bluuebunny/crossref_metadata_2025 huggingface dataset:
Effectiveness of Leflunomide in Patients with Juvenile Idiopathic Arthritis in Clinical Practice
Authors: FOELDVARI IVAN , WIERK ANGELA
Published: May 2010

Objective.

To evaluate the effectiveness of leflunomide in children with juvenile idiopathic arthritis (JIA) as used in actual clinical practice.

Methods.

We conducted a retrospective review of medical records of patients with JIA who initiated leflunomide treatment between April 2001 and October 2006. Data derived from these charts included patient baseline characteristics, reason for starting leflunomide, adverse events, joint outcomes, Childhood Health Assessment Questionnaire (CHAQ) scores, visual analog scale pain and well-being scores, and current treatment status.

Results.

Fifty-eight patients (33 female, 25 male) were included in this study. Forty-eight patients were switched from methotrexate (MTX) to leflunomide, primarily because of MTX-related adverse events, and leflunomide was added to ongoing MTX in 10 patients. The mean duration of leflunomide therapy was 1.45 years. The mean swollen joint count decreased from 1.40 at treatment initiation to 0.60 at last followup, while the mean tender joint count decreased from 1.83 to 0.29. Improvements were also observed in CHAQ, pain, and well-being scores. At last followup, 44.8% of patients were continuing leflunomide therapy, 29.3% had discontinued because of remission, and the rest had discontinued treatment because of side effects (22.4%) or other reasons (3.4%).

Conclusion.

Leflunomide treatment, as employed in actual clinical practice, was well tolerated and resulted in substantial improvements in joint and functional status outcomes in children with JIA. Approximately 30% of the patients attained remission during leflunomide therapy. Leflunomide is thus a safe and effective alternative for patients with JIA who cannot tolerate or do not respond to MTX monotherapy.
Tumor Necrosis Factor-α Blockers in SAPHO Syndrome: Table 1.
Authors: BEN ABDELGHANI KAOUTHER , DRAN DELPHINE GERARD , GOTTENBERG JACQUES-ERIC , MOREL JACQUES , SIBILIA JEAN , COMBE BERNARD
Published: May 2010

Objective.

To analyze the clinical efficacy of anti-tumor necrosis factor-α (TNF-α) therapy in treatment of synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome, we describe cases of refractory SAPHO syndrome and review cases treated with anti-TNF-α reported in the literature.

Methods.

We describe 6 cases of patients with SAPHO syndrome treated with anti-TNF-α between 2004 and 2008. Therapeutic response was evaluated according to improvement in pain score, amelioration of disease activity, and improvement in function. The efficacy of treatment was considered to be reduced need for analgesics and/or antiinflammatory therapy.

Results.

In our series, 4 patients received infliximab, 1 etanercept, and 1 adalimumab. These treatments brought clinical response in 4 patients (66.6%): response was sustained with infliximab in 1 case for 7 months; with adalimumab in another case for 22 months; and with etanercept in 2 cases for 1 and 42 months, respectively. In contrast, 2 other patients showed no response to infliximab. Improvement was initially temporary after infusions 1 and 2, then pain recurred at Week 14. Skin lesions were healed in 3 of 4 cases, but recurred or worsened in 2 cases, after infusion 2 of infliximab. Treatment was generally well tolerated. Paradoxical psoriasis was noted in 2 cases and urticaria in 1.

Conclusion.

Given our results and those from the literature, TNF-α blockers should be considered in the therapeutic strategy of refractory cases of SAPHO syndrome, despite their effect seeming less impressive than in other spondyloarthropathies.
The Course of Symptoms for Whiplash-Associated Disorders in Sweden: 6-Month Followup Study
Authors: CRUTEBO SARA , NILSSON CHARLOTT , SKILLGATE EVA , HOLM LENA W.
Published: May 2010

Objective.

To describe symptom patterns and the course for recovery in persons with whiplash-associated disorders (WAD) over 6 months after a car collision, and to investigate associated gender differences.

Methods.

The study population was based on insurance claimants, 18–74 years of age, who reported WAD after a collision, between January 2004 and January 2005. At baseline and again 6 months later they were asked to complete a questionnaire that included questions about presence and severity of pain and other possible WAD symptoms. It also included measurements of posttraumatic stress as well as anxiety and depression.

Results.

A total of 1105 persons were studied. The most common symptoms at baseline after neck pain were reduced cervical range of motion (in 83.9% of men, 82.2% of women), headache (61.0% and 69.3%, respectively), and low back pain (35.9% and 36.1%). Some symptoms were already transient at baseline and symptoms such as neck pain, reduced cervical range of motion, headache, and low back pain decreased further over the 6 months. Baseline prevalence of depression was around 5% in both women and men, whereas posttraumatic stress and anxiety were more common in women (19.7% and 11.7%, respectively) compared to men (13.2% and 8.6%). The majority of all reported associated symptoms were mild at both baseline and followup.

Conclusion.

Our findings support that the symptom pattern of WAD and the prevalence for many of the symptoms decreased over a 6-month period.
Role of BANK1 Gene Polymorphisms in Biopsy-proven Giant Cell Arteritis
Authors: TORRES ORLANDO , PALOMINO-MORALES ROGELIO , CASTAÑEDA SANTOS , VAZQUEZ-RODRIGUEZ TOMAS R. , MORADO INMACULADA C. , MIRANDA-FILLOY JOSE A. , AMIGO-DIAZ ENCARNACION , VICENTE ESTHER F. , ORTEGO-CENTENO NORBERTO , FERNANDEZ-GUTIERREZ BENJAMIN , MARTIN JAVIER , GONZALEZ-GAY MIGUEL A.
Published: May 2010

Objective.

