finally, we discuss recent intriguing results suggesting that the type of signal(s) encountered by T2 cells leads to their differential maturation toward the follicular mature versus marginal zone mature B‐cell populations. These combined observations suggest important implications with regard to B‐cell selection and tolerance, potential novel therapeutic targets for B‐cell lymphomas, and how the intricate balance of commensal organisms and other microenvironmental signals interact to promote the generation of ‘innate‐like’ versus adaptive effector B‐cell populations.
Mechanisms of selection mediated by interleukin‐7, the preBCR, and hemokinin‐1 during B‐cell development
Authors: Milne Craig D. , Fleming Heather E. , Zhang Yu , Paige Christopher J.
Published: December 2004

Summary:  Many of the stromal‐derived signals and factors that regulate B lymphopoiesis have been identified. We review recent evidence from our laboratory that shows that there are at least three phases during B‐cell development when cells direct their own maturation, independent of stromal cells. Following the expression of the preB‐cell receptor (preBCR), cells acquire the ability to proliferate in low levels of interleukin‐7 (IL‐7), which acts as a self‐selecting mechanism to expand cells that have successfully expressed a preBCR in environments that are non‐permissive to preBCR– cells. Second, the preBCR is required for a contact‐mediated event between B‐cell progenitors. Disruption at this stage prevents the further maturation of progenitors to the lipopolysaccharide (LPS)‐responsive stage. Finally, the transition from IL‐7 receptor to mature antigen receptor‐based signaling is enhanced by a novel member of the tachykinin family, hemokinin‐1. This series of maturation, survival, and differentiation signals is generated by B‐lineage cells as they progress through developmental checkpoints on the way to becoming functionally mature cells.
Basal B‐cell receptor signaling in B lymphocytes: mechanisms of regulation and role in positive selection, differentiation, and peripheral survival
Authors: Fuentes‐Pananá Ezequiel M. , Bannish Gregory , Monroe John G.
Published: December 2004

Summary:  B‐cell development is a highly ordered multistep process dependent upon signals generated by the pre‐B and B‐cell antigen receptor (BCR). BCR signals drive maturation of the B cell by integrating a number of parallel and sequential biological processes that result in generation of fully immunocompetent B cells. Among these biological processes are positive selection through several developmental checkpoints, negative selection of potentially self‐reactive B cells, and activation of the mature B cell. In addition, recent studies have shown that developing and mature B cells rely on the constant activity of the BCR for their continued survival. Ligand (antigen)‐dependent and ‐independent mechanisms of BCR signaling have been proposed, but their specific contributions to B‐cell maturation and differentiation in the bone marrow and periphery are not completely clear. We discuss here a model, whereby ligand‐independent basal BCR activity would be sufficient to trigger B‐cell development through to the mature stage. However, long‐term survival and formation of specific mature B‐cell populations may be dependent on ligand–receptor interactions.
Tolerance‐induced receptor selection: scope, sensitivity, locus specificity, and relationship to lymphocyte‐positive selection
Authors: Aït‐Azzouzene Djemel , Skog Patrick , Retter Marc , Kouskoff Valerie , Hertz Marc , Lang Julie , Kench Jennifer , Chumley Michael , Melamed Doron , Sudaria Janice , Gavin Amanda , Martensson Annica , Verkoczy Laurent , Duong Bao , Vela José , Nemazee David
Published: December 2004

Summary:  Receptor editing is a mode of immunological tolerance of B lymphocytes that involves antigen‐induced B‐cell receptor signaling and consequent secondary immunoglobulin light chain gene recombination. This ongoing rearrangement often changes B‐cell specificity for antigen, rendering the cell non‐autoreactive and sparing it from deletion. We currently believe that tolerance‐induced editing is limited to early stages in B‐cell development and that it is a major mechanism of tolerance, with a low‐affinity threshold and the potential to take place in virtually every developing B cell. The present review highlights the contributions from our laboratory over several years to elucidate these features.
The molecular basis and biological significance of VH replacement
Authors: Zhang Zhixin , Burrows Peter D. , Cooper Max D.
Published: December 2004

