Serodiagnosis of Borreliosis: Indirect Immunofluorescence Assay, Enzyme-Linked Immunosorbent Assay and Immunoblotting
Iwona Wojciechowska-Koszko • Iwona Mączyńska • Zbigniew Szych • Stefania Giedrys-Kalemba
Abstract Lyme disease is an infectious, multi-system, tick-borne disease caused by genospecies of Borrelia burgdorferi bacteria sensu lato, characterized by remarkable heterogeneity. In this situation choosing an optimal antigen array for diagnostic tests seems problematic. The serological tests for borrelia routinely done in laboratories often produce ambiguous results, which makes a proper diagnosis rather complicated and thus delays the implementation of an appropriate treatment regimen. Thirtyseven outpatients and eight inpatients with suspected borreliosis diagnosis hospitalized at the Clinics of the Pomeranian Medical University (Szczecin, Poland), participated in the study. In order to detect the antibodies against Borrelia sensu lato three kinds of serological tests were used: indirect immunofluorescence assay (IIFA), enzyme-linked immunosorbent assay (ELISA), and immunoblot. The IIFA and immunoblot tests conducted on 45 patients (100%) produced positive results for both the IgM and IgG antibody types. In the case of ELISA, positive or borderline results were observed in only 24 patients (53.3%). The immunoblot test for IgM most frequently detected antibodies against the outer surface protein C (OspC) antigen (p25), and, in the case of IgG, against the recombinant variable surface antigen (VlsE). The IIFA screening test used for diagnosing Lyme borreliosis produced the highest percentage of positive results, which were then confirmed by immunoblot, but not by ELISA. Therefore using only ELISA as a screening test or for diagnosing Lyme borreliosis seems debatable.
Keywords Lyme borreliosis ELISA IIFA Immunoblot VlsE protein OspC protein
Relapse of Acute Lymphoblastic Leukemia in Children in the Context of Microarray Analyses
Joanna Szczepanek • Jan Styczyński • Olga Haus • Andrzej Tretyn • Mariusz Wysocki
Abstract Over the last four decades the treatment of patients with newly diagnosed childhood acute lymphoblastic leukemia (ALL) has improved remarkably. However, still about 20% of children with ALL relapse despite risk-adapted polychemotherapy. The prognosis of relapsed ALL is relatively poor, even with modern aggressive chemotherapy. Identification of the biological and genetic mechanisms contributing to recurrence in patients with ALL is critical for the development of effective therapeutic strategies to treat refractory leukemic patients. Allogeneic hematopoietic stem-cell transplantation is the treatment of choice for many children with relapsed ALL. The gene expression profile obtained by microarray technology could provide important determinants of the drug response and clinical outcome in childhood ALL. Incorporation of the data on expression levels of newly identified genes into existing strategies of risk stratification might improve clinical management. Current microarray data show correlation of in vitro drug resistance with significant patterns of gene expression and explain clinical differences between early and late relapse. Genes involved in cell proliferation, self-renewal and differentiation, protein biosynthesis, carbohydrate metabolism, and DNA replication and repair are usually among those highly expressed in relapsed lymphoblasts. Current status and future perspectives of microarray data on gene expression and drug resistance profile in relapsed pediatric ALL are discussed in this review.
Keywords Gene expression profile Copy number abnormalities Microarray Children Acute lymphoblastic leukemia Relapse
CD46 Plasticity and Its Inflammatory Bias in Multiple Sclerosis
Siobhan Ni Choileain • Anne L. Astier
Abstract Known as a link to the adaptive immune system, a complement regulator, a ‘‘pathogen magnet’’ and more recently as an inducer of autophagy, CD46 is the human receptor that refuses to be put in a box. This review summarizes the current roles of CD46 during immune responses and highlights the role of CD46 as both a promoter and attenuator of the immune response. In patients with multiple sclerosis (MS), CD46 responses are over-whelmingly pro-inflammatory with notable defects in cytokine and chemokine production. Understanding the role of CD46 as an inflammatory regulator is a distant goal considering the darkness in which its regulatory mechanisms reside. Further research into the regulation of CD46 expression through its internalization and processing will undoubtedly extend our knowledge of how the balance is tipped in favor of inflammation in MS patients.
Keywords CD46 Multiple sclerosis T cell Regulation
Tuning of CD40–CD154 Interactions in Human B-Lymphocyte Activation: A Broad Array of In Vitro Models for a Complex In Vivo Situation
Sonia Ne´ron • Philippe J. Nadeau • Andre´ Darveau • Jean-Franc¸ois Leblanc
Abstract Naive and memory B-lymphocyte populations can be activated through the binding of CD154 to CD40, a receptor that is constitutively expressed on the surface of these cells. Models based on the in vitro stimulation of human B lymphocytes through CD40 have greatly contributed to our understanding of the human immune response in healthy individuals and patients suffering from immune disorders. The nature of the engineered CD40 ligands is as diverse as the in vitro models used in studies of CD40-activated B lymphocytes. Monoclonal anti-CD40 antibodies, recombinant CD154 proteins, soluble CD154? membranes as well as CD154? cell lines have turned out to be very useful tools, and are still in use today. As for any receptor–ligand interaction, parameters such as duration and strength of contact, timing, affinity, and receptor density are major determinants of CD40 binding by CD154 or anti-CD40. Furthermore, variation in the intensity of CD40 stimulation has been shown to influence proliferation, differentiation and immunoglobulin secretion of human hybridomas, B-cell lines, tonsil and blood B lymphocytes. The objective of this review is to present an overview of the great diversity of CD40 agonists used in in vitro models of B-lymphocyte activation, with a particular emphasis on variations in the resulting strength of CD40 signaling generated by these models. A better understanding of these models could open up new avenues for the rational use of human B lymphocytes as antigen-presenting cells in cellular therapies.
Keywords CD40–CD154 intensity B lymphocytes In vitro models
Antiviral Signaling Through Retinoic Acid-Inducible Gene-I-Like Receptors
Tomoh Matsumiya • Tadaatsu Imaizumi • Hidemi Yoshida • Kei Satoh
Abstract The innate immune system is essential for the first line of host defense against micropathogens. In virus-infected cells, exposed viral nucleotides are sensed by pattern recognition receptors (PRRs), resulting in the induction of type I interferon. Retinoic acid-inducible gene-I-like receptors (RLRs) are a member of PRRs and are known to be crucial molecules in innate immune responses. Upon viral recognition, RLRs recruit their specific adaptor molecules, leading to the activation of antiviral signaling molecules including interferon regulatory factor-3 and nuclear factor-jB. Mitochondrial antiviral signaling (MAVS) protein is also known as one of the adaptor molecules responsible for antiviral signaling triggered by RLRs. Recent reports have identified numerous intracellular molecules involved in the antiviral responses mediated by RLRs/MAVS. Several viral proteins interfere with the RLR/MAVS signaling, allowing the virus to evade the host defense. In this review, we comprehensively update RLR-dependent antiviral signaling with special reference to the RLRs/MAVS-mediated responses.
Keywords Innate immunity RLRs MAVS
Dual Peripheral Actions of Immune Cells in Neuropathic Pain
Halina Machelska
Abstract Ability to perceive physiological pain is essential in protecting the individual from tissue destruction. In contrast, pathological chronic pain is an expression of maladaptive alterations outlasting its biological usefulness. In such conditions even eating, speaking or wearing clothes might be painful, as in neuropathic pain. Such pain is caused by diseases or injuries affecting nerves (e.g. diabetes, trigeminal neuralgia or amputation). Neuropathic pain is not an exclusive neuronal phenomenon but also involves immune responses. Damaged peripheral nerves are infiltrated by mast cells, granulocytes, macrophages and T lymphocytes. It is widely emphasized that these cells, via secretion of inflammatory mediators (e.g. proin-flammatory cytokines, chemokines), contribute to the generation of neuropathic pain. However, leukocytes are also a source of analgesic mediators such as anti-inflam-matory cytokines and opioid peptides. Recent findings indicate that immune cell-derived opioid peptides can interact with opioid receptors in the injured nerves and ameliorate neuropathic pain. Targeting opioid-containing immune cells might represent a new disease-modifying approach based on the use of beneficial effects of neuroinflammation in painful neuropathies. This review analyzes both detrimental and advantageous actions of leukocytes at peripheral nerves in neuropathic pain.