Giant cell arteritis (GCA) is a complex polygenic disease in which more than 1 genetic locus is likely to contribute to disease susceptibility and clinical expression. BANK, an adaptor molecule, has been suggested to participate in the B cell antigen receptors-mediated calcium homeostasis. We assessed for the first time the implication of BANK1 functional variants in susceptibility to GCA.

Methods.

Two hundred twenty-two patients with biopsy-proven GCA and 534 matched controls were assessed. DNA from patients and controls was obtained from peripheral blood. Samples were genotyped for 3 putative functional BANK1 gene polymorphisms (rs17266594 T/C, rs10516487 G/A, rs3733197 G/A) using a TaqMan allele discrimination assay.

Results.

No significant differences were observed in genotype distribution between patients with biopsy-proven GCA and controls for these 3 gene polymorphisms. A trend for a decreased risk of having GCA was observed in individuals carrying the BANK1 rs3733197 GG genotype (patients with GCA 43.9% compared to 51.6% in controls; p = 0.06, OR 0.73, 95% CI 0.53–1.02). The frequency of BANK1 rs3733197 allele G was marginally decreased in patients with biopsy-proven GCA compared to controls (p = 0.09, OR 0.82, 95% CI 0.64–1.04). Haplotype analysis of 3-single-nucleotide polymorphisms found no statistically significant differences between patients with GCA and controls. No significant differences for the BANK1 gene polymorphisms were found when patients were stratified according to specific clinical features of the disease.

Conclusion.

Our results do not support a major implication of the BANK1 locus in susceptibility to GCA.
Invariant NKT Cell Development Requires a Full Complement of Functional CD3 ζ Immunoreceptor Tyrosine-Based Activation Motifs
Authors: Becker Amy M. , Blevins Jon S. , Tomson Farol L. , Eitson Jennifer L. , Medeiros Jennifer J. , Yarovinsky Felix , Norgard Michael V. , van Oers Nicolai S. C.
Published: May 2010

Invariant NKT (iNKT) cells regulate early immune responses to infections, in part because of their rapid release of IFN-γ and IL-4. iNKT cells are proposed to reduce the severity of Lyme disease following Borrelia burgdorferi infection. Unlike conventional T cells, iNKT cells express an invariant αβ TCR that recognizes lipids bound to the MHC class I-like molecule, CD1d. Furthermore, these cells are positively selected following TCR interactions with glycolipid/CD1d complexes expressed on CD4+CD8+ thymocytes. Whereas conventional T cell development can proceed with as few as 4/10 CD3 immunoreceptor tyrosine-based activation motifs (ITAMs), little is known about the ITAM requirements for iNKT cell selection and expansion. We analyzed iNKT cell development in CD3 ζ transgenic lines with various tyrosine-to-phenylalanine substitutions (YF) that eliminated the functions of the first (YF1,2), third (YF5,6), or all three (YF1–6) CD3 ζ ITAMs. iNKT cell numbers were significantly reduced in the thymus, spleen, and liver of all YF mice compared with wild type mice. The reduced numbers of iNKT cells resulted from significant reductions in the expression of the early growth response 2 and promyelocytic leukemia zinc finger transcription factors. In the mice with few to no iNKT cells, there was no difference in the severity of Lyme arthritis compared with wild type controls, following infections with the spirochete B. burgdorferi. These findings indicate that a full complement of functional CD3 ζ ITAMs is required for effective iNKT cell development.
Lupus Serum IgG Induces Skin Inflammation through the TNFR1 Signaling Pathway
Authors: Deng Guo-Min , Liu Lena , Kyttaris Vasileios C. , Tsokos George C.
Published: May 2010

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by high autoantibody levels and multiorgan tissue damage, including kidney and skin. Cutaneous manifestations are frequent in patients with SLE, yet the etiology and pathogenesis of skin injury in SLE remains unclear. We reasoned that lupus serum containing high levels of autoreactive Ig contributes to skin injury. In this article, we report that serum from SLE patients and lupus-prone mice induces skin inflammation following intradermal injection into normal mice. Lupus serum depleted of IgG failed to cause skin inflammation. Monocytes, but not lymphocytes, were found to be crucial in the development of lupus serum-induced skin inflammation, and lupus serum IgG induced monocyte differentiation into dendritic cells (DCs). TNF-α and TNFR1, but not TNFR2, were required for the development of lupus serum-induced skin inflammation. TNFR1, not TNFR2, represented the main molecule expressed in the skin lesions caused by injected lupus serum. Our studies demonstrated that lupus serum IgG causes skin injury by involving the TNFR1 signaling pathway and monocyte differentiation to DCs. Accordingly, disruption of the TNFR1-mediated signaling pathway and blockade of DC generation may prove to be of therapeutic value in patients with cutaneous lupus erythematosus.
Fusion Proteins for Versatile Antigen Targeting to Cell Surface Receptors Reveal Differential Capacity to Prime Immune Responses
Authors: Kratzer Roland , Mauvais François-Xavier , Burgevin Anne , Barilleau Émilie , van Endert Peter
Published: May 2010