Summary:  First observed in mouse pre‐B‐cell lines and then in knock‐in mice carrying self‐reactive IgH transgenes, VH replacement has now been shown to contribute to the primary B‐cell repertoire in humans. Through recombination‐activating gene (RAG)‐mediated recombination between a cryptic recombination signal sequence (RSS) present in almost all VH genes and the flanking 23 base pair RSS of an upstream VH gene, VH replacement renews the entire VH‐coding region, while leaving behind a short stretch of nucleotides as a VH replacement footprint. In addition to extending the CDR3 region, the VH replacement footprints preferentially contribute charged amino acids. VH replacement rearrangement in immature B cells may either eliminate a self‐reactive B‐cell receptor or contribute to the generation of self‐reactive antibodies. VH replacement may also rescue non‐productive or dysfunctional VHDJH rearrangement in pro‐B and pre‐B cells. Conversely, VH replacement of a productive immunoglobulin H gene may generate non‐productive VH replacement to disrupt or temporarily reverse the B‐cell differentiation process. VH replacement can thus play a complex role in the generation of the primary B‐cell repertoire.
Modulation and function of caspase pathways in B lymphocytes
Authors: Graves Jonathan D. , Craxton Andrew , Clark Edward A.
Published: December 2004

Summary:  During their development, B‐lineage cells are selected to mature, to die, to divide, or to survive and wait, ready to respond to external signals. The homeostatic balance between growth, death, and survival is mediated by signaling pathways through the B‐cell antigen receptor (BCR) complex, cytokine and chemokine receptors or cell–cell coreceptor interactions. The BCR complex is a master regulator essential at key checkpoints during development. These checkpoints involve various processes, including negative selection (deletion), anergy, receptor editing, and positive selection. Without BCRs or downstream BCR‐signaling components, B‐lineage cells arrest during development. Removal of BCRs from mature B cells leads to their death. Here, we discuss signaling pathways in B cells that activate members of the caspase family of cysteine proteases. In some B‐cell subsets, BCR signaling activates caspases, which in turn induce a program leading to cell death. However, in other contexts, caspases are involved in the proliferation of B cells. The outcome depends in part on the presence or absence of modifiers that affect signaling thresholds and on which caspases are activated. These mechanisms allow the coordinated regulation of proliferation and apoptosis that is essential for lymphoid homeostasis.
The avian B‐cell receptor complex: distinct roles of Igα and Igβ in B‐cell development
Authors: Pike Kelly A. , Baig Ehtesham , Ratcliffe Michael J. H.
Published: December 2004

Summary:  The bursa of Fabricius has evolved in birds as a gut‐associated site of B‐cell lymphopoiesis that is segregated from the development of other hematopoietic lineages. Despite differences in the developmental progression of chicken as compared to murine B‐cell lymphopoiesis, cell‐surface immunoglobulin (sIg) expression has been conserved in birds as an essential checkpoint in B‐cell development. B‐cell precursors that express an sIg complex that includes the evolutionarily conserved Igα/β heterodimer colonize lymphoid follicles in the bursa, whereas B‐cell precursors that fail to express sIg due to non‐productive V(D)J recombination are eliminated. Productive retroviral gene transfer has allowed us to introduce chimeric receptor constructs into developing B‐cell precursors in vivo. Chimeric proteins comprising the extracellular and transmembrane regions of murine CD8α fused to the cytoplasmic domain of chicken Igα efficiently supported B‐cell development in precursors that lacked endogenous sIg expression. By contrast, expression of an equivalent chimeric receptor containing the cytoplasmic domain of Igβ actively inhibited B‐cell development. Consequently, the cytoplasmic domains of Igα and Igβ play functionally distinct roles in chicken B‐cell development.
Oil Prices and Stocks in the Second Quarter of 2004
Authors:   OPEC Secretariat
Published: December 2004

Notwithstanding forecasting difficulties, the oil supply and demand balance has proved to be a good indicator of the state of the market and stock levels, which, in turn, influence price behaviour.

In periods where OECD commercial stock levels lie within a certain range, currently around 2,450–2,650 million barrels, the range of prices is larger than when stock levels are very high or very low. In both the latter extreme situations, prices are prone to rapid movements, undermining market stability. Other factors, of course, also influence price fluctuations.

The general opinion among regularly published oil market reports points to the inevitability of a higher‐than‐normal build in stocks in the second quarter of 2004. If the resulting surplus is not handled in a timely and effective manner, there is likely to be excessive downward pressure on prices, which, if left unattended, would lead to a protracted spell of volatility.
Expression and regulation of novel human β‐defensins in gingival keratinocytes
Authors: Premratanachai P. , Joly S. , Johnson G. K. , McCray P. B. , Jia H. P. , Guthmiller J. M.
Published: December 2004