Keywords Analgesia Cytokines Inflammation Leukocytes Nerve injury Opioids
Legal and Ethical Aspects of Ghostwriting in Medicine
Agata Wnukiewicz-Kozłowska
Abstract Ghostwriting in medicine represents a highly significant problem in both legal and ethical terms, and particularly in recent years owing to a sudden increase in the practice. The main goal in this paper is to present the legal and ethical rules connected with the ghostwriting phenomenon. The problem is presented in the context of international, European and Polish law. From a legal perspective the issues bound up with ghostwriting are those of the notion and authorship of a work, authors’ rights (both moral rights and copyright), the content of these rights and their nature, as well as the question of the transfer of such rights. From the point of view of ethics there arises a need for reflection on honesty, accuracy and credibility as defined both generally and scientifically.
Keywords Ghostwriting Authors’ rights (copyright and moral rights) Transfer of authors’ rights
Validation of Basophil CD164 Upregulation for Pollen Allergy Diagnosis
Anna Wolanczyk-Medrala • Wojciech Barg • Jerzy Liebhart • Bernard Panaszek • Grazyna Nadobna • Marta Litwa • Grzegorz Gogolewski • Wojciech Medrala
Abstract The aim of the study was to evaluate the sensitivity and specificity of allergen-induced basophil CD164 upregulation in patients with seasonal allergic rhinitis caused by allergy to grass pollens. This study was performed in 24 patients with allergy to grass pollens, and in 25 healthy controls. The protocol for allergen-induced basophil CD164 upregulation consisted of whole blood samples processing and staining with anti-CCR3/anti-CD164 antibodies added to a buffer at the beginning of stimulation. We observed dose-dependent allergen-induced basophil CD164 upregulation with 100% of specificity in both used allergen concentrations (12 and 1.2 ng/ml). Higher allergen concentration resulted in 100% and lower concentration in only 70.83% sensitivity. We have observed in the patients statistically significant correlations between anti-IgE stimulation and both allergen concentrations (for 12 ng/ml, r = 0.71, p \ 0.0001; and for 1.2 ng/ml, r = 0.64, p \ 0.001). We conclude that assessment of allergen-induced basophil CD164 upregulation is a very useful method for in vitro determination of allergy to grass pollens. This method seems to be a very promising tool in laboratory testing of allergies to other allergens.
Keywords Allergy Basophil CD164 Flow cytometry Basophil activation test
How do Tumors Actively Escape from Host Immunosurveillance?
Jacek R. Wilczyn´ ski • Markus Duechler
Abstract The immunological background for the process of tumor growth is still obscure. However, our understanding of what happens could have important consequences, namely in the context of cancer immunotherapy. A tumor is able to grow in the host environment either because it is recognizable as normal tissue and tolerated by host immune cells, or because it can ‘‘escape’’ from host immunosur- veillance. According to the second option the mechanisms of tumor recognition and consequent destruction are actively disturbed by such processes as: change of tumor immuno- genicity, production of tumor-derived regulatory molecules, and interaction of cancer cells with tumor-infiltrating immune cells. The results of studies devoted to the problem of immunoregulation in the tumor environment seem to support the ‘‘escape’’ hypothesis.
Keywords Tumor Immunosurveillance Immunoediting
The Center of Accessibility: Db Control of V(D)J Recombination
Michael L. Sikes • Ruth E. McMillan • Justin M. Bradshaw
Abstract Developmental patterning of antigen receptor gene assembly in lymphocyte precursors correlates with decondensation of the chromatin surrounding individual gene segments. Ongoing V(D)J recombination is associated with hyperacetylation of histones H3 and H4 and the expression of sterile germline transcripts across the region of recombinational accessibility. Likewise, histone acetyl-transferase and SWI/SNF chromatin remodeling complexes each appear to be required for recombination, and the PHD-finger of RAG-2 preferentially associates with recombination signal sequence (RSS) chromatin that contains H3 trimethylated on lysine 4. However, the regulatory mechanisms that direct chromatin alteration and rear-rangement have proven elusive, due in large part to the interdependency of individual stages in gene activation, our limited understanding of functional significance of changes to the histone code, and the difficulty of modeling recombinational accessibility in existing experimental systems. Examining Tcrb assembly in developing thymocytes, we review the central roles of RSS elements and germline promoters as foci for epigenetic reorganization of recombinationally accessible gene segments in light of recent findings and persistent questions.
Keywords T cell receptor Tcrb Transcription V(D)J recombination Thymocytes Double negative
Dysregulation of Thymic Clonal Deletion and the Escape of Autoreactive T Cells
Charles J. Kroger • Rafael R. Flores • Maurice Morillon • Bo Wang • Roland Tisch
Abstract Events ongoing in the thymus are critical for deleting developing thymocytes specific for tissue antigens, and establishing self-tolerance within the T cell compart- ment. Aberrant thymic negative selection, however, is believed to generate a repertoire with increased self-reac- tivity, which in turn can contribute to the development of T cell-mediated autoimmunity. In this review, mechanisms that regulate the efficacy of negative selection and influ- ence the deletion of autoreactive thymocytes will be discussed.
Keywords Antigen-presenting cells Autoimmunity Central tolerance Thymocytes
Flaws in the Medical Literature: Who’s to Blame?
Jerome P. Kassirer
Interleukin-27: Biological Properties and Clinical Application
Marek Jankowski • Piotr Kopiński • Anna Goc
Abstract Interleukin (IL)-27 is a novel cytokine secreted by stimulated antigen-presenting cells. Initial studies on the biology of IL-27 provided evidence for its role in the initiation of TH1 responses; however, subsequent work has indicated that IL-27 has broad inhibitory effects on TH1, TH2, and TH17 subsets of T cells as well as the expansion of inducible regulatory T cells. The involvement of IL-27 in the regulation of angiogenesis and antiviral response has also recently been reported. The aim of this review is to highlight the potential areas of IL-27 clinical application, especially the management of neoplastic and viral diseases as well as autoimmune disorders, including rheumatoid arthritis and multiple sclerosis. The review will also serve to elaborate on the molecular mechanisms involved in the expression of this cytokine and signaling from the IL-27 receptor.
Keywords IL-27 Cancer Multiple sclerosis Rheumatoid arthritis HIV Immunotherapy
Tumor-Resident CD8+ T-cell: The Critical Catalyst in IL-12-Mediated Reversal of Tumor Immune Suppression
Nejat K. Egilmez • Mehmet O. Kilinc
Abstract Tumor-resident T cells display a functionally impaired effector/memory (Tem) phenotype. Sustained intratumoral administration of IL-12, on the other hand, can restore cytolytic function to pre-existing CD8? Tem, resulting in effective tumor kill. Whereas cytotoxic T lymphocytes (CTL) are generally assumed to mediate tumor regression via direct tumor cytotoxicity, recent work revealed that activated CD8? Tem mobilize a systemic, multi-component effector cascade that includes both innate and adaptive immune mechanisms. Here we summarize these mechanisms, review how tumor-resident CD8? Tem orchestrate this cascade and discuss the potential clinical implications of these findings.