Targeting of proteins to APCs is an attractive strategy for eliciting adaptive immune responses. However, the relationship between the choice of the targeted receptor and the quality and quantity of responses remains poorly understood. We describe a strategy for expression of Ags including hydrophobic proteins as soluble fusion proteins that are optimized for proteasome-dependent MHC class I-restricted cross-presentation and form stable complexes with a wide variety of targeting Abs. Upon s.c. immunization, these complexes were initially taken up by CD169+ lymph node subcapsular sinus macrophages. In the OVA model system, receptor-targeted antigenic complexes primed specific T and B cell responses in vitro and in vivo at least 100-fold more efficiently than Ag alone. Comparison of 10 targeting receptors allowed us to establish a ranking with respect to priming of CD8+ T cell responses and demonstrated striking differences with respect to the relative efficacy of CD8+ and CD4+ T cell subset and B cell priming. The described fusion proteins should help in developing optimized strategies for targeted delivery of protein Ags in the context of tolerization or vaccination.
Increased Hematopoietic Cells in the mertk−/− Mouse Peritoneal Cavity: A Result of Augmented Migration
Authors: Williams Julie C. , Wagner Nikki J. , Earp H. Shelton , Vilen Barbara J. , Matsushima Glenn K.
Published: May 2010

The peritoneal cavity is recognized as an important site for autoreactive B cells prior to their transit to other immune tissues; however, little is known of the genes that may regulate this process. Mice lacking the receptor tyrosine kinase, Mertk, display a lupus-like autoimmune phenotype with splenomegaly and high autoantibodies titers. In this study, we investigate whether Mertk regulates the composition of peritoneal cells that favor an autoimmune phenotype. We found an increase in the number of macrophages, dendritic cells (DCs), plasmacytoid DCs, T cells, and B cells in the peritoneal cavity of mertk−/− mice when compared with wild-type mice. This disparity in cell numbers was not due to changes in cell proliferation or cell death. In adoptive transfer experiments, we showed an increase in migration of labeled donor cells into the mertk−/− peritoneal cavity. In addition, bone marrow chimeric mice showed hematopoietic-derived factors were also critical for T cell migration. Consistent with this migration and the increase in the number of cells, we identified elevated expression of CXCL9, its receptor CXCR3, and IL-7R on peritoneal cells from mertk−/− mice. To corroborate the migratory function of CXCR3 on cells, the depletion of CXCR3 donor cells significantly reduced the number of adoptively transferred cells that entered into the peritoneum of mertk−/− mice. This control of peritoneal cells numbers correlated with autoantibody production and was exclusively attributed to Mertk because mice lacking other family members, Axl or Tyro 3, did not display dysregulation in peritoneal cell numbers or the autoimmune phenotype.
The Differential Evolutionary Dynamics of Avian Cytokine and TLR Gene Classes
Authors: Downing Tim , Lloyd Andrew T. , O’Farrelly Cliona , Bradley Daniel G.
Published: May 2010

The potential for investigating immune gene diversity has been greatly enhanced by recent advances in sequencing power. In this study, variation at two categories of avian immune genes with differing functional roles, pathogen detection and mediation of immune mechanisms, was examined using high-throughput sequencing. TLRs identify and alert the immune system by detecting molecular motifs that are conserved among pathogenic microorganisms, whereas cytokines act as mediators of resulting inflammation and immunity. Nine genes from each class were resequenced in a panel of domestic chickens and wild jungle fowl (JF). Tests on population-wide genetic variation between the gene classes indicated that allele frequency spectra at each group were distinctive. TLRs showed evidence pointing toward directional selection, whereas cytokines had signals more suggestive of frequency-dependent selection. This difference persisted between the distributions considering only coding sites, suggesting functional relevance. The unique patterns of variation at each gene class may be constrained by their different functional roles in the immune response. TLRs identify a relatively limited number of exogeneous pathogenic-related patterns and would be required to adapt quickly in response to evolving novel microbes encountered in new environmental niches. In contrast, cytokines interact with many molecules in mediating the power of immune mechanisms, and accordingly respond to the selective stimuli of many infectious diseases. Analyses also indicated that a general pattern of high variability has been enhanced by widespread genetic exchange between chicken and red JF, and possibly between chicken and gray JF at TLR1LA and TLR2A.
CommensalEscherichia coliReduces Epithelial Apoptosis through IFN-αA–Mediated Induction of Guanylate Binding Protein-1 in Human and Murine Models of Developing Intestine
Authors: Mirpuri Julie , Brazil Jennifer C. , Berardinelli Andrew J. , Nasr Tala R. , Cooper Kiesha , Schnoor Michael , Lin Patricia W. , Parkos Charles A. , Louis Nancy A.
Published: May 2010

Appropriate microbial colonization protects the developing intestine by promoting epithelial barrier function and fostering mucosal tolerance to luminal bacteria. Commensal flora mediate their protective effects through TLR9-dependent activation of cytokines, such as type I IFNs (α, β) and IL-10. Although IFN-β promotes apoptosis, IFN-α activates specific antiapoptotic target genes whose actions preserve epithelial barrier integrity. We have recently identified guanylate binding protein-1 (GBP-1) as an antiapoptotic protein, regulated by both type I and type II IFNs, that promotes intestinal epithelial barrier integrity in mature intestine. However, the mechanisms by which commensal bacteria regulate epithelial apoptosis during colonization of immature intestine and the contributions of GBP-1 are unknown. The healthy newborn intestine is initially colonized with bacterial species present in the maternal gastrointestinal tract, including nonpathogenic Escherichia coli. Therefore, we examined the influence of commensal E. coli on cytokine expression and candidate mediators of apoptosis in preweaned mice. Specifically, enteral exposure of 2 wk-old mice to commensal E. coli for 24 h selectively increased both IFN-αA and GBP-1 mRNA expression and prevented staurosporine-induced epithelial apoptosis. Exogenous IFN-αA treatment also induced GBP-1 expression and protected against staurosporine-induced apoptosis in a GBP-1 dependent manner, both in vitro and ex vivo. These findings identify a role for IFN-αA–mediated GBP-1 expression in the prevention of intestinal epithelial apoptosis by commensal bacteria. Thus IFN-αA mediates the beneficial effects of commensal bacteria and may be a promising therapeutic target to promote barrier integrity and prevent the inappropriate inflammatory responses seen in developing intestine as in necrotizing enterocolitis.
Dendritic Cell-Directed CTLA-4 Engagement during Pancreatic β Cell Antigen Presentation Delays Type 1 Diabetes
Authors: Karumuthil-Melethil Subha , Perez Nicolas , Li Ruobing , Prabhakar Bellur S. , Holterman Mark J. , Vasu Chenthamarakshan
Published: May 2010