This study evaluated the expression and regulation of β‐defensins DEFB‐104 and the recently identified DEFB‐105–14 in gingival keratinocytes. Keratinocytes from healthy subjects were exposed to cytokines, Escherichia coli lipopolysaccharide or Candida species. Total RNA was extracted and defensin expression analyzed by reverse transcription‐polymerase chain reaction. Three patterns of expression were seen: no expression, constitutive expression and inducible expression. Constitutive mRNA expression was evident for DEFB‐104, 107, 109, 111, and 112. DEFB‐108 and 114 were induced by interleukin (IL)‐1β and Candida species. For DEFB‐108 expression, synergism was observed when IL‐1β was combined with tumor necrosis factor‐α or interferon‐γ. Downregulation of DEFB‐109 occurred following treatment with Candida albicans. These findings suggest a role for multiple β‐defensins in response to oral infection. Further investigation is needed to better understand their function, both in terms of antimicrobial activities and contributions to innate and acquired immunity.
Genome size of human oral Treponema species by pulsed‐field gel electrophoresis
Authors: Correia F. F. , Plummer A. R. , Paster B. J. , Dewhirst F. E.
Published: December 2004

The genome sizes of seven strains of oral treponemes were determined using pulsed‐field gel electrophoresis (PFGE). These strains represent members from six of the currently known cultivable oral treponeme groups. The PFGE fragments were digitally recorded and then quantitated using GIMP v 1.2, an image manipulation program. The results show that the six oral treponeme genomes are comparable in size, ranging from approximately 2.2 to 2.5 Mbp. The genome sizes of these strains are 20–25% smaller than Treponema denticola strains, which have genome sizes of approximately 2.8–3.0 Mbp.
Functional analysis of H2O2‐generating systems in Botrytis cinerea: the major Cu‐Zn‐superoxide dismutase (BCSOD1) contributes to virulence on French bean, whereas a glucose oxidase (BCGOD1) is dispensable
Authors: Rolke Yvonne , Liu Songji , Quidde Thomas , Williamson Brian , Schouten Alexander , Weltring Klaus‐Michael , Siewers Verena , Tenberge Klaus B. , Tudzynski Bettina , Tudzynski Paul
Published: December 2004

The oxidative burst, a transient and rapid accumulation of reactive oxygen species (ROS), is a widespread defence mechanism of higher plants against pathogen attack. There is increasing evidence that the necrotrophic fungal pathogen Botrytis cinerea itself generates ROS, and that this capability could contribute to the virulence of the fungus. Two potential H2O2‐generating systems were studied with respect to their impact on the interaction of B. cinerea and its host plant Phaseolus vulgaris. A Cu‐Zn‐superoxide dismutase gene (bcsod1) and a putative glucose oxidase gene (bcgod1) were cloned and characterized, and deletion mutants were created using a gene‐replacement methodology. Whereas the Δbcgod1‐mutants displayed normal virulence on bean leaves, the Δbcsod1 mutants showed a significantly retarded development of lesions, indicating that the Cu‐Zn SOD‐activity is an important single virulence factor in this interaction system. Whether dismutation of (fungal or host) superoxide, or generation of H2O2 (or both), are important for pathogenesis in this system remains to be elucidated.
Recent advance in the study of caspase‐like proteases and Bax inhibitor‐1 in plants: their possible roles as regulator of programmed cell death
Authors: Watanabe Naohide , Lam Eric
Published: December 2004

Programmed cell death (PCD) is a common process in multicellular organisms during development and in response to pathogens and stress signals. In animal systems, it is well established that a class of cysteine protease called caspase plays a central role in signalling and executing PCD. No caspase orthologue has been uncovered from any plant genomic database so far, but recent structural element‐based iterative searches have uncovered the presence of a putative caspase‐related protease family designated as metacaspases in plants. Furthermore, a structural homologue of Bcl‐2‐like proteins such as Bax and Bcl‐2, which act as important regulators to modulate caspase action in animal cells, has not been found in any plant genomic databases. Clearly, the molecular components of plant PCD machinery and many key interactions in the regulatory network of plant PCD remain obscure. However, recent discoveries from numerous laboratories have provided good evidence for the involvement of caspase‐like proteases in the control of cell death activation in plants, and there is accumulating evidence for a plant homologue of Bax inhibitor‐1, which was first identified as an antagonist of Bax action in yeast, as an evolutionarily conserved protein and that may act as a key regulator for a common cell death pathway in plants and animals.
Viral suppression of RNA silencing in plants
Authors: Moissiard Guillaume , Voinnet Olivier
Published: December 2004

RNA silencing is a conserved eukaryotic pathway involved in suppression of gene expression via sequence‐specific interactions that are mediated by nt 21–24‐long RNA molecules. In plants, cell‐autonomous and noncell‐autonomous steps of RNA silencing form the basis of an elaborate immune system that is activated by, and targeted against, viruses. As a counter‐defensive strategy, viruses have evolved suppressor proteins that inhibit various stages of the silencing process. These suppressors are diverse in sequence and structure and appear to be encoded by virtually any type of plant viruses. In this review, we consider the impact of silencing suppression on virus infections and its possible contribution to symptom development. We examine the presumed mode of action of some silencing suppressors and discuss their value as molecular probes of the RNA silencing mechanism. Finally, the biotechnological applications of silencing suppression are considered.
Inhibitory p41 isoform of invariant chain and its potential target enzymes cathepsins L and H in distinct populations of macrophages in human lymph nodes
Authors: Zavašnik‐Bergant Valentina , Schweiger Ana , Bevec Tadeja , Golouh Rastko , Turk Vito , Kos Janko
Published: December 2004