Keywords Tumor microenvironment Immune therapy CD8? T cells Immune suppression IL-12
Detection of b-Herpesviruses in Polish Adult Cord Blood Stem Cell Recipients by Real-Time PCR: Single Centre Study
Tomasz Dzieciątkowski • Maciej Przybylski • Grzegorz Władysław Basak • Tigran Torosian • Agnieszka Tomaszewska • Wiesław Wiktor Jędrzejczak • Grazyna Młynarczyk
Abstract Umbilical cord blood transplantation (UCBT) is known to be associated with increased risk of infections, compared to bone marrow or peripheral blood stem cell transplantation. In viral diseases for which specific treatment is available, real-time PCR assays are reliable diagnostic tools for timely initiation of appropriate therapy and for rapid assessment of the efficacy of antiviral treatment strategies. A retrospective review of samples from a group of seven adult cord blood stem cell recipients was made. Serum samples taken up to 180 days after transplantation were examined with quantitative real-time PCR for measurement of viral load (CMV, HHV-6, and HHV-7). Cytomegalovirus (CMV) DNA was detected in samples taken from four patients (57%) in the period of 20–80 days after transplantation. Products of amplification of human herpesvirus 6 (HHV-6) DNA were found in samples taken between days 25 and 37 following UCBT from only one patient (14%). On the other hand, the majority of patients (n = 6, 86%) had HHV-7 DNA detected in the period 15–58 days after transplantation. Co-infection with HHV-7 was demonstrated at onset of all episodes of microbiolog- ically confirmed CMV or HHV-6 infection. Our obser- vations indicate that real-time PCR is not only useful for monitoring herpesviral infections in transplant recipients, but is also a powerful method for clarifying the relation- ships between the viral load and clinical symptoms. Further investigation with a much larger group of patients will be needed to confirm these observations and translate them into a clinical approach.
Keywords Umbilical cord blood transplantation Post-transplant infections Herpesviruses Real-time PCR
Iron and Immunity: Immunological Consequencesof Iron Deficiency and Overload
Bobby J. Cherayil
Abstract The influence of iron on immune function has been long appreciated. However, the molecular basis for this interaction is less well understood. Recently, there have been several important advances that have shed light on the mechanisms that regulate mammalian iron metabolism. The new insights provide a conceptual framework for understanding and manipulating the cross-talk between iron homeostasis and the immune system. This article will review what is currently known about how disturbances of iron metabolism can affect immunity and how activation of the immune system can lead to alterations in iron balance.
Keywords Iron Metabolism Macrophage Inflammation Lymphocyte
Autoimmune Versus Oligodendrogliopathy: The Pathogenesis of Multiple Sclerosis
Jin Nakahara • Sadakazu Aiso • Norihiro Suzuki
Abstract Multiple sclerosis (MS) is the most common inflammatory demyelinating disease of the central nervous system (CNS); it affect millions of patients worldwide and the number of patients is on the rise. Current treatment options are fairly limited and there is a strong unmet need for disease-targeted therapies for MS. The most widely accepted hypothesis for the pathogenesis of MS is that it is a primary autoimmune disease in which myelin-specific T cells play a central role in the progression of demyelination. According to this hypothesis, a powerful immune suppression or a reconstruction of the immune system to abrogate disease-specific leukocytes early in the development of the disease is expected to halt or even reverse the disease, since remyelination is an exceptionally efficient regenerative process in the CNS. However, recent neuro-pathological studies have provided evidence of primary oligodendrogliopathy as a cause of demyelination, suggesting that immune reactions may be a mere secondary event in the course of MS. On the other hand, some recent clinical trial results of new immune-suppressive treatments showed a nearly complete blockade of relapses and significant, albeit incomplete, neurological improvement. Therefore, which hypothesis—autoimmunity or oligoden- drogliopathy—lights the correct path to a ‘‘cure’’ for MS?
Keywords Multiple sclerosis Pathogenesis Autoimmune Oligodendrogliopathy
Monocyte and Macrophage Abnormalities in Systemic Lupus Erythematosus
Yi Li • Pui Y. Lee • Westley H. Reeves
Abstract Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with profound effects on multiple organ systems. In patients with SLE, the immune system is subverted to target numerous self antigens and the ensuing inflammatory response elicits a vicious cycle of immune-cell activation and tissue damage. Both genetic and environmental factors are essential for the develop- ment of this debilitating condition, although the exact cause remains unclear. Early studies on the pathogenesis of lupus centered on the adaptive immune system as lym- phocyte abnormalities were thought to be the primary cause of autoimmunity. In the past decade, however, this paradigm has shifted with rapid advances in the field of innate immunity. These developments have yielded important insights into how the autoimmune response in SLE is initiated and maintained. Monocytes and macro- phages are an essential arm of the innate immune system with a multitude of immunological functions, including antigen presentation, phagocytosis, and cytokine produc-tion. Aberrations of monocyte/macrophage phenotype and function are increasingly recognized in SLE and animal models of the disease. In this review we summarize the current knowledge of monocyte/macrophage abnormalities in human SLE and discuss their implications for under-standing the pathogenesis of lupus.
Keywords Systemic lupus erythematosus Monocytes
Macrophages
Polymorphisms in the Genes Encoding TGF-b1, TNF-a, and IL-6 Show Association with Type 1 Diabetes Mellitus in the Slovak Population
Juraj Javor • Stanislav Ferencik • Maria Bucova • Martina Stuchlikova • Emil Martinka • Lubomir Barak • Lujza Strbova • Hans Grosse-Wilde • Milan Buc
Abstract Numerous cytokines have been shown to par- ticipate in the pathogenesis of type 1 diabetes (T1D). As gene polymorphisms can influence cytokine production or function, they may potentially contribute to genetic predis- position to the disease. The aim of this study was therefore to investigate the role of 22 single nucleotide polymorphisms (SNPs) in 13 cytokine and cytokine receptor genes in genetic susceptibility to T1D. Polymerase chain reaction with sequence-specific primers was used to genotype cytokine SNPs and HLA-DRB1 alleles in 151 diabetics and 140 healthy individuals of Slovak origin. Univariate analysis showed that transforming growth factor (TGF)-b1 codon 10 TT homozygotes were significantly more susceptible to developing T1D than C allele carriers (Pc = 0.0066, OR = 2.46). Furthermore, tumor necrosis factor (TNF)-a –308 A allele carriers were also significantly overrepresented among the diabetics (Pc = 0.0031, OR = 2.62); however, the association of the –308 A allele with T1D might be due to its strong linkage disequilibrium with the susceptibility allele HLA-DRB1*0301. An association was also found with interleukin (IL)-6 –174 G/C and nt565 G/A SNPs; however, its significance was lost when statistical correction was applied. These data suggest that the TGF-b1 codon 10 SNP is among numerous genetic variations with small individual effects on T1D development. Moreover, a possible role of TNF-a and IL-6 SNPs cannot be ruled out, although their association with T1D was due to strong LD with the HLA class II susceptibility allele or did not with-stand statistical correction, respectively.