The levels of expression of alternatively spliced variants of CTLA-4 and insufficient CTLA-4 signaling have been implicated in type 1 diabetes. Hence, we hypothesized that increasing CTLA-4–specific ligand strength on autoantigen-presenting dendritic cells (DCs) can enhance ligation of CTLA-4 on T cells and lead to modulation of autoreactive T cell response. In this study, we show that DC-directed enhanced CTLA-4 engagement upon pancreatic β cell Ag presentation results in the suppression of autoreactive T cell response in NOD mice. The T cells from prediabetic NOD mice treated with an agonistic anti–CTLA-4 Ab-coated DC (anti–CTLA-4-Ab DC) showed significantly less proliferative response and enhanced IL-10 and TGF-β1 production upon exposure to β cell Ags. Furthermore, these mice showed increased frequency of Foxp3+ and IL-10+ T cells, less severe insulitis, and a significant delay in the onset of hyperglycemia compared with mice treated with control Ab-coated DCs. Further analyses showed that diabetogenic T cell function was modulated primarily through the induction of Foxp3 and IL-10 expression upon Ag presentation by anti–CTLA-4-Ab DCs. The induction of Foxp3 and IL-10 expression appeared to be a consequence of increased TGF-β1 production by T cells activated using anti–CTLA-4-Ab DCs, and this effect could be enhanced by the addition of exogenous IL-2 or TGF-β1. Collectively, this study demonstrates the potential of a DC-directed CTLA-4 engagement approach not only in treating autoimmunity in type 1 diabetes, but also in altering diabetogenic T cell function ex vivo for therapy.
High-Affinity B Cell Receptor Ligation by Cognate Antigen Induces Cytokine-Independent Isotype Switching
Authors: Turner Marian L. , Corcoran Lynn M. , Brink Robert , Hodgkin Philip D.
Published: May 2010

The selection of an appropriate Ig isotype is critical for an effective immune response against pathogens. Isotype regulation is sensitive to external signals, particularly cytokines secreted by Th cells. For example, IL-4 induces isotype switching to IgG1 via a STAT6-dependent signaling pathway. In this study, we show that BCR ligation also induces IgG1 switching in mouse B cells. The extent of switch induction by Ag is affinity-dependent, and high-affinity Ag binding leads to IgG1 switching levels comparable to those induced by saturating IL-4. However, the Ag-induced IgG1 switch does not require additional cytokine signals and occurs in a STAT6-independent manner. Thus, BCR ligation represents a novel pathway for direct isotype switching leading to IgG1 secretion.
Amphioxus SARM Involved in Neural Development May Function as a Suppressor of TLR Signaling
Authors: Yuan Shaochun , Wu Kui , Yang Manyi , Xu Liqun , Huang Ling , Liu Huiling , Tao Xin , Huang Shengfeng , Xu Anlong
Published: May 2010

Among five Toll/IL-1R resistance adaptors, sterile α and Toll/IL-1R resistance motif containing protein (SARM) is the only one conserved from Caenorhabditis elegans to human. However, its physiologic roles are hardly understood, and its involvement in TLR signaling remains debatable. In this study, we first demonstrated a predominant expression of amphioxus SARM (Branchiostoma belcheri tsingtauense SARM) in neural cells during embryogenesis and its predominant expression in the digestive system from larva to adult, suggesting its primitive role in neural development and a potential physiologic role in immunity. We further found that B. belcheri tsingtauense SARM was localized in mitochondria and could attenuate the TLR signaling via interacting with amphioxus MyD88 and tumor necrosis receptor associated factor 6. Thus, amphioxus SARM appears unique in that it may play dual functions in neural development and innate immunity by targeting amphioxus TLR signaling.
NK Cells Delay Allograft Rejection in Lymphopenic Hosts by Downregulating the Homeostatic Proliferation of CD8+ T Cells
Authors: Zecher Daniel , Li Qi , Oberbarnscheidt Martin H. , Demetris Anthony J. , Shlomchik Warren D. , Rothstein David M. , Lakkis Fadi G.
Published: May 2010