Activation of the CD4+ T‐cell mediated immune response relies on the proteolytic capacity of enzymes involved in modulating major histocompatibility complex (MHC) II‐associated antigen presentation in antigen‐presenting cells (APC). The MHC II‐associated chaperone molecule p41 isoform of invariant chain (inhibitory p41 Ii) has been suggested to regulate stability and activity of cathepsin L in these APC. In the present study the human lymph node distribution of non‐inhibitory p31 Ii and inhibitory p41 Ii have been compared by differential labelling, using two specific monoclonal antibodies. The distribution of p41 Ii, but not p31 Ii, matched the distribution of cathepsins L and H in subcapsular and cortical sinuses and germinal centres. Co‐localization of p41 Ii with cathepsin H was confirmed in strongly CD68+ sinus‐lining macrophages, acting as APC. Furthermore, p41 Ii was determined together with cathepsins L and H in tingible body macrophages, highly phagocytic, but not antigen‐presenting cells inside germinal centres. With respect to the physiological function that these two populations of macrophages have in human lymph nodes, our results support a regulatory function of p41 Ii towards cathepsins L and H in human macrophages, associated with the processes of phagocytosis rather than antigen presentation.
Inhibition of murine allergic airway disease by Bordetella pertussis
Authors: Kim Young‐Suk , Kwon Keun‐Sang , Kim Dae‐Ki , Choi Il‐Whan , Lee Hern‐Ku
Published: December 2004

Whole‐cell pertussis vaccines have been shown to selectively induce T helper 1 (Th1)‐type responses in human and animals. In this study, we investigated whether whole‐cell B. pertussis could inhibit allergic airway reactions in a murine model of asthma induced by ovalbumin (OVA). Systemic administration of whole‐cell B. pertussis strongly inhibited allergic airway reactions such as eosinophil recruitment into the airway, lung inflammation, and airway hyperresponsiveness to methacholine. The inhibitory effect of whole‐cell B. pertussis was mediated by chromosomal DNA and pretreatment of DNA with CpG methylase or DNase I resulted in a loss of the inhibitory effect. Treatment of animals with B. pertussis DNA significantly decreased the Th2 cytokine (interleukins IL‐4 and IL‐5) concentrations in the airways without increasing Th1 cytokines. These results suggest that B. pertussis DNA containing unmethylated CpG appears to be responsible for the inhibitory effect of whole cell B. pertussis on the allergic airway reactions through inhibition of the Th2 response.
Increased activation‐induced cell death in peripheral lymphocytes of rheumatoid arthritis patients: the mechanism of action
Authors: Tang Xiaolei , Yocum David E. , Dejonghe David , Nordensson Kathryn , Lake Douglas F. , Richard John
Published: December 2004

Recently, we have described a soluble survival signal for activated lymphocytes from CD14+ cells. As a result of the importance of T lymphocytes in the pathogenesis of rheumatoid arthritis (RA), we speculate a possible role for CD14+ cells in supporting the outgrowth of autoreactive lymphocytes in RA. To address this issue further, supernatants from activated CD14+ cells (CD14 cocktails) in both normal controls and RA patients were collected. The relative strength of the CD14 cocktails from normal controls and RA patients was compared. The data showed that depletion of CD14+ cells resulted in a much higher increase of activation‐induced cell death (AICD) and a decrease of lymphocyte proliferation in the peripheral blood mononuclear cells of RA patients compared to normal controls. Interestingly, CD14 cocktails from RA patients provide much stronger protection against AICD compared to those from normal controls. The observed soluble survival signal from CD14+ cells is a general phenomenon because CD14 cocktails prevent both phytohaemagglutinin A‐p‐ and anti‐CD3‐induced AICD. Furthermore, supernatants collected from human dendritic cell cultures also prevent activated lymphocytes from undergoing AICD. The data implicate an important role of the CD14+ cell and its secreted form of survival signal in the pathogenesis of RA.
Expression of Epstein–Barr virus‐induced gene 3 and other interleukin‐12‐related molecules by human intestinal epithelium
Authors: Maaser Christian , Egan Laurence J. , Birkenbach Mark P. , Eckmann Lars , Kagnoff Martin F.
Published: December 2004