Keywords Cytokines Interleukin-6 Single nucleotide polymorphisms Transforming growth factor-b1 Tumor necrosis factor-a Type 1 diabetes
Genetic Modification of T Cells Improves the Effectiveness of Adoptive Tumor Immunotherapy
Marek Jakóbisiak • Jakub Gołąb
Abstract Appropriate combinations of immunotherapy and gene therapy promise to be more effective in the treat- ment of cancer patients than either of these therapeutic approaches alone. One such treatment is based on the appli- cation of patients’ cytotoxic T cells, which can be activated, expanded, and genetically engineered to recognize particular tumor-associated antigens (TAAs). Because T cells recog- nizing TAAs might become unresponsive in the process of tumor development as a result of tumor evasion strategies, immunogenic viral antigens or alloantigens could be used for the expansion of cytotoxic T cells and then redirected through genetic engineering. This therapeutic approach has already demonstrated promising results in melanoma patients and could be used in the treatment of many other tumors. The graft-versus-leukemia, or more generally graft-versus-tumor, reaction based on the application of a donor lymphocyte infusion can also be ameliorated through the incorporation of suicide genes into donor lymphocytes. Such lymphocytes could be safely and more extensively used in tumor patients because they could be eliminated should a severe graft-ver- sus-host reaction develop.
Keywords Adoptive tumor immunotherapy Gene therapy Graft-versus-tumor
Rebalancing Immune Specificity and Function in Cancer by T-Cell Receptor Gene Therapy
Akshata Udyavar • Terrence L. Geiger
Abstract Adoptive immunotherapy with tumor-specific T lymphocytes has demonstrated clinical benefit in some cancers, particularly melanoma. Yet isolating and expanding tumor-specific cells from patients is challenging and there is limited ability to control T-cell affinity and response characteristics. T-cell receptor (TCR) gene ther- apy, in which T lymphocytes for immunotherapy are redirected using an introduced rearranged TCR, has emerged as an important alternative. Successful TCR gene therapy requires consideration of a number of issues, including TCR specificity and affinity, optimal gene ther- apy constructs, types of T cells administered, and the survival and activity of the modified cells. In this review we highlight the rationale for and experience with TCR gene therapy as well as new approaches to enhancing it.
Keywords T-cell receptor Adoptive immunotherapy Cancer Gene therapy
Antimicrobial Peptides in the Brain
Yanhua Su • Kai Zhang • Hermann J. Schluesener
Abstract Antimicrobial peptides (AMPs) are an evolutionarily conserved component of the innate immune system of many species. The brain is an immunologically privileged organ but can produce a robust immune response against pathogens and cell debris, promoting rapid and efficient clearance. AMPs may be critically involved in the innate immune system of the brain. Though the mechanisms of AMPs’ action in the brain still need further elucidation, many studies have shown that AMPs are multifunctional molecules in the brain. In addition to antimicrobial action, they take part in congenital and adaptive immune reactions (immunoregulation), function as signaling molecules in tissue repair, inflammation and other important processes through different mechanisms, and they might, in addition, become diagnostic markers of brain disease.
Keywords Antimicrobial peptides Brain Antimicrobial activity Immunomodulatory activity Signaling molecules
Biological Factors Involved in Implant-Anchored Orthodontics and in Prosthetic-Implant Therapy: A Literature Review
Joanna Antoszewska • Katarzyna Raftowicz-Wójcik • Beata Kawala • Teresa Matthews-Brzozowska
Abstract During the past few years, the application of orthodontic miniscrews and dental implants has been expanded. However, failures have necessitated ongoing investigation of potential risk factors. The aim of this overview was to conduct an assessment of the immuno- logical response following application of cortical temporary anchorage devices—titanium miniscrew implants—in orthodontic patients. A scrupulous search of the database revealed only two matching items; therefore studies eval- uating the immune response subsequent to insertion of dental implants were reviewed. Thorough assessment revealed the following as factors associated with dental implant rejection: (1) correlation of the volume of gingival and peri-implant crevicular fluid and the amount of inter- leukin (IL)-1b with mucosal inflammation, thus serving as a peri-implantitis evaluation index; (2) significantly more frequent marginal bone loss around implants in patients with IL-1B-511 2/2 genotype; (3) humoral response to Staphylococcus aureus. However, since there is almost no evidence-based evaluation of the allergic/inflammatory reaction either to orthodontic titanium miniscrews them- selves or in adolescents and young adults, who comprise the largest group of orthodontic patients, this issue requires further investigation. It is essential in order to achieve successful, sophisticated and modern treatment of malocclusions.
Keywords Orthodontics Miniscrew implants Immunological response
The Incidence and Significance of Pattern-Recognition Receptors in Chronic Viral Hepatitis Types B and C in Man
Iwona Mozer-Lisewska • Jan Sikora • Arleta Kowala-Piaskowska • Mariusz Kaczmarek • Grzegorz Dworacki • Jan Żeromski
Abstract Chronic viral hepatitis B and C are among the most common and devastating liver diseases worldwide. Immune response plays a crucial role in the course of both diseases. In spite of the importance of the adaptive arm of the immune response, there is a growing role of innate immunity, the earliest confronted with viral attack. Pattern- recognition receptors (PRRs) and, in particular, Toll-like receptors (TLRs) are molecules which are able not only to recognize foreign invaders, but also quickly mount an antiviral defense. Activation of PRRs has been demon- strated in both hepatitis types, i.e. in situ in the liver and on while blood cells. Both viruses, HCV and HBV, are able to subvert the PRR-mediated antiviral response by means of various proteins and enzymes. HCV acts via the non- structural proteins NS2 and NS3/4A, while HBV HBeAg is inversely correlated with TLR activity. Viral counterattack is particularly directed toward dendritic cells, those creating the link with the adaptive immune response. Apart from TLRs, other PRRs such as RIG-1 and MDA-5 are also able to recognize viral infection and participate in the activation of type I interferon synthesis. TLRs manifest gene polymorphism, which was shown to affect several consequences associated with chronic viral hepatitis such as liver cirrhosis and the outcome of liver allotransplanta- tion. There have been numerous attempts to take advantage of the existence and activity of PRRs for the patients’ benefit. Several authors examined the role of TLR synthetic agonists as inducers of TLR activation. In hepatitis C the most promising agonists appear to be TLR3, 7, and 9 for potential antiviral therapy. PRRs may also act as potent adjuvants in HBV vaccines. Their baseline mRNA levels may have predictive value in the course of antiviral therapy.
Keywords Innate immunity Pattern recognition receptors Viral hepatitis
Human Mast Cells and Mastocytosis: Harnessing MicroRNA Expression as a New Approach to Therapy?
Lorenzo Deho’ • Silvia Monticelli
Abstract MicroRNAs (miRNAs) are short, non-coding RNAs that have emerged as key post-transcriptional regula- tors in a wide variety of organisms and critical cellular processes. Because any one miRNA can regulate the expres- sion of a distinct set of genes, differential miRNA expression can shape the repertoire of proteins that are actually expressed during development, differentiation, or disease. To understand what goes wrong when a cell becomes transformed requires knowledge of the processes that ensure normal development. It is now clear that miRNAs may act as oncogenes and/or tumor suppressors within gene regulatory networks, thereby contributing to the development of cancer. Mast cells are long- lived cells, widely distributed throughout vascularized tissues, in particular near surfaces that are exposed to the environment (such as skin, airways, and the gastrointestinal tract), where they contribute to bacterial clearance, enhancement of adap- tive immune responses, modulation of inflammation, and the degradation of toxic peptides and venoms. Here we review current knowledge in the field of mast-cell differentiation and disease in humans and mice and discuss future directions and links between mast-cell differentiation, oncogenic transfor- mation, and microRNAs as well as possible new points of entry for therapeutic intervention.
Keywords Mast cells MicroRNA Mastocytosis Gene regulation Disease
Intercellular Exchange of Surface Molecules and its Physiological Relevance
Kathryn Brown • Mehmet Fidanboylu • Wilson Wong
Abstract For many decades, cellular immunologists have relied on the expression of various cell surface molecules to divide cells into different types and subtypes to study their function. However, in recent years, a large and fast- expanding body of work has described the transfer of surface molecules, including MHC class I and II mole- cules, between cells, both in vitro and in vivo. The function of this process is still largely unknown, but it is likely to have a significant role in the control of the immune system. It is also likely that this process takes place in a regulated rather than stochastic manner, thus providing another way for the immune system to orchestrate its function. In this review we will summarize the key findings so far, exam- ining the mechanisms of transfer, the consequences of this transfer as shown by in vitro experiments, and possible consequences for the wider immune response.