T cells present in lymphopenic environments undergo spontaneous (homeostatic) proliferation resulting in expansion of the memory T cell pool. Homeostatically generated memory T cells protect the host against infection but can cause autoimmunity and allograft rejection. Therefore, understanding the mechanisms that regulate homeostatic T cell proliferation is germane to clinical settings in which lymphodepletion is used. In this study, we asked whether NK cells, which regulate immune responses in lymphocyte-replete hosts, also regulate homeostatic T cell proliferation under lymphopenic conditions. We found that T cells transferred into genetically lymphocyte-deficient RAG−/− mice proliferate faster and generate more CD8+ memory T cells if NK cells were absent. CD8+ T cells that underwent homeostatic proliferation in the presence of NK cells generated mostly effector memory (CD44highCD62Llow) lymphocytes, whereas those that divided in the absence of NK cells were skewed toward central memory (CD44highCD62Lhigh). The latter originated predominantly from proliferation of the “natural” central memory CD8+ T cell pool. Regulation of homeostatic proliferation by NK cells occurred independent of perforin but was reversed by excess IL-15. Importantly, NK depletion enhanced CD8+ T cell recovery in T cell-depleted wild-type mice and accelerated rejection of skin allografts, indicating that regulation of homeostatic proliferation by NK cells is not restricted to genetically lymphocyte-deficient animals. These results demonstrate that NK cells downregulate homeostatic CD8+ T cell proliferation in lymphopenic environments by competing for IL-15. Concomitant NK and T cell depletion may be undesirable in transplant recipients because of enhanced expansion of memory CD8+ T cells that increase the risk of rejection.
Structural and Functional Insights of RANKL–RANK Interaction and Signaling
Authors: Liu Changzhen , Walter Thomas S. , Huang Peng , Zhang Shiqian , Zhu Xuekai , Wu Ying , Wedderburn Lucy R. , Tang Peifu , Owens Raymond J. , Stuart David I. , Ren Jingshan , Gao Bin
Published: May 2010

Bone remodeling involves bone resorption by osteoclasts and synthesis by osteoblasts and is tightly regulated by the receptor activator of the NF-κB ligand (RANKL)/receptor activator of the NF-κB (RANK)/osteoprotegerin molecular triad. RANKL, a member of the TNF superfamily, induces osteoclast differentiation, activation and survival upon interaction with its receptor RANK. The decoy receptor osteoprotegerin inhibits osteoclast formation by binding to RANKL. Imbalance in this molecular triad can result in diseases, including osteoporosis and rheumatoid arthritis. In this study, we report the crystal structures of unliganded RANK and its complex with RANKL and elucidation of critical residues for the function of the receptor pair. RANK represents the longest TNFR with four full cysteine-rich domains (CRDs) in which the CRD4 is stabilized by a sodium ion and a rigid linkage with CRD3. On association, RANK moves via a hinge region between the CRD2 and CRD3 to make close contact with RANKL; a significant structural change previously unseen in the engagement of TNFR superfamily 1A with its ligand. The high-affinity interaction between RANK and RANKL, maintained by continuous contact between the pair rather than the patched interaction commonly observed, is necessary for the function because a slightly reduced affinity induced by mutation produces significant disruption of osteoclast formation. The structures of RANK and RANKL–RANK complex and the biological data presented in the paper are essential for not only our understanding of the specific nature of the signaling mechanism and of disease-related mutations found in patients but also structure based drug design.
Distinct Roles for IL-2 and IL-15 in the Differentiation and Survival of CD8+ Effector and Memory T Cells
Authors: Mitchell Diana M. , Ravkov Eugene V. , Williams Matthew A.
Published: May 2010

IL-2 provides a memory differentiation signal to CD8+ T cells during the primary response that impacts the ability of the subsequent memory pool to mount a successful recall response. In this study, we find that although primary effector CTL development is modestly decreased in the absence of IL-2, the persistence of short-term and long-term effector memory CD8+ T cells on pathogen clearance is greatly diminished. Furthermore, secondary challenge of CD8+ memory T cells lacking the high-avidity IL-2R results in a failure to repopulate the effector pool. The role of IL-2 in promoting effector differentiation is not shared with the highly related cytokine, IL-15. Although IL-15 supports the survival of effector CD8+ T cells after pathogen clearance, its absence does not impair either primary or secondary effector CTL differentiation, nor does it impact the differentiation of long-term effector memory CD8+ T cells. These findings indicate a unique role for IL-2, but not IL-15, in promoting the differentiation not only of primary effector CD8+ T cells, but also of CD8+ memory T cells capable of secondary effector differentiation.
Human Neuronal Cells Possess Functional Cytoplasmic and TLR-Mediated Innate Immune Pathways Influenced by Phosphatidylinositol-3 Kinase Signaling
Authors: Peltier Daniel C. , Simms Allison , Farmer Jocelyn R. , Miller David J.
Published: May 2010

Innate immune pathways are early defense responses important for the immediate control and eventual clearance of many pathogens, where signaling is initiated via pattern recognition receptor (PRR)-mediated events that occur in a ligand- and cell-type specific manner. Within CNS neurons, innate immune pathways are likely crucial to control pathogens that target these essential yet virtually irreplaceable cells. However, relatively little is known about the induction and regulation of neuronal PRR signaling. In this report, we used human neuronal cell lines and primary rat neuronal cultures to examine PRR expression and function. We found that several innate immune receptor ligands, including Sendai virus, the dsRNA mimetic polyinosinic-polycytidylic acid, and LPS all activated differentiation-dependent neuronal innate immune pathways. Functional genetic analyses revealed that IFN regulatory factor 3-mediated pathways that resulted in IFN-β transcriptional upregulation were activated in cultured human neuronal cells by the PRRs TLR3, MDA5, or RIG-I in a ligand-specific manner. Furthermore, genome-wide transcriptional array and targeted genetic and pharmacologic analyses identified PI3K signaling as crucial for the induction of innate immune pathways in neurons. These results indicate that human neuronal cells possess specific and functional PRR pathways essential for the effective induction of innate immune responses, and suggest that neurons can play an active role in defense against neurotropic pathogens.
Impact of TCR Reactivity and HLA Phenotype on Naive CD8 T Cell Frequency in Humans
Authors: Legoux François , Debeaupuis Emilie , Echasserieau Klara , De La Salle Henri , Saulquin Xavier , Bonneville Marc
Published: May 2010