Antigen‐presenting cells, including dendritic cells, monocytes and macrophages, produce members of the interleukin‐12 (IL‐12) family that are important in initiating and maintaining cell‐mediated immune responses. These include IL‐12p35 and p19 that dimerize with IL‐12p40 to form IL‐12 (also termed IL‐12p75) and IL‐23, respectively, and Epstein–Barr virus‐induced gene 3 (EBI3) protein (a protein related to IL‐12p40), that forms a dimer with p28, termed IL‐27. Intestinal epithelial cells, which are the initial site of contact between the host and enteric pathogens, can act as antigen‐presenting cells, and are known to express mediators important in inflammatory and immune responses. In the current studies, we hypothesized that intestinal epithelial cells express members of the IL‐12 family, which can function as an early signalling system important in mucosal immunity. Using in vitro and in vivo model systems of human intestinal epithelium, we demonstrate the regulated expression of EBI3, IL‐12p35 and p19 by human intestinal epithelial cells. However, intestinal epithelial cells do not coexpress IL‐12p40 or p28 that are required to generate heterodimeric IL‐12p75, IL‐23 and IL‐27. To the extent that IL‐12p35, p19 and EBI3 cannot form IL‐12p75, IL‐23 or IL‐27 heterodimers in intestinal epithelial cells, these data suggest that those cells may express other, currently unknown, molecules that can associate with EBI3, IL‐12p35 and/or p19 or, alternatively, intestinal epithelial cells may release IL‐12‐related molecules that by themselves, or in combination with other molecules in the mucosal microenvironment, mediate biological activities.
Prenatal exposure to bisphenol A up‐regulates immune responses, including T helper 1 and T helper 2 responses, in mice
Authors: Yoshino Shin , Yamaki Kouya , Li Xiaojuan , Sai Tao , Yanagisawa Rie , Takano Hirohisa , Taneda Shinji , Hayashi Hideyuki , Mori Yoki
Published: December 2004

The effect of prenatal exposure to bisphenol A (BPA) on the immune system in mice was investigated. Virgin female mice were fed varying doses of BPA, on a daily basis, over a period of 18 days commencing on the day of pairing with stud males (day 0). On day 77, their male offspring of 8 weeks were immunized with hen egg lysozyme (HEL). Three weeks later, anti‐HEL immunoglobulin G (IgG) in sera, and proliferative responses of spleen cells to the antigen, were measured. Anti‐HEL IgG2a and interferon‐γ (IFN‐γ), secreted from splenic lymphocytes, were measured as indicators of T helper 1 (Th1) immune responses, while anti‐HEL IgG1 and interleukin‐4 (IL‐4) were measured as indicators of Th2 responses. The results showed that fetal exposure to BPA was followed by significant increases in anti‐HEL IgG as well as antigen‐specific cell proliferation. Both Th1 responses (including anti‐HEL IgG2a and IFN‐γ production) and Th2 responses (including anti‐HEL IgG1 and IL‐4 production) were augmented by prenatal exposure to BPA, although the augmentation of Th1 responses appeared to be greater than that of Th2 responses. Two‐colour flow cytometric analysis showed that mice exposed prenatally to BPA had 29% and 100% more splenic CD3+ CD4+ and CD3+ CD8+ cells, respectively, than control animals. Similar results were obtained from females whose mothers had consumed BPA during pregnancy. These results suggest that prenatal exposure to BPA may result in the up‐regulation of immune responses, especially Th1 responses, in adulthood.
Polyinosinic‐polycytidylic acid‐mediated stimulation of human γδ T cells via CD11c+ dendritic cell‐derived type I interferons
Authors: Kunzmann Volker , Kretzschmar Eva , Herrmann Thomas , Wilhelm Martin
Published: December 2004