Keywords Intercellular transfer MHC Antigen presentation
Immunomodulatory Effects of IFN-b and Lovastatin on Immunophenotype of Monocyte-Derived Dendritic Cells in Multiple Sclerosis
Halina Bartosik-Psujek • Jacek Tabarkiewicz • Krystyna Pocinska • Sebastian Radej • Zbigniew Stelmasiak • Jacek Rolinski
Abstract Multiple sclerosis (MS) is an autoimmune disease of the central nervous system and current MS treatment is only partially effective. Recent data suggest that statins may be potent immunomodulatory agents. In order to evaluate their role in MS, we analyzed the in vitro effects of interferon (IFN)-b and lovastatin on the differ- entiation and maturation of monocyte-derived dendritic cells (DCs) of MS patients. Twenty-seven patients with relapsing–remitting MS were recruited for the study. DC differentiation and maturation were evaluated based on surface phenotypic changes and the expressions of CD14, CD83, CD1a, CD80, CD86, CD206, and C209 were ana- lyzed by flow cytometry. The results showed that IFN-b and lovastatin affect DC phenotype. Both agents decrease the expression of CD1a, which indicates a weakened pre- sentation of glycolipid antigens. IFN-b causes up-regulated and lovastatin down-regulated expression of CD86, which results in a biased Th-cell responses in MS. Furthermore, high doses of lovastatin cause a decrease in CD209 expression on the surface of DCs and can limit their migration to various tissues. One of the mechanisms of the beneficial action of IFN-b and statins may be associated with their influence on DCs.
Keywords Dendritic cells Interferon beta Lovastatin Multiple sclerosis
Hypoxia-inducible Factor 1 as one of the ‘‘Signaling Drivers’’ of Toll-like Receptor-Dependent and Allergic Inflammation
Vadim V. Sumbayev • Sally A. Nicholas
Abstract Hypoxia-inducible factor 1 (HIF-1) is a hete- rodimeric transcription complex which plays a crucial role in cellular adaptation to low oxygen availability. In the last years there has been increasing evidence about the role of this factor in inflammatory/innate immune reactions. It has also been found to contribute to different types of allergic inflammation. In this review the current knowledge about the accumulation and role of HIF-1 in Toll-like receptor- mediated and allergic inflammation is summarized. Dif- ferential biochemical mechanisms employed to stabilize the protein in different cases are discussed.
Keywords Inflammation Allergy Toll-like receptors Hypoxia HIF-1
Recent Developments in Immune Activation by Uric Acid Crystals
Gilbert Ng • Elaine M. T. Chau • Yan Shi
Abstract Uric acid crystals, the causative agent of gout, have recently gained widespread attention due to their role as a natural endogenous adjuvant. Uric acid crystals, first sensed extracellularly by membrane lipid alterations, are internalized and subsequently activate the NLRP3 inflam- masome. Currently, various aspects of this particular novel pathway are poorly defined. This short review will focus on some recent discoveries regarding this simple crystalline structure and address areas requiring further investigation. The fact that uric acid crystals activate innate host defense mechanisms, triggering robust inflammation and immune activation, may lead to engineering potent adjuvants for future vaccines. Furthermore, the elucidation of uric acid’s mechanism of inflammation may lay the foundation for other solid inflammatory structures such as silica, asbestos, and alum.
Keywords Uric acid Gout Adjuvant Vaccine Lipid sorting NLRP3 inflammasome Inflammation
Impact of Human IgA Antibodies on Complement-Dependent Cytotoxicity Mediated by Combinations of EGF-R-Directed Antibodies
Stefan Lohse • Matthias Peipp • Thomas Beyer • Thomas Valerius • Michael Dechant
Abstract Dual combinations of non-crossblocking epidermal growth factor receptor (EGF-R)-directed monoclonal antibodies were demonstrated to effectively induce complement-dependent cytotoxicity (CDC) of tumor cells, whereas individual antibodies were ineffec- tive. Here the modulating effects of different antibody isotypes on CDC were studied by adding them as a third antibody. Two different combinations of non-crossblocking EGF-R antibodies of human IgG1 isotype, 018/003 and 425/005, were investigated against the A431 and A1207 cell lines. As a third antibody, human IgG1, IgA1, and IgA2 isotype variants of the therapeutic EGF-R antibody 225 were employed that bind to an EGF-R epitope distinct from the other EGF-R antibodies. In this model, the human IgG1 antibody proved to further enhance CDC, whereas both IgA antibodies significantly blocked CDC. The IgG1 and IgA variants increased target opsonization at similar levels, but the isotypes differed in their effects on C1q fixation. Addition of IgG1 significantly enhanced comple- ment factor binding on the target surface, whereas both IgA antibodies reduced complement binding. Control experi- ments revealed this blocking effect to be not specific to IgA antibodies, but to antibody constructs incapable of acti- vating the complement system. Interestingly, the effects caused by the IgA2 isotype were consistently stronger than those by IgA1, which may be caused by stronger steric hindrance due to its reduced hinge flexibility. These results demonstrate that monoclonal IgA antibodies inhibit IgG- mediated complement activation in vitro and suggest that the appearance of IgA antibodies within a polyclonal immune response might inhibit complement activation in vivo.
Keywords IgA Complement CDC
Don’t Get Spooked! How to Collaborate with a Professional Medical Communicator (And Avoid Ghostwriting)
Cindy W. Hamilton
Abstract Substantial confusion exists about the role of medical writers and editors (hereafter, medical communi- cators) in medical publication. Much of the confusion is due to the failure to recognize the difference between terms. Ghostwriting is unethical, whereas professional medical communication refers to legitimate writing and editing ser- vices provided by individuals who comply with ethical guidelines. The purpose of this article is to shed light on this subject by reviewing relevant guidelines and by providing practical tips for authors interested in collaborating with medical communicators. Specifically, this article addresses a series of questions, such as what to expect from medical communicators, how to evaluate them, and how to collabo- rate ethically and efficiently with them. To ensure that the process is ethical, authors should begin collaborating with the medical communicator early in the process, continue doing so throughout manuscript development, and control manuscript content. In addition, authors should disclose substantial contributions and funding sources of the medical communicator and all other individuals not meeting authorship criteria. To ensure that the process is efficient, authors should delegate time-consuming technical writing and editing tasks to the medical communicator.
Keywords Interprofessional relations Medical education Professional ethics Writing standards
Slime Production by Staphylococcus aureus and Staphylococcus epidermidis Strains Isolated from Patients with Diabetic Foot Ulcers
Adrianna Podbielska • Hanna Galkowska • Ewa Stelmach • Grazyna Mlynarczyk • Waldemar L. Olszewski
Abstract Slime production is a very important factor related to biofilm formation. The objective of the present study was to determine the frequency of slime production by Staphylococcus aureus and Staphylococcus epidermidis strains recovered from 50 patients with diabetic foot ulcers. Slime production was determined using the Congo red agar (CRA) method and compared with immunocytochemistry for the production of polysaccharide intercellular adhesin (PIA). Out of 55 S. aureus strains, 69% produced slime as shown by the CRA method. Of them, 84.2% also produced PIA. Of 17 CRA-negative strains, 70.6% produced PIA. Out of 20 S. epidermidis strains, 75% were CRA positive and 93.3% produced PIA. All CRA-negative S. epidermidis produced PIA. In conclusion, PIA production is a very common trait of S. aureus and S. epidermidis isolates obtained from diabetic foot ulcer patients.