The impact of MHC phenotype on the shaping of the peripheral naive T cell repertoire in humans remains unknown. To address this, we compared the frequency and antigenic avidity of naive T cells specific for immunodominant self-, viral, and tumor Ags presented by a human MHC class I allele (HLA-A*02, referred to as A2) in individuals expressing or not this allele. Naive T cell frequencies varied from one Ag specificity to another but were restrained for a given specificity. Although A2-restricted T cells showed similar repertoire features and antigenic avidities in A2+ and A2− donors, A2 expression had either a positive, neutral, or negative impact on the frequency of A2-restricted naive CD8 T cells, depending on their fine specificity. We also identified in all donors CD4 T cells specific for A2/peptide complexes, whose frequencies were not affected by MHC class I expression, but nevertheless correlated with those of their naive CD8 T cell counterparts. Therefore, both selection by self-MHC and inherent TCR reactivity regulate the frequency of human naive T cell precursors. Moreover this study also suggests that T cell repertoire shaping by a given self-MHC allele is dispensable for generation of immunodominant T cell responses restricted by this particular allele.
Cytokine Requirements for the Differentiation and Expansion of IL-17A– and IL-22–Producing Human Vγ2Vδ2 T Cells
Authors: Ness-Schwickerath Kristin J. , Jin Chenggang , Morita Craig T.
Published: May 2010

Human γδ T cells expressing the Vγ2Vδ2 TCR play important roles in immune responses to microbial pathogens by monitoring prenyl pyrophosphate isoprenoid metabolites. Most adult Vγ2Vδ2 cells are memory cytotoxic cells that produce IFN-γ. Recently, murine γδ T cells were found to be major sources of IL-17A in antimicrobial and autoimmune responses. To determine if primate γδ T cells play similar roles, we characterized IL-17A and IL-22 production by Vγ2Vδ2 cells. IL-17A–producing memory Vγ2Vδ2 cells exist at low but significant frequencies in adult humans (1:2762 T cells) and at even higher frequencies in adult rhesus macaques. Higher levels of Vγ2Vδ2 cells produce IL-22 (1:1864 T cells), although few produce both IL-17A and IL-22. Unlike adult humans, in whom many IL-17A+ Vγ2Vδ2 cells also produce IFN-γ (Tγδ1/17), the majority of adult macaques IL-17A+ Vδ2 cells (Tγδ17) do not produce IFN-γ. To define the cytokine requirements for Tγδ17 cells, we stimulated human neonatal Vγ2Vδ2 cells with the bacterial Ag, (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate, and various cytokines and mAbs in vitro. We find that IL-6, IL-1β, and TGF-β are required to generate Tγδ17 cells in neonates, whereas Tγδ1/17 cells additionally required IL-23. In adults, memory Tγδ1/17 and Tγδ17 cells required IL-23, IL-1β, and TGF-β, but not IL-6. IL-22–producing cells showed similar requirements. Both neonatal and adult IL-17A+ Vγ2Vδ2 cells expressed elevated levels of retinoid-related orphan receptor γt. Our data suggest that, like Th17 αβ T cells, Vγ2Vδ2 T cells can be polarized into Tγδ17 and Tγδ1/17 populations with distinct cytokine requirements for their initial polarization and later maintenance.
A minimalist model of characteristic earthquakes
Authors: Vázquez-Prada M. , González Á. , Gómez J. B. , Pacheco A. F.
Published: May 2010

Abstract. In a spirit akin to the sandpile model of self-organized criticality, we present a simple statistical model of the cellular-automaton type which simulates the role of an asperity in the dynamics of a one-dimensional fault. This model produces an earthquake spectrum similar to the characteristic-earthquake behaviour of some seismic faults. This model, that has no parameter, is amenable to an algebraic description as a Markov Chain. This possibility illuminates some important results, obtained by Monte Carlo simulations, such as the earthquake size-frequency relation and the recurrence time of the characteristic earthquake.
B
achelier,
L
ouis (1870–1946)
Authors: Bru Bernard
Published: May 2010

In his thesis, “theory of speculation”, defended in 1900, Bachelier modeled the prices of stocks in the Paris stock market by a continuous random process, which he constructed and which has been known since then as
Brownian motion
. He could then calculate the prices of the major financial products of the Belle Epoque, and also, by introducing time and continuity to classical probability theory, he reinvigorated the field itself and anticipated the development of the theory of stochastic processes in the 1930s and decades thereafter.
S
amuelson,
P
aul
A
.
Authors: Merton Robert C.
Published: May 2010

Paul Samuelson's research contributions to quantitative finance have been foundational and wide‐ranging. He was a pioneer in recognizing the importance of option and warrant pricing to finance. His 1965 pricing model introduced geometric Brownian as the prototypical underlying stock price process, developed the partial differential equations for pricing that later produced the Black–Scholes formula, formulated and analyzed the pricing of options that permit early exercise, and introduced the binomial model approximation for geometric Brownian motion. Samuelson was the first to derive the martingale property of properly anticipated speculative price changes in formulating what has come to be known as the
efficient market hypothesis
. Some of his other contributions include reconciling the axioms of expected utility theory with the Markowitz–Tobin mean–variance criterion of choice, exploring the foundations of diversification and optimal portfolio selection with fat‐tailed, infinite‐variance return distributions, and using dynamic portfolio‐selection models to study the systematic dependence on age of optimal portfolio strategies, in particular, optimal long‐horizon investment strategies.
Mandelbrot, Benoit
Authors: Cont Rama
Published: May 2010