The recognition of pathogen‐associated molecular patterns (PAMPs) by the innate immune system is a crucial step in inducing effective immune responses. Double‐stranded RNA [mimicked by polyinosinic‐polycytidylic acid (poly(I:C)], synthesized by various types of viruses, represents one important member of these immunostimulatory microbial components. Here we report that poly(I:C) has potent γδ T‐cell costimulatory capacity. Within peripheral blood mononuclear cells, poly(I:C)‐stimulated γδ T cells expressed increased levels of CD69 and exhibited significantly enhanced antigen‐mediated proliferation in response to isopentenylpyrophosphate (IPP). Among several recombinant cytokines tested, type I interferons (IFN‐α, IFN‐β) and interleukin‐15 (IL‐15) showed a similar activation pattern of γδ T cells. γδ T‐cell clones and purified γδ T cells did not respond to poly(I:C), indicating indirect effects of this compound. Depletion of CD11c+ dendritic cells (DC), which express Toll‐like receptor 3 (TLR3), known to recognize poly(I:C), abrogated poly(I:C)‐mediated stimulation of γδ T cells. In addition, the supernatant of poly(I:C)‐treated CD11c+ DC was able to mimic the stimulatory effects of poly(I:C) on γδ T cells. Experiments with neutralizing antibodies indicated that type I IFNs, but not IL‐15, contributed to the poly(I:C)‐mediated activation of γδ T cells. In conclusion, γδ T‐cell activation by immunostimulatory double‐stranded RNA, such as poly(I:C), is indirectly mediated via type I IFNs derived from TLR3‐expressing CD11c+ DCs. These results suggest that upon confrontation with certain viruses, γδ T cells can be rapidly activated by type I interferons and may contribute to effective antiviral responses.
Dual biological functions of an interleukin‐1 receptor antagonist–interleukin‐10 fusion protein and its suppressive effects on joint inflammation
Authors: Chang Deh‐Ming , Shyue Song‐Kun , Liu Shao‐Hsiang , Chen Yen‐Teen , Yeh Chiou‐Yueh , Lai Jenn‐Huang , Lee Herng‐Sheng , Chen Ann
Published: December 2004

The aim of this study was to construct and purify a novel interleukin‐1 receptor antagonist (IL‐1ra)–interleukin‐10 (IL‐10) fusion protein and determine its biological function and anti‐inflammatory effects. The isolated cDNAs of two inhibitory cytokines (IL‐1ra, IL‐10) were used to construct a cDNA for the IL‐1ra–IL‐10 fusion protein. The expressed recombinant cytokines and fusion product were purified and their biological properties analysed. The anti‐IL‐1 effect was evaluated by using a thymocyte‐proliferation assay, and the IL‐10 effect was investigated by the inhibition of interferon‐γ (IFN‐γ) production from splenocytes. The clinical response and histological analyses were studied in an adjuvant arthritic rat model. The fusion protein was 38 000 molecular weight in size. Sodium dodecyl sulphate–polyacrylamide gel electrophoresis (SDS–PAGE) and immunoblotting demonstrated that the purified protein was recognized by both IL‐1ra and IL‐10 antibodies. The fusion protein significantly inhibited IL‐1‐mediated thymocyte proliferation and concanavalin A (ConA)‐primed IFN‐γ production from splenocytes. The fusion protein also suppressed joint swelling (paw circumference reduced from 5·0 ± 0·2 to 4·1 ± 0·1 cm; paw thickness ≈ 2 mm in difference) and synovial inflammation in adjuvant arthritis of rats. Our investigations indicate that this fusion protein effectively suppresses inflammatory arthritis and may initiate a trend for future clinical application to target multiple molecules at the same time.
Transferrin is required for early T‐cell differentiation
Authors: Macedo M. Fatima , De Sousa Maria , Ned Renee M. , Mascarenhas Claudia , Andrews Nancy C. , Correia‐Neves Margarida
Published: December 2004

Transferrin, the major plasma iron carrier, mediates iron entry into cells through interaction with its receptor. Several in vitro studies have demonstrated that transferrin plays an essential role in lymphocyte division, a role attributed to its iron transport function. In the present study we used hypotransferrinaemic (Trfhpx/hpx) mice to investigate the possible involvement of transferrin in T lymphocyte differentiation in vivo. The absolute number of thymocytes was substantially reduced in Trfhpx/hpx mice, a result that could not be attributed to increased apoptosis. Moreover, the proportions of the four major thymic subpopulations were maintained and the percentage of dividing cells was not reduced. A leaky block in the differentiation of CD4− CD8− CD3− CD44− CD25+ (TN3) into CD4− CD8− CD3− CD44− CD25− (TN4) cells was observed. In addition, a similar impairment of early thymocyte differentiation was observed in mice with reduced levels of transferrin receptor. The present study demonstrates, for the first time, that transferrin itself or a pathway triggered by the interaction of transferrin with its receptor is essential for normal early T‐cell differentiation in vivo.
4‐1BB and OX40 stimulation enhance CD8 and CD4 T‐cell responses to a DNA prime, poxvirus boost vaccine
Authors: Munks Michael W. , Mourich Dan V. , Mittler Robert S. , Weinberg Andrew D. , Hill Ann B.
Published: December 2004