Keywords Slime production Staphylococci Polysaccharide intercellular adhesin
Erratum to: Complement: Coming Full Circle
Gae¨lle Le Friec • Claudia Kemper
Erratum to: Arch Immunol Ther Exp (2009) 57:393–407
DOI 10.1007/s00005-009-0047-4
The elements of the first author’s name were wrongly coded in the metadata of this article, with the result that the name was listed incorrectly in all indexing services. Her given name is Gae¨lle; her surname, Le Friec.
Experimental Anticancer Therapy with Vascular-disruptive Peptide and Liposome-entrapped Chemotherapeutic Agent
Aleksander Sochanik • Iwona Mitrus • Ryszard Smolarczyk • Tomasz Cichoń • Mirosław Snietura • Maria Czaja • Stanisław Szala
Abstract Vasculature is essential for the sustained growth of solid tumors and metastases. Tumor cells surviving vas- cular-disruptive therapeutic intervention (especially those present at the tumor rim) can contribute to tumor regrowth. The aim was to strengthen, by carrier-mediated delivery of a chemotherapeutic, the curative effects of a bifunctional anti- vascular oligopeptide capable of inducing vascular shut- down and tumor shrinkage. For the in vitro experiments and animal therapy, ACDCRGDCFC-GG-D(KLAKLAK)2 peptide (900 lM in D-PBSA, i.e. Dulbecco’s PBS without Ca2? and Mg2?) and size-calibrated, passively or actively targeted liposomes based on distearoylphosphatidylcholine,cholesterol, and N-carbamoyl-methoxypolyethyleneglycol coupled to distearoylphosphatidylethanolamine (PEG– DSPE) and containing gradient-entrapped doxorubicin were used. The KB (human nasopharyngeal carcinoma) cell line overexpressing folate receptors was used in the fluorescence studies of liposomal uptake. The B16-F10 melanoma cell line was used for confirming, by flow cytometry and confocal microscopy, doxorubicin intracellular transfer as well as to induce experimental tumors in C57BL/6 mice. Animal therapy was achieved with injections of vascular- disrupting peptide, doxorubicin-loaded liposomes, or alter- nating combined therapy. The results (tumor growth inhibition and survival) were compared using the Mann– Whitney U test and the log-rank test. Necrosis in H&E- stained tumor sections was assessed microscopically by pathologists. Treatment of C57BL/6 mice bearing B16-F10 experimental tumors with a combination of vascular- disruptive peptide and doxorubicin-carrying pegylated liposomes (either passively targeted liposomes (PTL) or folate receptor targeted) gave better therapeutic effects when tumor development was re-challenged with a second cycle of combined therapy. Marked inhibition of tumor growth and a statistically significant extension of the lifespan of the treated mice were observed when the re-challenge involved the use of folate receptor-targeted liposomes (FTL). Anti- cancer therapy involving vascular-disruptive peptide and doxorubicin delivered via pegylated folate receptor-targeted liposomes is more effective than either monotherapy, especially when tumor growth is re-challenged with the therapeutic combination.
Keywords Vascular-disruptive agents Pegylated liposomes Doxorubicin Combined antitumor therapy
Comparison of Three Methods of DNA Extraction in Endocervical Specimens for Chlamydia trachomatis Infection by Spectrophotometry, Agarose Gel, and PCR
Anahita Jenab • Rasoul Roghanian • Naser Golbang • Pouran Golbang • Leili Chamani-Tabriz
Abstract Chlamydia trachomatis is the major cause of sexually transmitted disease in the world. The aim of this study was to determine the best method of DNA extraction for detecting C. trachomatis by polymerase chain reaction (PCR) in sexually active women (n = 80) attending Shahid Beheshti Hospital in Isfahan, Iran. Endocervical swabs were collected from 80 women, 22 of whom were asymptomatic and 58 symptomatic. Three different DNA extraction methods were used in this study (phenol- chlorophorm, proteinase K, and boiling). DNA yield was evaluated by spectrophotometry, agarose gel, and PCR. The internal control was assayed by b-globin primers (PCO4, GH20). The DNA cryptic plasmid was selected as the target for C. trachomatis and samples were examined by PCR using specific KL1 and KL2 primers. It was shown that DNA extraction by boiling was the most sensitive with the highest yield of DNA. Of the 80 samples, 17 (21.25%) showed positivity for C. trachomatis by PCR. The highest rate of C. trachomatis infection was found in the group aged between 35 and 45 years old and those who used withdrawal or an intrauterine device as methods of con- traception. It was demonstrated that DNA extraction by boiling was the least expensive and a very rapid method that gave the highest DNA yield. The infection rate in the sexually active women, including symptomatic and asymptomatic, was 21.25%, with a presumably high prevalence compared with other studies done in this field.
Keywords Chlamydia trachomatis Endocervical smears DNA extraction PCR Agarose gel Spectrophotometry
Regulatory T Cell as a Target for Cancer Therapy
Lucas Cunha Dias de Rezende • Ian Victor Silva • Letı´cia Batista Azevedo Rangel • Marco Cesar Cunegundes Guimara˜es
Abstract Advances in our understanding of CD4? CD25?Foxp3? regulatory T cells (TRegs) enabled the characterization of their activities in maintaining peripheral tolerance, preventing autoimmune diseases, and limiting chronic inflammatory diseases. Ironically, an effective action of these cells during tumor development can limit beneficial responses by suppressing immunity and limiting antitumor resistance, whereas one of the main functions of the immune system is to eliminate malignant cells. During the last years, the immunological role, mechanism of action, and clinical importance of these cells were pro- foundly characterized and the relationship between this subset of lymphocytes and cancerous cells arises as a key factor that influences tumor development. Recent insights obtained from clinical studies and experimental mouse models expand our perception of the potential role of TRegs in cancer treatment. In this review we describe the basic mechanisms of TReg origin and differentiation, their potential role in cancer, as well as the future perspectives concerning the modulation of these cells as a potential approach for anticancer strategies.
Keywords Cancer Immunotherapy Regulatory lymphocytes Foxp3
Adoptive T-cell Immunotherapy of Cancer Using Chimeric Antigen Receptor-Grafted T Cells
David Marc Davies • John Maher
Abstract Harnessing the power of the immune system to target cancer has long been a goal of tumor immunologists. One avenue under investigation is the modification of T cells to express a chimeric antigen receptor (CAR). Expression of such a receptor enables T-cell specificity to be redirected against a chosen tumor antigen. Substantial research in this field has been carried out, incorporating a wide variety of malignancies and tumor-associated anti- gens. Ongoing investigations will ensure this area continues to expand at a rapid pace. This review will explain the evolution of CAR technology over the last two decades in addition to detailing the associated benefits and disadvan- tages. The outcome of recent phase I clinical trials and the impact that these have had upon the direction of future research in this field will also be addressed.
Keywords Chimeric antigen receptor T-cell Cancer Adoptive transfer Survival
B Cells: From Early Development to Regulating Allergic Diseases
Konstantinos Samitas • Jan Lo¨tvall • Apostolos Bossios
Abstract B lymphocytes are characterized by a unique and highly specialized developmental pathway that is responsible for their vast phenotypic and function diversity. B cell development is strictly regulated to ensure sufficient specific humoral immunity while at the same time avoiding any errors that would compromise B cell functionality. The generation and maintenance of mature B cells from the constant flux of bone marrow progenitors is a complex process that is generally poorly understood, although great progress has been made in recent years. B cells have for long been considered mainly as antibody-producing cells and therefore believed to play an important role in the pathophysiology of allergic diseases, primarily through their ability to produce IgE antibodies. However, recent findings have revealed new aspects of their role in immune responses that place them again under the spotlight as important immune regulators, independent of antibody production. This review focuses on the developmental processes responsible for the numerous phenotypes and functions of the B-lymphocyte pool and the different aspects of effector B cell functionality in the context of allergy.