Benoit Mandelbrot, the founder of fractal geometry, has been, among numerous other contributions to fields ranging from mathematics to hydrology, an early contributor to the then‐nascent field of stochastic modeling in finance. Obsessed with the wild variability of financial market prices, he was the first to advocate the use of heavy‐tailed distributions and power laws, Lévy processes, and long‐range dependence for modeling market fluctuations.
Merton, Robert C.
Authors: Chan Alex Hamilton
Published: May 2010

Robert C. Merton is John and Natty McArthur University Professor at Harvard Business School. He shared the Nobel Prize in Economic Sciences in 1997. He introduced Ito calculus to finance and economics and made significant contributions in asset pricing, corporate finance, empirical finance, and financial systems. His most notable works include the intertemporal capital asset pricing model, the Black–Scholes–Merton option pricing formula, the Merton jump‐diffusion model, and the Merton structural model for credit risk.
Utility Theory: Historical Perspectives
Authors: Žitković Gordan
Published: May 2010

We present a short survey of the history of utility theory. Starting from the seminal idea of Daniel Bernoulli, we proceed to discuss the work of Herman Gossen and its importance for the “Marginalist revolution”. The next milestone is the advent of axiomatic approaches, starting with the work of Franz Alt, John von Neumann, and Oskar Morgenstern. Various critiques of the expected‐utility model are discussed. On the conceptual side, we mention the “Subjectivist revolution” lead by Leonard Savage, and, on the empirical side, we discuss the paradoxes of Maurice Allais and Daniel Ellsberg and their partial resolution in the work by Daniel Kahneman and Amos Tversky. Finally, we touch upon the concept of risk aversion and the place of utility theory in modern finance.
Option Pricing Theory: Historical Perspectives
Authors: Jarrow Robert A.
Published: May 2010

This article traces the history of the option pricing theory from the turn of the twentieth century to the present. This historical perspective is divided into four sections. The first, entitled “the early years”, discusses the development of option pricing theory before the Black–Scholes–Merton model (1973). The second section discusses the Black–Scholes–Merton model and its extensions. The third section discusses the Heath–Jarrow–Morton model for pricing interest rate derivatives. The last section discusses credit risk derivative pricing models.
Modern Portfolio Theory
Authors: French Craig W.
Published: May 2010

Although the prehistory of modern portfolio theory stretches back all the way to Bernoulli, the more proximate origins lie in the work of Markowitz and others in the 1950s. The discovery of the capital asset pricing model in the 1960s brought this line to intellectual maturity by embedding the portfolio choice problem in a proper asset‐pricing equilibrium framework. Subsequent work has been involved with extensions, refinements, and applications.
Long‐Term Capital Management
Authors: Rosenfeld Eric
Published: May 2010

The collapse of Long‐Term Capital Management in September 1998 served as an inflection point in the historical development of quantitative finance, both theoretical and applied. Their risk management system was state of the art, but the Russian financial crisis tested that system and found it wanting.
Bubbles and Crashes
Authors: Kaizoji Taisei , Sornette Didier
Published: May 2010

We review some of the hypotheses offered to explain the market crashes that often follow asset price bubbles. Starting from historical accounts and syntheses of past bubbles and crashes, we put the problem in perspective with respect to the development of the efficient‐market hypothesis. We then present the models based on heterogeneous agents and the limits to arbitrage that prevent rational agents from bursting bubbles before they inflate. Then, we explore another set of explanations of why rational traders would be led to actually profit from and surf on bubbles, by anticipating the behavior of noise traders or by realizing the difficulties in synchronizing their actions. We end by discussing a complex system approach, in which bubbles are the result of a collective emergent organization of human agents interaction through social imitation and herding. In this framework, the end of a bubble is modeled as a bifurcation (or phase transition), which offers new insights for diagnostic and prognostic. The key insight is that diagnosing bubbles may be feasible when the positive feedback mechanisms that give rise to transient “superexponential” price growth are taken into account.
Ross, Stephen
Authors: Mehrling Perry
Published: May 2010

The central focus of the work of Stephen Ross has been to tease out the consequences of the assumption that all riskless arbitrage opportunities have already been exploited and none remain. This principle of no arbitrage lies behind the fundamental theorem of asset pricing and the martingale equivalence theorem, the two central results of finance, as well as Ross's own arbitrage pricing theory.
Fisher, Irving
Authors: Dimand Robert W.
Published: May 2010

The American economist Irving Fisher (1867–1947) of Yale University introduced general equilibrium analysis into North American economics in his 1891 dissertation, and went on to become a leading monetary and capital theorist. The “Fisher equation” of hisAppreciation and Interest(1896) viewed nominal interest as the sum of real interest and expected inflation (which he later modeled as a distributed lag of price changes). The “Fisher diagram” ofThe Rate of Interest(1907) showed optimal consumption and saving in a two‐period model, the basis of all subsequent analyses of intertemporal allocation. Fisher'sThe Purchasing Power of Money(1911) restated the quantity theory of money, with monetary shocks driving output fluctuations in the short run but affecting only nominal variables in the long run. His 1926 paper correlating unemployment and a distributed lag of inflation was reprinted in 1973 as “Lost and Found: I Discovered the Phillips Curve—Irving Fisher.” The “Fisher index”, the geometric mean of the Paasche and Laspeyres indexes, is now widely used as an index number. Emphasizing that inflation makes money and bonds risky, Fisher was an enthusiast for investment in common stocks in the 1920s. He shattered his public reputation with his October 1929 statement that stock prices had reached a permanently high plateau.
Modigliani, Franco
Authors: Szenberg Michael , Ramrattan Lall
Published: May 2010