4‐1BB (CD137) is a tumour necrosis factor receptor (TNFR) family member, expressed primarily on CD8 T cells after activation. Signalling through 4‐1BB has been reported to enhance CD8 T‐cell expansion and to protect activated CD8 T cells from death, resulting in an enlarged memory population. Although stimulating 4‐1BB has been shown to significantly improve the immune response to weak immunogens such as tumours, little is known about its effect on the CD8 T‐cell response to a powerful viral vector such as vaccinia. To test 4‐1BB's ability to improve the murine CD8 T cell response to a DNA prime, poxvirus boost vaccine, similar to those used for human immunodeficiency virus and simian immunodeficiency virus vaccines, we administered 4‐1BB agonist antibody at the time of the poxvirus boost. 4‐1BB stimulation increased the number of functional memory CD8 T cells by two‐ to fourfold. However, we saw a similar enhancement at the peak of the response and in the memory phase, thus we found no evidence in the context of virus infection that 4‐1BB stimulation could increase the percentage of CD8 T cells that survive the acute activation phase to become memory cells. OX40 (CD134) is an analogous TNFR family member expressed primarily on activated CD4 T cells. OX40 stimulation increased the number of antigen‐specific CD4 T cells approximately threefold. Stimulating both 4‐1BB and OX40 enhanced the CD8 T‐cell response more than 4‐1BB alone. Thus stimulating these receptors can improve the response to a powerful virus vector, and may be useful in vaccine development.
Deficiency of BLNK hampers PLC‐γ2 phosphorylation and Ca2+ influx induced by the pre‐B‐cell receptor in human pre‐B cells
Authors: Taguchi Tomoko , Kiyokawa Nobutaka , Takenouch Hisami , Matsui Jun , Tang Wei‐Ran , Nakajima Hideki , Suzuki Kyoko , Shiozawa Yusuke , Saito Masahiro , Katagiri Yohko U. , Takahashi Takao , Karasuyama Hajime , Matsuo Yoshinobu , Okita Hajime , Fujimoto Junichiro
Published: December 2004

B‐cell linker protein (BLNK) is a component of the B‐cell receptor (BCR) as well as of the pre‐BCR signalling pathway, and BLNK–/– mice have a block in B lymphopoiesis at the pro‐B/pre‐B cell stage. A recent report described the complete loss or drastic reduction of BLNK expression in approximately 50% of human childhood pre‐B acute lymphoblastic leukaemias (ALL), therefore we investigated BLNK expression in human pre‐B ALL cell lines. One of the four cell lines tested, HPB‐NULL cells, was found to lack BLNK expression, and we used these human pre‐B ALL cell lines that express and do not express BLNK to investigate the intracellular signalling events following pre‐BCR cross‐linking. When pre‐BCR was cross‐linked with anti‐μ heavy‐chain antibodies, significant phosphorylation of intracellular molecules, including Syk, Shc, ERK MAP kinase, and AKT, and an activation of Ras were observed without regard to deficiency of BLNK expression, suggesting that BLNK is not required for pre‐BCR‐mediated activation of MAP kinase and phosphatidyl‐inositol 3 (PI3) kinase signalling. By contrast, phospholipase C‐γ2 (PLC‐γ2) phosphorylation and an increase in intracellular Ca2+ level mediated by pre‐BCR cross‐linking were observed only in the BLNK‐expressing cells, indicating that BLNK is essential for PLC‐γ2‐induced Ca2+ influx. Human pre‐B cell lines expressing and not expressing BLNK should provide an in vitro model for investigation of the role of BLNK in the pre‐BCR‐mediated signalling mechanism.
The use of membrane translocating peptides to identify sites of interaction between the C5a receptor and downstream effector proteins
Authors: Auger Graham A. , Smith Brenda M. , Pease James E. , Barker Michael D.
Published: December 2004

The complement fragment C5a is a potent leucocyte chemoattractant and activator, mediating its effects through a G‐protein‐coupled receptor. Whilst the C‐terminal domain of this receptor has been shown to be essential for receptor desensitization and internalization, it is not known which domains couple to the receptor's heterotrimeric G proteins. In this report we have used a membrane translocating sequence (MTS) to examine the effects of the four intracellular domains of the human C5a receptor (C5aR) on the receptor's signalling via Gαi family heterotrimeric G proteins in intact RBL‐2H3 cells. The results indicate that all of the intracellular domains couple to downstream signalling, with the proximal region of the C terminus being a major binding site and intracellular loop 3 playing a role in G protein activation or receptor desensitization.
Differential production of interleukin‐10 and interleukin‐12 in mononuclear cells from leprosy patients with a Toll‐like receptor 2 mutation
Authors: Kang Tae Jin , Yeum Chung Eun , Kim Byoung Chul , You Eun‐Young , Chae Gue‐Tae
Published: December 2004