Keywords B cell development Bone marrow Regulation Allergy Effector B cell
Involvement of Envelope-Glycoprotein Glycans in HIV-1 Biology and Infection
Milan Raska • Jan Novak
Abstract Infection of host cells with HIV-1 depends on a highly glycosylated virus envelope glycoprotein (Env) and host-cell receptors. Glycans participate substantially in Env folding and in the binding of virions to the host-cell surface and indirectly affect cellular uptake of HIV-1. Moreover, Env glycans could protect HIV-1 from host’s neutralizing antibodies, but some glycans, on the other hand, represent targets for neutralizing antibodies. Variability of Env and its glycans in the HIV-1 strains from around the world as well as in patients during disease progression contributes sub- stantially to further HIV-1 spreading in spite of the progress in basic HIV-1 research, vaccine development, and highly active antiretroviral therapy of HIV-1 infections.
Keywords HIV-1 gp120 glycosylation gp120 folding gp120 antibody recognition
Microbiological Findings and Treatment of EBV-Associated Hemophagocytic Lymphohistiocytosis: A Case Report
Maciej Przybylski • Tomasz Dziecia˛tkowski • Dorota Zduńczyk • Wiesław Wiktor Jędrzejczak • Mirosław Łuczak
Abstract Epstein–Barr virus (EBV) is the major triggering factor for hemophagocytic syndrome or hemophagocytic lymphohistiocytosis (HLH). In patients with EBV-HLH, the EBV-infected T cells or natural killer cells are mostly mono- or oligoclonally proliferating, whereby hypercytokinemia plays a major role and causes hemophagocytosis, cellular damage, and dysfunction of various organs. This report describes the detection and treatment of EBV-associated HLH in the case of a 17-year-old male. Serum samples and skin swabs were tested for the presence of viral DNA using real-time PCR techniques. To confirm the molecular bio- logical tests, electron microscopy was also performed. EBV DNA was detected with real-time PCR in both blood sam- ples and skin swabs. The level of viral DNA constantly decreased during the applied therapy. The presence of the virus in the skin was confirmed by the appearance of herpes virus-like particles detected by electron microscopy in fluid taken from skin ulcerations. The results show that in terms of treatment, special therapeutic measures are required to control the cytokine storm generated by EBV and to suppress proliferating EBV genome-containing cells because the clinical course is often fulminate and results in a poor outcome. Therefore the potential of chemotherapy with a combination of steroids, etoposide, and cyclosporine to control HLH was assessed in the adolescent, who met the stringent diagnostic criteria for this reactive disorder of the mononuclear phagocyte system.
Keywords Epstein–Barr virus Hemophagocytic lymphohistiocytosis Real-time PCR
Dysregulation of the Receptor Activator of NF-jB Ligand and Osteoprotegerin Production Influence the Apoptosis of Multiple Myeloma Patients’ Bone Marrow Stromal Cells Co-Cultured with Myeloma Cells
Barbara Zdzisińska • Agnieszka Bojarska-Junak • Adam Walter-Croneck • Martyna Kandefer-Szerszeń
Abstract The interaction of multiple myeloma (MM) cells and bone marrow stromal cells (BMSCs) induces profound changes in the bone marrow environment, influencing osteoclastogenesis and MM cell survival. Dif- ferences in receptor activator of NF-jB ligand (RANKL) and osteoprotegerin (OPG) production in BMSCs derived from MM patients and control subjects and the apoptosis of BMSCs and MM cells in co-cultures of both cell types were examined. RANKL and OPG expressions were examined by ELISA and semiquantitative RT-PCR. Apoptosis of BMSCs after contact with RPMI8226 and U266 cells was measured by flow cytometry and the level of ALP activity by the spectrophotometric method. OPG production by BMSCs was significantly inhibited after direct contact with RPMI8226 cells. Production of soluble RANKL was enhanced and the increase was more significant in the BMSCs of the MM patients than in those of the controls. In co-cultures of BMSCs and MM cells, significant apoptosis was detected with a concomitant decrease in ALP activity. This apoptosis decreased significantly in the presence of RANK-Fc, an antagonist of RANKL. Disturbances in the RANKL/OPG system are more profound in the BMSCs of MM patients than in those of control subjects after direct contact with RPMI8226 cells. Moreover, direct contact with RPMI8226 and U266 cells induces apoptosis of BMSCs which is mediated by an overproduction of RANKL.
Keywords Multiple myeloma Bone marrow stromal cells RANKL OPG Apoptosis
P2X7 Receptor Signaling Pathway as a Therapeutic Target for Neurodegenerative Diseases
Takato Takenouchi • Kazunari Sekiyama • Akio Sekigawa • Masayo Fujita • Masaaki Waragai • Shuei Sugama • Yoshifumi Iwamaru • Hiroshi Kitani • Makoto Hashimoto
Abstract A recent study suggested that neuroinflamma- tion plays a major role in the pathogenesis of a number of neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. Although the precise mechanism is obscure, dysregulation of the signaling transduction pathway in microglia may enhance inflammation, leading to synaptic dysfunction and ultimately to neuronal cell death. The expression and function of the P2X7 receptor (P2X7R), an ATP-gated ion channel abundantly expressed in microglia in the brain, is significantly up-regulated in the postmortem brain of Alzheimer’s disease patients and various neurodegenerative disease animal models. This supports the role of the P2X7R pathway in the progression of neurodegeneration. Blocking P2X7R using brilliant blue G, a P2X7R antagonist that can cross the blood–brain barrier, has been shown to result in the amelioration of neuropathology in various animal models. Taken together, these results raise the possibility that the P2X7R signaling pathway could be a therapeutic target for treating various neurodegenerative diseases.
Keywords P2X7 receptor Microglia Neuroinflammation Neurodegenerative disease
Immunoprophylaxis of Tuberculosis: An Update of Emerging Trends
Neelja Singhal • Deepa Bisht • Beenu Joshi
Abstract Developing effective prophylactics to combat tuberculosis is currently in an exploratory stage. The HIV pandemic and emergence of multi- and extensively drug- resistant strains of Mycobacterium tuberculosis indicate that the current preventive measures against this ever- evolving pathogen are inadequate. The currently available vaccine BCG in its present form affords variable protection which usually wanes with aging. Various reasons have been cited to explain the discrepancies in the efficacy of BCG, including generic differences in the different BCG vaccine strains used in immunization program throughout the world. The low efficacy of BCG vaccine has promoted the search for novel vaccines for tuberculosis. The search strategies aim at completely replacing the existing vaccine and/or augmenting/improving the current BCG vaccine. Among new vaccine candidates are live attenuated M. tuberculosis vaccines, recombinant BCG, DNA vaccines, subunit vaccine, and fusion protein-based vaccines. More than 200 new vaccine candidates have been developed as a result of research work over the past few years. To date, at least eight vaccine candidates are undergoing clinical evaluation, with a few of them successfully qualifying in the first phase of clinical testing. These recent advances present an optimistic insight whereby a new tuberculosis vaccine might be expected to be available for public use in the next few years.