Franco Modigliani, the 1980 Nobel laureate, was a leader in Keynesian economics. He has moved Keynesian theory to the empirical forefront by constructing the first Federal Reserve Board macroeconometric model in the country. Modigliani has further expanded the Keynesian consumption function in the direction of his life cycle hypothesis (LCH), and the Keynesian investment function in the direction of the Modigliani and Miller (M&M) hypothesis, creating a research program for current economic analysis. A particular signature of Modigliani's Keynesian contribution is his specification of the financial sector as the driver of the Federal Reserve Board econometric model, in which he incorporated his lifetime research on liquidity preference.
Arrow, Kenneth
Authors: Chichilnisky Graciela
Published: May 2010

This article summarizes the theory of markets under uncertainty, developed by Arrow and Debreu. It describes the achievements of the theory, the critical issues that it raises, and its large legacy. This article also focuses on the way Arrow introduced securities: how he defined them and what were the most useful developments of this theory. It mentions the theory of insurance that Arrow pioneered together with Malinvaud and others, and Arrow's theory of risk bearing that follows the axiomatic treatment of Von Neumann and Morgenstern, Milnor, Hernstein, De Groot, and Villegas. In terms of Arrow's legacy, it is now known that the classic expected utility theory embraces normal or frequent risks at the expense of neglecting rare events, even those with important consequences such as catastrophes, causing paradoxical experimental behavior. Kenneth Arrow encouraged the creation of a more recent extension of classic axiomatic theory of choice under uncertainty, and, in the early 1990s, we proposed axioms that treat symmetrically frequent and rare events, leading to a new definition of rationality and of choices under uncertainty that conform better to the experimental evidence. The introduction of markets with “endogenous uncertainty” in the early 1990s extended and challenged the foundation of the Arrow–Debreu theory of markets by considering risks that are created by the workings of the economy, resulting in the breakdown of the equivalence between markets with and without uncertainty that prevails in the Arrow–Debreu theory. This led to a new world of uncertainty creation through financial innovation and regulation that is at the heart of the financial markets turmoil of 2008–2009. In 1999, Arrow himself contributed to the theory of endogenous uncertainty in his work with Frank Hahn.
Kolmogorov, Andrei Nikolaevich
Authors: Shiryaev Albert N.
Published: May 2010

Kolmogorov created many concepts and obtained fundamental results in practically all branches of mathematics—theory of probability, trigonometric series, mathematical logic, dynamical system, ergodic theory, information theory, and many others.
Bernoulli, Jacob
Authors: Sylla Edith Dudley
Published: May 2010

In
The Art of Conjecturing
(1713), Jacob Bernoulli aimed at applying the mathematics previously developed in Christiaan Huygens'
On Reckoning in Games of Chance
to civil, moral, and economic matters. Although most of the mathematics in Bernoulli's book derived from commercial arithmetic, algebra, and combinatorics, Jacob Bernoulli's greatest achievement in the book was to prove what was later called the
weak law of large numbers
. On the basis of this law, Bernoulli proposed that the probabilities of events could be discovered,
a posteriori
, from the results many times observed in similar situations.
Rubinstein, Edward Mark
Authors: Namvar Ethan
Published: May 2010

Mark Rubinstein has been described as a “brilliant scholar,” one who “marches to his own drumbeat,” and is known among colleagues as a risk taker and innovator. As an individual, Rubinstein is often characterized as intellectually fearless. He is known by many of his students as a sincere mentor who has extraordinary passion and intellect.

Having developed the binomial options model with Stephen A. Ross and John C. Cox, he revolutionized the way professionals value options. For this and earlier work on asset pricing models, he was elected President of the American Finance Association for 1993. Along with his colleagues Hayne E. Leland and John W. O'Brien, Rubinstein developed and commercialized the use of portfolio insurance, which was ultimately cited as one of the causes of the stock market crash of 1987, and his firm developed the first exchange‐traded fund in 1992. The International Association of Financial Engineers (IAFE) named him as the 1995 IAFE/SunGard Financial Engineer of the Year, making him the third winner after Robert Merton and Fischer Black.
Infinite Divisibility
Authors: Pérez‐Abreu Víctor
Published: May 2010

We define one‐dimensional infinite divisibility with emphasis on characteristic functions, stochastic integral representations, and classes of examples.
Ornstein–Uhlenbeck Processes
Authors: Pérez‐Abreu Víctor
Published: May 2010

We give brief information on one‐dimensional Gaussian and non‐Gaussian Ornstein–Uhlenbeck processes with emphasis on extensions and stationary properties.
Heavy Tails
Authors: Davis Richard A.
Published: May 2010

The log‐returns of most financial assets exhibit bursts of outlying observations that are characteristic of heavy tails. As such, models formulated for financial time series must capture heavy‐tailedness. Regular variation is a natural and often used concept to describe and model heavy‐tailed phenomena. This article first provides some evidence for heavy tails in log‐returns and then describes the basics of regular variation. It turns out that the two most commonly used models for financial time series, the GARCH and heavy‐tailed stochastic volatility (SV) processes, have finite‐dimensional distributions that are regularly varying. Regular variation is also a powerful tool for deriving large sample properties of important statistics of financial time series, from maxima to sample autocorrelations of functions of the process. These techniques show that although GARCH and SV processes share many common features, there can be a substantial difference in the large sample properties of the maxima and sample autocorrelations.