Toll‐like receptor 2 (TLR2) is a key mediator of the immune response to mycobacterial infections, and mutations in TLR2 have been shown to confer susceptibility to infection with mycobacteria. This study investigated the profiles of cytokines, such as interferon (IFN)‐γ, interleukin (IL)‐10, IL‐12 and tumour necrosis factor (TNF)‐α in response to Mycobacterium leprae in peripheral blood mononuclear cells (PBMC) with the TLR2 mutation Arg677Trp, a recently reported polymorphism that is associated with lepromatous leprosy. In leprosy patients with the TLR2 mutation, production of IL‐2, IL‐12, IFN‐γ, and TNF‐α by M. leprae‐stimulated PBMC were significantly decreased compared with that in groups with wild‐type TLR2. However, the cells from patients with the TLR2 mutation showed significantly increased production of IL‐10. There was no significant difference in IL‐4 production between the mutant and wild‐type during stimulation. Thus, these results suggest that the TLR2 signal pathway plays a critical role in the alteration of cytokine profiles in PBMC from leprosy patients and the TLR2 mutation Arg677Trp provides a mechanism for the poor cellular immune response associated with lepromatous leprosy.
The potential for Toll‐like receptors to collaborate with other innate immune receptors
Authors: Mukhopadhyay Subhankar , Herre Jurgen , Brown Gordon D. , Gordon Siamon
Published: December 2004

Cells of the innate immune system express a large repertoire of germ‐line encoded cell‐surface glycoprotein receptors including Toll‐like receptors (TLRs). TLRs recognize conserved motifs on microbes and induce inflammatory signals. Evidence suggests that individual members of the TLR family or other non‐TLR surface antigens either physically or functionally interact with each other and cumulative effects of these interactions instruct the nature and outcome of the immune response to a particular pathogen.
Nest predators affect spatial dynamics of breeding red‐backed shrikes (Lanius collurio)
Authors: Roos Staffan , Pärt Tomas
Published: December 2004

Predation may be a strong selective factor affecting individual behaviour and life histories. However, few studies have investigated whether predators affect breeding habitat selection of prey species.

We tested whether breeding habitat selection and reproduction of a tropical migrant, the red‐backed shrike (Lanius collurioL.), was related to the presence of breeding pairs of its potential nest predators, magpie (Pica picaL.), hooded crow (Corvus corone cornixL.) and jackdaw (C. monedulaL.).

Only magpie and hooded crow territories were associated with an elevated risk of predation based on an artificial nest experiment with nests mimicking red‐backed shrike nests. Predation risk on real red‐backed shrike nests was also higher close to nests of hooded crow and magpie than elsewhere in the landscape.

Occupation frequency of known red‐backed shrike territory sites during 3 years of study increased with increasing mean distance to the nearest magpie nest.

Changes in spatial distribution of corvids affected the spatial distribution of red‐backed shrikes. Vacant red‐backed shrike territory sites were more likely to become occupied in the next year when magpie and hooded crows had moved away from the site, while occupied sites were more likely to be abandoned in the next year when at least hooded crows had moved closer.

Our results suggest that breeding territories of nest predators may affect breeding habitat selection of prey species. Thus, a large part of an observed spatial dynamics of prey species may be caused by a corresponding spatial dynamics of predators. Because sink territories are occupied more irregularly than source territories, we suggest that the dynamics in predator sinks may be the driving force of the spatial dynamics of prey species.
Large‐scale spatial dynamics of vole populations in Finland revealed by the breeding success of vole‐eating avian predators
Authors: Sundell Janne , Huitu Otso , Henttonen Heikki , Kaikusalo Asko , Korpimäki Erkki , Pietiäinen Hannu , Saurola Pertti , Hanski Ilkka
Published: December 2004

Voles in northern Europe have been shown to exhibit cyclic population dynamics, with a latitudinal gradient in cycle length, amplitude and interspecific synchrony.

Previous studies have been based on a relatively sparse network of sampling sites. In the absence of spatially comprehensive long‐term records of vole dynamics, we analysed a proxy of vole density, bird‐ringing data on vole‐eating avian predators, Tengmalm's owl (Aegolius funereus L.), the Ural owl (Strix uralensis Pall.), the long‐eared owl (Asio otus L.) and the rough‐legged buzzard (Buteo lagopus Pontoppidan) to study spatial population dynamics of voles.

We demonstrate that the breeding success of the avian predators is highly dependent on the abundance of voles, which is also reflected in the numbers of nestlings ringed in a particular area in each year.

Our results show the expected increase in cycle length from south to north in Finland, but also from west to east, and in contrast to previous studies, increasing irregularity of the cyclic dynamics towards the north.

Fluctuations of vole populations have been synchronous over large distances, up to several hundred kilometres. Such large‐scale synchrony is more likely to be caused by movements of vole‐eating predators and/or by climatic perturbations than by dispersal of voles.

We could not conclusively verify the recent suggestion that vole population dynamics have become less regular across Finland, although certain long‐term changes are apparent.