Keywords BCG M. tuberculosis Vaccine Prophylactics
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CD4+ T Cell Epitope Discovery and Rational Vaccine Design
Daniela Santoro Rosa • Susan Pereira Ribeiro • Edecio Cunha-Neto
Abstract T cell epitope-driven vaccine design employs bioinformatic algorithms to identify potential targets of vaccines against infectious diseases or cancer. Potential epitopes can be identified with major histocompatibility complex (MHC)-binding algorithms, and the ability to bind to MHC class I or class II indicates a predominantly CD4? or CD8? T cell response. Furthermore, an epitope-based vaccine can circumvent evolutionary events favoring immune escape present in native proteins from pathogens. It can also focus on only the most relevant epitopes (i.e. conserved and promiscuous) recognized by the majority of the target population. Mounting evidence points to the critical role of CD4? T cells in natural antigen encounter and active immunization. In this paper the need for CD4? T cell help in vaccine development, the selection of CD4? T cell epitopes for an epitope-based vaccine, and how the approach can be used to induce a protective effect are reviewed.
Keywords Vaccine design CD4? T cells T cell help Epitope prediction Epitope-based vaccines
Plasma TNF-a and IL-10 Level-Based Prognostic Model Predicts Outcome of Patients with Diffuse Large B-Cell Lymphoma in Different Risk Groups Defined by the International Prognostic Index
Ewa Lech-Maranda • Jacques Bienvenu • Florence Broussais-Guillaumot • Krzysztof Warzocha • Anne-Sophie Michallet • Tadeusz Robak • Bertrand Coiffier • Gilles Salles
Abstract Tumor necrosis factor (TNF)-a and interleukin (IL)-10 are key cytokines involved in lymphoma devel- opment. Their pretreatment plasma levels were reported to influence the clinical course of non-Hodgkin’s lymphoma. In this study the impact of combined elevation of TNF-a and IL-10 on disease features and outcome of patients with diffuse large B-cell lymphoma (DLBCL) were investi- gated. Plasma TNF-a and IL-10 levels were determined at the time of diagnosis in a group of 106 DLBCL patients uniformly treated with anthracycline-based regimens. Three risk groups depending on the pretreatment levels of the cytokines were identified: low-, intermediate-, and high-risk groups. In univariate analysis, the cytokine intermediate- and high-risk groups were associated with lower probability of achieving a complete remission (odds ratio [OR] = 0.2, 95% confidence interval [CI] 0.06–0.6, p = 0.006 and OR = 0.05, 95% CI 0.01–0.2, p \ 0.0001, respectively) and shorter progression-free survival (PFS) (OR = 4.4, 95% CI 1.9–10.2, p \ 0.001 and OR = 9.7, 95% CI 4.1–23.0, p \ 0.0001, respectively) and overall survival (OS) (OR = 4.2, 95% CI 1.7–10.1, p = 0.002 and OR = 11.2, 95% CI 4.4–28.4, p \ 0.0001, respectively) in comparison with the cytokine low-risk group. In multi- variate analysis, the cytokine intermediate- and high-risk groups also correlated with shorter PFS (relative risk [RR] = 4.5, 95% CI 1.9–10.9, p = 0.001 and RR = 5.8, 95% CI 2.2–15.3, p \ 0.0001, respectively) and OS (RR = 4.6, 95% CI 1.8–12.0, p = 0.001 and RR = 7.5, 95% CI 2.7–20.9, p \ 0.0001, respectively) regardless of the International Prognostic Index (IPI) scoring system. The TNF-a and IL-10 level-based index may work as an additional model to the IPI for predicting the survival of DLBCL patients. This model may help to identify patients in a given IPI risk group for whom more accurate and risk-adapted treatment could be advised.
Keywords Tumor necrosis factor a Interleukin-10 International Prognostic Index Diffuse large B-cell lymphoma
Nanogram Doses of Alum-Adjuvanted HBs Antigen Induce Humoral Immune Response in Mice When Orally Administered
Józef Kapusta • Tomasz Pniewski • Jacek Wojciechowicz • Piotr Bociąg • Andrzej Płucienniczak
Abstract Mucosal immunity elicited by plant-based and other orally administered vaccines can serve as the first line of defense against most pathogens infecting through mucosal surfaces, but it is also considered for systemic immunity against blood–borne diseases such as hepatitis B (HB). Previous oral immunization trials based on multiple administration of high doses of HBs antigen elicited an immune response; however, a reproducible and long-lasting immunization protocol was difficult to design. The objec- tive of this study was to evaluate the effect of dose and timing of orally delivered alum-adsorbed antigen on the magnitude of the anti-HBs humoral response. Mice were immunized orally by gavage intubation or parenterally by intramuscular injection three times, once every 2 weeks, with doses of 5, 50, or 500 ng alum-adjuvanted HBsAg. A low dose (10 ng) of HBsAg was orally administered three times in different time intervals: 2, 4, 6, and 8 weeks. The three consecutive 5-ng oral doses of the antigen induced immune response at the protective level (C10 mIU/ml), significantly higher than the reaction elicited by three 50 or 500 ng doses. In contrast, intramuscular delivery of these doses did not differ significantly; however, they induced a five to six times higher immune response than oral immu- nization. The 8-week period between each of the three oral immunizations appeared to be favorable to the anti-HBs humoral responses compared with the shorter schedules. The results presented here clearly identify the importance of low doses of antigen administered orally in extended intervals for a significantly higher anti-HBs response. This finding provides some indications concerning the strategy of orally administered vaccines, including plant-based ones.
Keywords HBs antigen HBsAg Oral immunization Anti-HBV oral vaccine
The Role of Thymic Stromal Lymphopoietin in Allergic Inflammation and Chronic Obstructive Pulmonary Disease
Cailong Fang • Leonard Q. C. Siew • Chris J. Corrigan • Sun Ying
Abstract Thymic stromal lymphopoietin (TSLP) primes dendritic cells to promote a Th2 inflammatory response. Its action is mediated by a heterodimeric receptor which consists of the interleukin-7 receptor a chain and the TSLP receptor chain (TSLPR). TSLPR resembles the common c chain subunit utilized by many type 1 cytokine receptors. Normal epithelial cells, keratinocytes, and stromal cells constitutively express TSLP. Dendritic cells that are acti- vated by TSLP promote the development of CD4? T cells into pro-inflammatory Th2 cells. TSLP thus plays a potentially important role in the pathogenesis of allergic inflammation in asthma and atopic dermatitis. TSLP also has direct effects on other types of cells in the bronchial mucosa. It is over-expressed in the bronchial mucosa in chronic obstructive pulmonary disease (COPD), which is traditionally described as a Th1-related disease, as well as severe asthma, which is traditionally described as a Th2- related disease. In this review we will discuss TSLP expression, function, and available and potential mecha- nisms in both allergic inflammation and COPD.
Keywords TSLP Asthma COPD
Lentiviral Vectors in Gene Therapy: Their Current Status and Future Potential
David Escors • Karine Breckpot
Abstract The concept of gene therapy originated in the mid twentieth century and was perceived as a revolutionary technology with the promise to cure almost any disease of which the molecular basis was understood. Since then, several gene vectors have been developed and the feasi- bility of gene therapy has been shown in many animal models of human disease. However, clinical efficacy could not be demonstrated until the beginning of the new century in a small-scale clinical trial curing an otherwise fatal immunodeficiency disorder in children. This first success, achieved after retroviral therapy, was later overshadowed by the occurrence of vector-related leukemia in a signifi- cant number of the treated children, demonstrating that the future success of gene therapy depends on our under- standing of vector biology. This has led to the development of later-generation vectors with improved efficiency, specificity, and safety. Amongst these are HIV-1 lentivirus- based vectors (lentivectors), which are being increasingly used in basic and applied research. Human gene therapy clinical trials are currently underway using lentivectors in a wide range of human diseases. The intention of this review is to describe the main scientific steps leading to the engineering of HIV-1 lentiviral vectors and place them in the context of current human gene therapy.
Keywords Gene therapy Lentivirus-based vector